Chapter 34: Endocrine Disorders

The classic concept that endocrine effects are the result of substances secreted into the blood with effects on a distant target cell has been updated to account for other ways in which hormonal effects occur. Specifically, some hormone systems involve the stimulation or inhibition of metabolic processes in neighboring cells (eg, within the pancreatic islets or cartilage). This phenomenon is termed paracrine. Other hormone effects reflect the action of hormones on the same cells that produced them. This action is termed autocrine. The discoveries of local production of ghrelin, somatostatin, cholecystokinin, incretins, and many other hormones in the brain and gut support the concept of paracrine and autocrine processes in these tissues.

Another significant discovery in endocrine physiology was an appreciation of the role of specific hormone receptors in target tissues, without which the hormonal effects cannot occur. For example, in nephrogenic diabetes insipidus (DI), affected children have defective vasopressin or receptor function, and show the metabolic effects of DI despite more-than-adequate vasopressin secretion. Alternatively, abnormal activation of a hormone receptor leads to the effects of the hormone without its abnormal secretion. Examples of this phenomenon include McCune-Albright syndrome (precocious puberty and hyperthyroidism), testotoxicosis (familial male precocious puberty), and hypercalciuric hypocalcemia.

HORMONE TYPES

Hormones are of three main chemical types: peptides and proteins, steroids, and amines. The peptide hormones include the releasing factors secreted by the hypothalamus; the hormones of the anterior and posterior pituitary gland; pancreatic islet cells; parathyroid glands, lung (angiotensin II), heart, and brain (atrial and brain natriuretic hormones); and local growth factors such as insulin-like growth factor 1 (IGF-1). Steroid hormones are secreted primarily by the adrenal cortex, gonads, and kidney (active vitamin D [1,25(OH)₂ D3]). The amine hormones are secreted by the adrenal medulla (epinephrine) and the thyroid gland (triiodothyronine [T₃] and thyroxine [T₄]).

Peptide hormones and epinephrine act through cell surface receptors. The metabolic effects of these hormones are usually stimulation or inhibition of the activity of preexisting enzymes or transport proteins (posttranslational effects). The steroid hormones, thyroid hormone, and active vitamin D, in contrast, act more slowly and bind to cytoplasmic receptors inside the target cell and subsequently to specific regions on nuclear DNA. Their metabolic effects are generally caused by stimulating or inhibiting the synthesis of new enzymes or transport proteins (transcriptional effects).

Metabolic processes that require rapid response, such as blood glucose or calcium homeostasis, are usually controlled by peptide hormones and epinephrine, while processes that respond more slowly, such as pubertal development and metabolic rate, are controlled by steroid hormones and thyroid hormone. The control of electrolyte homeostasis is intermediate and is regulated by a combination of peptide and steroid hormones (Table 34–1).

FEEDBACK CONTROL OF HORMONE SECRETION

Hormone secretion is regulated by feedback in response to changes in the internal environment. When the metabolic imbalance is corrected, stimulation of the hormone secretion ceases and may even be inhibited. Overcorrection of the imbalance stimulates secretion of a counterbalancing hormone or hormones so that homeostasis is maintained within relatively narrow limits.

Hypothalamic-pituitary control of hormonal secretion is regulated by feedback. End-organ failure (endocrine gland insufficiency) leads to decreased circulating concentrations of endocrine gland hormones and increased secretion of the respective hypothalamic releasing and pituitary hormones (see Table 34–1; Figure 34–1). If restoration of normal circulating concentration of hormones occurs, feedback inhibition at the pituitary and hypothalamus results in cessation of the previously stimulated secretion of releasing and pituitary hormones and restoration of their circulating concentrations to normal.

Similarly, if there is autonomous endocrine gland hyperfunction (eg, McCune-Albright syndrome, Graves disease, or adrenal tumor), the specific hypothalamic releasing and pituitary hormones are suppressed (see Figure 34–1).

Disturbances of growth and development are the most common problems evaluated by a pediatric endocrinologist. While most cases represent normal developmental variants, it is critical to identify abnormal growth patterns, as deviations from the norm can be the first or only manifestation of an endocrine disorder. Height velocity is the most critical parameter in evaluating a child’s growth. A persistent increase or decrease in height percentiles between age 2 years and the onset of puberty always warrants evaluation. Similarly, substantial deviations from target (midparental) height may be indications of underlying endocrine or skeletal disorders. It is more difficult to distinguish normal from abnormal growth in the first 2 years of life, as infants may have catch-up or catch-down growth during this period. Similarly, the variable timing of the onset of puberty makes early adolescence another period during which evaluation of growth abnormalities may require careful consideration.

Appropriate standards must be used to evaluate growth. The National Center for Health Statistics provides standard cross-sectional growth charts for North American children (see Chapter 9) and the World Health Organization (WHO) growth charts use an ethnically more diverse sample. Normal growth standards may vary with country of origin. Growth charts are available for some ethnic groups in North America and for some syndromes with specific growth disturbance such as Turner or Down syndromes. Current treatment practices for patients with Turner and Down syndrome (including the use of growth hormone in Turner syndrome) can cause children to grow differently than reflected in their specific growth charts.

TARGET HEIGHT & SKELETAL MATURATION

A child’s height potential is determined largely by genetic factors. The target height of a child is calculated from the mean parental height plus 6.5 cm for boys or minus 6.5 cm for girls. This calculation helps identify a child’s genetic growth potential. Most children achieve an adult height within 10 cm of the target height. Another parameter that determines growth potential is skeletal maturation or bone age. Beyond the neonatal period, bone age is evaluated by comparing a radiograph of the child’s left hand and wrist with the standards of Greulich and Pyle. Delayed or advanced bone age is not diagnostic of any specific disease, but the extent of skeletal maturation allows determination of remaining growth potential as a percentage of total height and allows prediction of ultimate height. Additionally, the bone age delay or advancement can change over time. For example, children with a previously delayed bone age may develop a bone age closer to their chronological age closer to the time of puberty.

SHORT STATURE

It is important to distinguish normal variants of growth (familial short stature and constitutional growth delay) from pathologic conditions (Table 34–2). Pathologic short stature is more likely in children who have a low growth velocity (crossing major height percentiles on the growth curve, < 4 cm/y) or who are significantly short for their family. Children with chronic illness or nutritional deficiencies may have poor linear growth, and this can be associated with inadequate weight gain and low body mass index (BMI). In contrast, endocrine causes of short stature are usually associated with maintenance or increase in BMI percentiles. Subtypes of short stature are discussed next.

1. Familial Short Stature & Constitutional Growth Delay

Children with familial short stature typically have normal birth weight and length. In the first 2 years of life, their linear growth velocity decelerates as they near their genetically determined percentile. Once the target percentile is reached, the child resumes normal linear growth parallel to the growth curve, usually between 2 and 3 years of age. Skeletal maturation and timing of puberty are consistent with chronologic age. The child grows along his/her own growth percentile and the final height is short but appropriate for the family (Figure 34–2).

Children with constitutional growth delay do not necessarily have short parents but have a growth pattern similar to those with familial short stature with a decline in linear growth velocity between ages 2 and 3 years and then maintenance of a normal growth velocity prior to puberty. The difference is that children with constitutional growth delay have a delay in skeletal maturation and a delay in the onset of puberty. In these children, growth continues beyond the time the average child stops growing, and final height is appropriate for target height (Figure 34–3).

2. Growth Hormone Deficiency

Human growth hormone (GH) is produced by the anterior pituitary gland. Secretion is stimulated by growth hormone-releasing hormone (GHRH) and inhibited by somatostatin. GH is secreted in a pulsatile pattern, and has direct growth-promoting and metabolic effects (Figure 34–4). GH also promotes growth indirectly by stimulating production of insulin-like growth factors, primarily IGF-1.

Growth hormone deficiency (GHD) is characterized by decreased growth velocity and delayed skeletal maturation in the absence of other explanations (Figure 34–5). Because GH promotes lipolysis, many GH-deficient children have excess truncal adiposity. GHD may be isolated or coexist with other pituitary hormone deficiencies and may be congenital (septo-optic dysplasia or ectopic posterior pituitary), genetic (GH or GHRH gene mutation), or acquired (craniopharyngioma, germinoma, histiocytosis, or cranial irradiation). Idiopathic GHD is the most common deficiency state with an incidence of about 1:4000 children. Patients have also been described with congenital GH-resistance syndromes. The presentation of GH resistance is similar to that of GHD, but short stature is often severe, with little or no response to GH therapy and may be accompanied by dysmorphic features.

Features of infantile GHD include normal birth weight and slightly reduced length, hypoglycemia (if accompanied by adrenal insufficiency), micropenis (if accompanied by gonadotropin deficiency), and conjugated hyperbilirubinemia (if other pituitary hormone deficiencies present). Growth retardation in isolated GHD and hypopituitarism may not present until late in infancy or childhood.

Laboratory tests to assess GH status may be difficult to interpret because there is significant overlap in GH secretion between normal and GH-deficient children. GH secretion is pulsatile, so random samples for measurement of serum GH are of no value in the diagnosis of GHD outside of the first week of life. Serum concentrations of IGF-1 give reasonable estimations of GH secretion and action in the adequately nourished child (see Figure 34–4), and are often used as a first step in the evaluation for GHD. IGF-binding protein 3 (IGFBP-3) is a much less sensitive marker of GH deficiency, but may be useful in the underweight child or in children younger than 4 years, since it is less affected by age or nutritional status. Provocative studies using such agents as insulin, arginine, levodopa, clonidine, or glucagon are traditionally done to clarify GH secretion, but are not physiologic and are often poorly reproducible, ultimately limiting their value in the clarification of GH secretion. The diagnosis of GHD is often a compilation of clinical and laboratory evidence and must be approached with care. All patients diagnosed with GHD should have an MRI of the hypothalamus and pituitary gland to evaluate for a tumor prior to starting therapy.

3. Small for Gestational Age/Intrauterine Growth Restriction

Small for gestational age (SGA) infants have a birth weight and/or length below the 3rd percentile for the population’s birth weight–gestational age relationship. SGA infants include constitutionally small infants and infants with intrauterine growth restriction (IUGR). Many children with mild SGA/IUGR and no intrinsic fetal abnormalities exhibit catch-up growth during the first 3 years, but 15%–20% remain short throughout life. Catch-up growth may also be inadequate in preterm SGA/IUGR infants with poor postnatal nutrition. Children who do not show catch-up growth may have normal growth velocity but follow a lower height percentile than expected for the family. In contrast to children with constitutional growth delay, those with SGA/IUGR have skeletal maturation that corresponds to chronologic age or is only mildly delayed. GH therapy for SGA/IUGR children with growth delay is FDA-approved and appears to increase growth velocity and final adult height.

4. Disproportionate Short Stature

There are more than 200 sporadic and genetic skeletal dysplasias that may cause disproportionate short stature. Measurements of arm span and upper-to-lower body segment ratio are helpful in determining whether a child has normal body proportions. If disproportionate short stature is found, a skeletal survey may be useful to detect specific radiographic features characteristic of some disorders. The effect of GH on most of these rare disorders is unknown.

5. Short Stature Associated with Syndromes

Short stature is associated with many genetic syndromes, including Turner, Down, Noonan, and Prader-Willi. Girls with Turner syndrome often have recognizable features such as micrognathia, webbed neck, low posterior hairline, edema of hands and feet, multiple pigmented nevi, and an increased carrying angle. However, short stature can be the only obvious manifestation of Turner syndrome. Consequently, any girl with unexplained short stature for family warrants a chromosomal evaluation. Although girls with Turner syndrome are not usually GH deficient, GH therapy can improve final height by an average of 6 cm. Duration of GH therapy is a significant predictor of long-term height gain; consequently, it is important that Turner syndrome be diagnosed early and GH started as soon as possible if the family desires to maximize height.

GH is approved for treatment of growth failure in Prader-Willi syndrome–associated GHD. GH improves growth, body composition, and physical activity. A few deaths have been reported in Prader-Willi children receiving GH, all of which occurred in very obese children, children with respiratory impairments, sleep apnea, or possibly unidentified respiratory infections. The role of GH in these deaths is unknown, but it is recommended that all patients with Prader-Willi syndrome be evaluated for upper airway obstruction and sleep apnea prior to starting GH therapy.

Children with Down syndrome should be evaluated for GHD only if their linear growth is abnormal compared with the Down syndrome growth chart. Given their increased malignancy risk, some families may be wary of adding GH therapy.

6. Psychosocial Short Stature (Psychosocial Dwarfism)

Psychosocial short stature refers to growth retardation associated with emotional deprivation. Undernutrition probably contributes to growth retardation in some of these children. Other symptoms include unusual eating and drinking habits, bowel and bladder incontinence, social withdrawal, and delayed speech. GH secretion in children with psychosocial short stature is diminished, but GH therapy is usually not beneficial. A change in the psychological environment at home usually results in improved growth and improvement of GH secretion, personality, and eating behaviors.

Clinical Evaluation

Laboratory investigation should be guided by the history and physical examination, including history of chronic illness and medications, birth weight and height, pattern of growth since birth, familial growth patterns, pubertal stage, dysmorphic features, body segment proportion, and psychological health. In a child with poor weight gain as the primary disturbance, a nutritional assessment is indicated. The following laboratory tests may be useful as guided by history and clinical judgment: (1) radiograph of left hand and wrist for bone age; (2) karyotype (girls) and/or Noonan syndrome testing; (3) thyroid function tests: thyroxine (T₄) and thyroid-stimulating hormone (TSH); (4) IGF-1 and/or IGFBP-3 in children younger than 4 years or in malnourished individuals; (5) complete blood count (to detect chronic anemia or leukocyte markers of infection); (6) erythrocyte sedimentation rate (often elevated in collagen-vascular disease, cancer, chronic infection, and inflammatory bowel disease); (7) urinalysis, blood urea nitrogen, and serum creatinine (occult renal disease); (8) serum electrolytes, calcium, and phosphorus (renal tubular disease and metabolic bone disease); (9) stool examination for fat, or measurement of serum tissue transglutaminase (malabsorption or celiac disease).

Growth Hormone Therapy

GH therapy is approved by the U.S. Food and Drug Administration (FDA) in children for GHD; growth restriction associated with chronic renal failure; Turner, Prader-Willi, and Noonan syndromes; children born small for gestational age (SGA) who fail to demonstrate catch-up growth by age 2; and SHOX gene mutations. GH therapy has also been approved for children with idiopathic short stature whose current height is more than 2.25 standard deviations below the normal range for age. With GH treatment, final height may be 5–7 cm taller in this population. The role of GH for idiopathic short stature is still unclear, especially due to the expense, long duration of treatment, and unclear psychological consequences. Side effects of recombinant GH are uncommon but include intracranial hypertension and slipped capital femoral epiphysis. With early diagnosis and treatment, children with GH deficiency reach normal or near-normal adult height. Recombinant IGF-1 injections may be used to treat children with GH resistance or IGF-1 deficiency, but improvements in growth may not be as substantial as seen with GH therapy for GH deficiency. Currently, the recommended schedule for GH therapy is subcutaneous recombinant GH given subcutaneously 6 or 7 days per week with total weekly dose of 0.15–0.47 mg/kg.

TALL STATURE

Although growth disturbances are usually associated with short stature, potentially serious pathologic conditions may also be associated with tall stature and excessive growth (Table 34–3). Excessive GH secretion is rare, particularly in children, and generally associated with a functioning pituitary adenoma. GH excess leads to gigantism if the epiphyses are open and to acromegaly if the epiphyses are closed. The diagnosis is confirmed by finding elevated random GH and IGF-1 levels and failure of GH suppression during an oral glucose tolerance test. Precocious puberty can also cause tall stature for age or rapid growth, but would be associated with early signs of puberty and an advanced bone age. Obese youth are also often tall for age, but they do not achieve a taller final height.

The posterior pituitary (neurohypophysis) is an extension of the ventral hypothalamus. Its two principal hormones—oxytocin and arginine vasopressin—are synthesized in the supraoptic and paraventricular nuclei of the ventral hypothalamus. These peptide hormones are packaged in granules with specific neurophysins and transported via the axons to their storage site in the posterior pituitary. Vasopressin is essential for water balance; it acts primarily on the kidney to promote reabsorption of water from urine. Oxytocin is most active during parturition and breast feeding and is not discussed further here.

ARGININE VASOPRESSIN (ANTIDIURETIC HORMONE) PHYSIOLOGY

Vasopressin release is controlled primarily by serum osmolality and intravascular volume. Release is stimulated by minor increases in plasma osmolality (detected by osmoreceptors in the anterolateral hypothalamus) and large decreases in intravascular volume (detected by baroreceptors in the cardiac atria). Disorders of vasopressin release and action include: (1) central (neurogenic) DI, (2) nephrogenic DI (see Chapter 24), and (3) the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

CENTRAL DIABETES INSIPIDUS

General Considerations

Central diabetes insipidus (DI) is an inability to synthesize and release vasopressin. Without vasopressin, the kidneys cannot concentrate urine, causing excessive urinary water loss. Genetic causes of central DI are rare and include mutations in the vasopressin gene and the WFS1 gene that causes DI, diabetes mellitus, optic atrophy, and deafness (Wolfram or DIDMOAD syndrome). The most common causes of pediatric central DI are midline defects (septo-optic dysplasia, holoprosencephaly); trauma (surgery, injury); infiltrative/neoplastic disease (tumors such as craniopharyngioma, germinoma, Langerhans cell histiocytosis, sarcoidosis); infectious (meningitis); and idiopathic.

Traumatic DI often has three phases. Initially, transient DI is caused by edema in the hypothalamus or pituitary area. In 2–5 days, unregulated release of vasopressin from dying neurons causes the SIADH. Finally, permanent DI occurs if a sufficient number of vasopressin neurons are destroyed.

Clinical Findings

Onset of DI is characterized by polyuria, nocturia, enuresis, and intense thirst, usually with a preference for cold water. Hypernatremia, hyperosmolality, and dehydration occur if insufficient fluid intake does not keep up with urinary losses. In infants, symptoms may also include failure to thrive, vomiting, constipation, and unexplained fevers. Some infants may present with severe dehydration, circulatory collapse, and seizures. Vasopressin deficiency may be masked in patients with panhypopituitarism due to the impaired excretion of free water associated with ACTH insufficiency; treatment with glucocorticoids may unmask DI in these patients.

DI is confirmed when serum hyperosmolality is associated with urine hypo-osmolarity. If the history indicates that the child can go through the night comfortably without drinking, outpatient testing is appropriate. Oral fluid intake is prohibited after midnight. Osmolality, sodium, and specific gravity of the first morning void are obtained. This can also be done as a water deprivation test in the hospital if screening results are unclear or if symptoms preclude safely withholding fluids at home. See “Essentials” box for diagnostic criteria. Children with central DI should have an MRI of the head with contrast to look for tumors or infiltrative processes.

Primary polydipsia must be distinguished from DI. Children with primary polydipsia tend to have lower serum sodium levels and usually can concentrate their urine with overnight fluid deprivation. Some may have secondary nephrogenic DI due to dilution of the renal medullary interstitium and decreased renal concentrating ability, but this resolves with restriction of fluid intake.

Treatment

Central DI is treated with oral or intranasal desmopressin acetate (DDAVP). The aim of therapy is to provide antidiuresis that allows uninterrupted sleep. Breakthrough urination should occur before the next dose. It is important to note that postsurgical DI can be associated with disruption of thirst mechanism, and for these patients, a prescribed volume of fluid intake needs to be determined. Children hospitalized with acute-onset DI can be managed with intravenous or subcutaneous vasopressin. Due to the amount of antidiuresis, electrolytes should be closely monitored to avoid water intoxication. Infants with DI should not be treated with DDAVP, since their primary source of nutrition is through liquid calories and this combination can result in water intoxication. For this reason, infants are treated with extra free water to maintain normal hydration. A formula with a low renal solute load and chlorothiazides may be helpful in infants with central DI.

FETAL DEVELOPMENT OF THE THYROID

As early as the 10th week of gestation, the fetal thyroid synthesizes thyroid hormone, which appears in the fetal serum by the 11th week of gestation and progressively increases throughout gestation. The fetal pituitary-thyroid axis functions largely independently of the maternal pituitary-thyroid axis because maternal TSH cannot cross the placenta. However, maternal thyroid hormone can cross the placenta in limited amounts.

At birth, there is a TSH surge peaking at about 70 mU/L within 30–60 minutes. Thyroid hormone serum level increases rapidly during the first days of life in response to this TSH surge. The TSH level decreases to childhood levels within a few weeks. The physiologic neonatal TSH surge can produce a false-positive newborn screen for hypothyroidism (ie, high TSH) if the blood sample for the screen is collected on the first day of life.

PHYSIOLOGY

Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the anterior pituitary gland to release TSH. In turn, TSH stimulates the thyroid gland to take up iodine and synthesize and release T₄ and T₃. This process is regulated by negative feedback involving the hypothalamus, pituitary, and thyroid (see Figure 34–1).

T₄ is the predominant thyroid hormone secreted by the thyroid gland. Most circulating T₃ and T₄ are bound to thyroxine-binding globulin (TBG), albumin, and prealbumin. Less than 1% of thyroxine exists in the free form. T₄ is deiodinated in the tissues to T₃, which binds to high-affinity nuclear thyroid hormone receptors in the cytoplasm and translocates to the nucleus, exerting its biologic effects by modifying gene expression. Causes of low T₄ are hypothyroidism (central or primary), prematurity, malnutrition and severe illness, and following therapy with T₃.

Total T₄ is also low in situations that decrease TBG, such as familial TBG deficiency, cirrhosis, or renal failure and in patients receiving glucocorticoids or androgens. Since these effects primarily involve TBG, TSH, and free T₄ (FT₄) levels remain in the normal range. Conversely, total T₃ and T₄ levels may be elevated in conditions associated with increased TBG levels (congenital TBG excess, pregnancy, estrogen therapy) and increased thyroid hormone binding to transport proteins. Again, patients are clinically euthyroid in this circumstance. A T3 resin uptake can help differentiate between binding protein problems and true hypo- or hyperthyroidism.

HYPOTHYROIDISM (CONGENITAL & ACQUIRED)

General Considerations

Thyroid hormone deficiency may be congenital or acquired (Table 34–4). It can be due to defects in the thyroid gland (primary hypothyroidism) or in the hypothalamus or pituitary (central hypothyroidism).

Congenital hypothyroidism occurs in about 1:3000–1:4000 infants. Untreated, it causes severe neurocognitive impairment. Most cases are sporadic resulting from hypoplasia or aplasia of the thyroid gland or failure of the gland to migrate to its normal anatomic location (ie, lingual or sublingual thyroid gland). Other causes are listed in Table 34–4. In severe maternal iodine deficiency, both the fetus and the mother are T₄-deficient, with irreversible brain damage to the fetus. Acquired hypothyroidism, particularly if goiter is present, is usually a result of chronic lymphocytic (Hashimoto) thyroiditis.

Several hundred patients with resistance to thyroid hormone have been described and present with elevations in T₄ and/or FT₄, with normal TSH. There is often a family history of the disorder. Clinical manifestations are highly variable due to differential expression of thyroid hormone receptor isoforms in different tissues.

Clinical Findings

A. Symptoms and Signs

Even when the thyroid gland is completely absent, most newborns with congenital hypothyroidism appear normal. However, because congenital hypothyroidism is associated with intellectual impairment, thyroid testing is included in the newborn screen and treatment must be initiated as early as possible. Jaundice associated with an unconjugated hyperbilirubinemia may be present in newborns with congenital hypothyroidism.

Features of juvenile hypothyroidism include poor linear growth; delayed bone age and retarded dental eruption; skin changes (dry, thick, scaly, coarse, pale, cool, or sallow); hair changes (dry, coarse, or brittle), hair loss; lateral thinning of the eyebrows; musculoskeletal findings (hypotonia and a slow relaxation component of deep tendon reflexes); physical and mental sluggishness; nonpitting myxedema; constipation; cold temperature intolerance; bradycardia; delayed puberty; occasional pseudopuberty (secondary to weak FSH activity of marked elevated TSH levels).

In hypothyroidism resulting from enzymatic defects, ingestion of goitrogens, or chronic lymphocytic thyroiditis, the thyroid gland may be enlarged. Thyroid enlargement in children is usually symmetrical, and the gland is moderately firm and not nodular. In chronic lymphocytic thyroiditis, however, the thyroid frequently has a cobblestone surface (see the following text).

B. Laboratory Findings

In primary hypothyroidism, the total T₄ and FT₄ may be normal or decreased and the serum TSH is elevated. Circulating autoantibodies to thyroid peroxidase and thyroglobulin may be present. In central hypothyroidism, the TSH is usually inappropriately normal and associated with a low total T₄ and FT₄. Serum prolactin may be elevated, resulting in galactorrhea. Other pituitary deficiencies may be present, as central hypothyroidism may be associated with congenital or acquired disorders of the hypothalamus or pituitary gland.

C. Imaging

Thyroid imaging, while helpful in establishing the cause of congenital hypothyroidism, does not affect the treatment plan and is not necessary. Bone age is delayed. Cardiomegaly is common. Long-standing primary hypothyroidism may be associated with thyrotrophic hyperplasia characterized by an enlarged sella or pituitary gland.

D. Screening Programs for Neonatal Hypothyroidism

All newborns should be screened for congenital hypothyroidism shortly after birth. Depending on the state, the newborn screen measures either the total T₄ or TSH level. Abnormal newborn screening results should be confirmed immediately with a venous T₄ and TSH level. Treatment should be started as soon as possible. Initiation of treatment in the first month of life and good compliance during infancy usually results in a normal neurocognitive outcome.

Treatment

Levothyroxine (75–100 mcg/m²/day) is the drug of choice for acquired hypothyroidism. In neonates with congenital hypothyroidism, the recommended initial dose is 10–15 mcg/kg/day. Serum total T₄ or FT₄ concentrations are used to monitor the adequacy of initial therapy because the high neonatal TSH may not normalize for weeks. Subsequently, T₄ and TSH are monitored in combination.

THYROIDITIS

1. Chronic Lymphocytic Thyroiditis (Chronic Autoimmune Thyroiditis, Hashimoto Thyroiditis)

General Considerations

Chronic lymphocytic thyroiditis is the most common cause of goiter and acquired hypothyroidism in childhood. It is more common in girls, and the incidence peaks during puberty. The disease is caused by an autoimmune attack on the thyroid. Increased risk of thyroid autoimmunity (and other endocrine autoimmune disorders) is associated with certain histocompatibility alleles. The following conditions are associated with increased risk for autoimmune (Hashimoto) thyroiditis: Down syndrome, Turner syndrome, celiac disease, vitiligo, alopecia, and type 1 diabetes.

Clinical Findings

A. Symptoms and Signs

The thyroid is characteristically enlarged, firm, freely movable, nontender, and symmetrical. It may be nodular. Onset is usually insidious. Occasionally, patients note a sensation of tracheal compression or fullness, hoarseness, and dysphagia. No local signs of inflammation or systemic infection are present. Most patients are euthyroid. Some patients are symptomatically hypothyroid, and few patients are symptomatically hyperthyroid. A detailed family history may reveal the presence of multiple autoimmune diseases in family members. Individuals at a high risk based on a chromosomal disorder or other autoimmune disease benefit from careful monitoring of growth and development, routine screening (in the case of Down syndrome, Turner syndrome, and type 1 diabetes), and a low threshold for measurement of thyroid function.

B. Laboratory Findings

Laboratory findings vary. Serum concentrations of TSH, T₄, and FT₄ are usually normal. Some patients are hypothyroid with an elevated TSH and low thyroid hormone levels. A few patients are hyperthyroid with a suppressed TSH and elevated thyroid hormone levels. Thyroid antibodies (antithyroglobulin, antithyroid peroxidase) are frequently elevated.

C. Imaging

Routine thyroid ultrasound is not indicated unless focal nodule or mass is palpated. Thyroid uptake scan adds little to the diagnosis. Surgical or needle biopsy is diagnostic but seldom necessary.

Treatment

There is controversy about the need to treat chronic lymphocytic thyroiditis with normal thyroid function. Full replacement doses of thyroid hormone may decrease the size of the thyroid, but may also result in hyperthyroidism. Hypothyroidism commonly develops over time. Consequently, patients require lifelong surveillance. Children with documented hypothyroidism should receive thyroid hormone replacement.

2. Acute (Suppurative) Thyroiditis

Acute thyroiditis is rare. The most common causes are group A streptococci, pneumococci, Staphylococcus aureus, and anaerobes. Thyroid abscesses may form. The patient is toxic with fever and chills. The thyroid gland is enlarged and exquisitely tender with associated erythema, hoarseness, and dysphagia. Thyroid function tests are typically normal. Patients have a leukocytosis, “left shift,” and elevated erythrocyte sedimentation rate. Antibiotic therapy is required.

3. Subacute (Nonsuppurative) Thyroiditis

Subacute thyroiditis (de Quervain thyroiditis) is rare. It is thought to be caused by viral infection with mumps, influenza, echovirus, coxsackievirus, Epstein-Barr virus, or adenovirus. Presenting features are similar to acute thyroiditis—fever, malaise, sore throat, dysphagia, and thyroid pain that may radiate to the ear. The thyroid is firm and enlarged. Sedimentation rate is elevated. In contrast to acute thyroiditis, the onset is generally insidious and serum thyroid hormone concentrations may be elevated.

HYPERTHYROIDISM

General Considerations

In children, most cases of hyperthyroidism are due to Graves disease, caused by antibodies directed at the TSH receptor that stimulate thyroid hormone production. Other causes include thyroiditis (acute, subacute, or chronic); autonomous functioning thyroid nodules; tumors producing TSH; McCune-Albright syndrome; exogenous thyroid hormone excess; and acute iodine exposure.

Clinical Findings

A. Symptoms and Signs

Hyperthyroidism is more common in females than males. In children, it most frequently occurs during adolescence. The course of hyperthyroidism may be cyclic, with spontaneous remissions and exacerbations. Symptoms include poor concentration, hyperactivity, fatigue, emotional labiality, personality disturbance/unmasking of underlying psychosis, insomnia, weight loss (despite increased appetite), palpitations, heat intolerance, increased perspiration, increased stool frequency, polyuria, and irregular menses. Signs include tachycardia, systolic hypertension, increased pulse pressure, tremor, proximal muscle weakness, and moist, warm, skin. Accelerated growth and development may occur. Thyroid storm is a rare condition characterized by fever, cardiac failure, emesis, and delirium that can result in coma or death. Most cases of Graves disease are associated with a diffuse firm goiter. A thyroid bruit and thrill may be present. Many cases are associated with exophthalmos.

B. Laboratory Findings

TSH is suppressed. T₄, FT₄, T₃, and free T₃ (FT₃) are elevated except in rare cases in which only the serum T₃ is elevated (T₃ thyrotoxicosis). The presence of thyroid-stimulating immunoglobulin (TSI) or thyroid eye disease confirms the diagnosis of Graves disease. TSH receptor-binding antibodies (TRAb) are usually elevated.

C. Imaging

Radioactive iodine uptake by the thyroid is increased in Graves disease, whereas in subacute and chronic thyroiditis it is decreased. An autonomous hyperfunctioning nodule takes up iodine and appears as a “hot nodule” while the surrounding tissue has decreased iodine uptake. In children with hyperthyroidism, bone age may be advanced. In infants, accelerated skeletal maturation may be associated with premature fusion of the cranial sutures. Long-standing hyperthyroidism causes osteoporosis.

Treatment

A. General Measures

Strenuous physical activity should be avoided in untreated hyperthyroidism.

B. Medical Treatment

1. β-Adrenergic blocking agents

These are adjuncts to therapy. They can rapidly ameliorate symptoms and are indicated in severe disease with tachycardia and hypertension. β₁-Specific agents such as atenolol are preferred because they are more cardioselective. Propranolol also decreases conversion of T₄ to active T₃, so is preferred in severe cases/thyrotoxicosis.

2. Antithyroid agents (methimazole)

Antithyroid agents are frequently used in the initial treatment of childhood hyperthyroidism. These drugs interfere with thyroid hormone synthesis, and usually take a few weeks to produce a clinical response. Adequate control is usually achieved within a few months. If medical therapy is unsuccessful, more definitive therapy, such as radioablation of the thyroid or thyroidectomy, should be considered. Propylthiouracil (PTU) is rarely utilized because of reports of severe hepatotoxicity.

Methimazole is initiated at a dose of 10–60 mg/day (0.5–1 mg/kg/day) given once a day. Initial dosing is continued until FT₄ or T₄ have normalized and signs and symptoms have subsided.

The optimal dose of antithyroid agent for maintenance treatment remains unclear. Recent studies suggest that 10–15 mg/day of methimazole provides adequate long-term control in most patients with a minimum of side effects. If the TSH becomes elevated, many providers decrease the dose of the antithyroid agent; others continue the same dose of antithyroid agent and add exogenous thyroid hormone replacement. Treatment usually continues for 2 years with the goal of inducing remission. If thyroid hormone levels are stable at that point, a trial off medication could be considered.

If vasculitis, arthralgia, arthritis, granulocytopenia, or hepatitis occur, the drug must be discontinued. Urticarial rash can sometimes be treated symptomatically.

3. Iodide

Large doses of iodide usually produce a rapid but short-lived blockade of thyroid hormone synthesis and release. This approach is recommended only for acute management of severely thyrotoxic patients or in preparation for thyroidectomy.

C. Radiation Therapy

Radioactive iodine ablation of the thyroid is usually reserved for children with Graves disease who do not respond to antithyroid agents, develop adverse effects from the antithyroid agents, fail to achieve remission after several years of medical therapy, or have poor medication adherence. Antithyroid agents should be discontinued 4–7 days prior to radioiodine treatment to allow radioiodine uptake by the thyroid. ¹³¹I is administered orally, concentrating in the thyroid and resulting in decreased thyroid activity. In the first 2 weeks following radioiodine treatment, hyperthyroidism may worsen as thyroid tissue is destroyed and thyroid hormone is released and temporary therapy with a β-adrenergic antagonist or methimazole may be necessary. In most cases, hypothyroidism develops and thyroid hormone replacement is needed. Long-term follow-up studies have not shown any increased incidence of thyroid cancer, leukemia, infertility, or birth defects when ablative doses of ¹³¹I were used.

D. Surgical Treatment

Subtotal and total thyroidectomies may also be considered in children with Graves disease. Surgery is indicated for extremely large goiters, goiters with a suspicious nodule, very young or pregnant patients, or patients refusing radioiodine ablation. Before surgery, a β-adrenergic blocking agent is given to treat symptoms, and antithyroid agents are given for several weeks to minimize the surgical risks associated with hyperthyroidism. Iodide (eg, Lugol solution, one drop every 8 hours, or saturated solution of potassium iodide, one to two drops three times per day) can be given for 1–2 weeks prior to surgery to reduce thyroid vascularity and inhibit release of thyroid hormone. Surgical complications include hypocalcemia due to hypoparathyroidism and recurrent laryngeal nerve damage. An experienced thyroid surgeon is crucial to good surgical outcome. After thyroidectomy, patients become hypothyroid and need thyroid hormone replacement.

Course & Prognosis

Partial remissions and exacerbations may continue for several years. Treatment with an antithyroid agent results in prolonged remissions in one-third to two-thirds of children.

Neonatal Graves Disease

Transient congenital hyperthyroidism (neonatal Graves disease) occurs in about 1% of infants born to mothers with Graves disease. It occurs when maternal TSH receptor antibodies cross the placenta and stimulate excess thyroid hormone production in the fetus and newborn. Neonatal Graves disease can be associated with irritability, intrauterine growth retardation (IUGR), poor weight gain, flushing, jaundice, hepatosplenomegaly, and thrombocytopenia. Severe cases may result in cardiac failure and death. Hyperthyroidism may develop several days after birth. In high-risk neonates, TSH receptor antibody (TRAb) level should be obtained at birth and free T4 and TSH obtained day of life 3–5. Immediate management should focus on the cardiac manifestations. Temporary treatment may be necessary with iodide, antithyroid agents, β-adrenergic antagonists, or corticosteroids. Hyperthyroidism gradually resolves over 1–3 months as maternal antibodies decline. As TRAbs may still be present in the serum of previously hyperthyroid mothers after thyroidectomy or radioablation, neonatal Graves disease should be considered in all infants of mothers with a history of hyperthyroidism.

THYROID CANCER

Thyroid cancer is rare in childhood. Children usually present with a thyroid nodule or an asymptomatic asymmetrical neck mass. Dysphagia and hoarseness are unusual symptoms. Thyroid function tests are usually normal. A “cold” nodule is often seen on a technetium or radioiodine uptake scan of the thyroid. Fine-needle aspiration biopsy of the nodule assists in the diagnosis.

The most common thyroid cancer is papillary thyroid carcinoma, a well-differentiated carcinoma arising from the thyroid follicular cell. Children frequently present with local metastases to the cervical lymph nodes and occasionally with pulmonary metastases. Despite its aggressive presentation, children with papillary thyroid carcinoma have a relatively good prognosis, with a 20-year survival rate greater than 90%. Treatment consists of total thyroidectomy and removal of all involved lymph nodes, usually followed by radioiodine ablation to destroy residual thyroid remnant and metastatic tissue left behind after surgery. Thyroid hormone replacement is started to suppress TSH stimulation of residual thyroid tissue and to treat the hypothyroidism that results from surgical removal of the thyroid gland. Since papillary thyroid carcinoma in children is associated with a high recurrence rate, regular follow-up with serum thyroglobulin levels (a tumor marker), neck ultrasound, and radioiodine whole body scan are required.

Follicular thyroid carcinoma, medullary thyroid carcinoma, anaplastic carcinoma, and lymphoma are less common thyroid malignancies. Medullary thyroid carcinoma, due to autosomal dominant mutations in the RET protooncogene, arises from the thyroid C cells, which secrete calcitonin, and it is associated with elevated serum calcitonin levels. It can occur sporadically or be inherited in multiple endocrine neoplasia (MEN) type 2 and familial medullary thyroid carcinoma. In affected families, all members should be screened for the mutation, and those identified with the mutation should be treated with prophylactic thyroidectomy in early childhood.

Serum calcium concentration is tightly regulated by the coordinated actions of the parathyroid glands, kidney, liver, and small intestine. Low serum calcium concentrations, detected by calcium-sensing receptors on the surface of parathyroid cells, stimulate parathyroid hormone (PTH) release. PTH in turn promotes release of calcium and phosphorus from the bone, reabsorption of calcium from the urinary filtrate, and excretion of phosphorus in the urine. Another essential cofactor in calcium homeostasis is 1,25-dihydroxy vitamin D (calcitriol). The first step in production of this active form of vitamin D occurs in the liver where dietary vitamin D is hydroxylated to 25-hydroxy vitamin D. The final step in formation of calcitriol is 1-hydroxylation, which takes place in the kidney under control of PTH. The primary effect of calcitriol is to promote the absorption of calcium from the intestines. In concert with PTH, however, it also facilitates calcium and phosphorus mobilization from bones. Deficiencies or excesses of PTH or calcitriol, abnormalities in their receptors, or abnormalities of vitamin D metabolism lead to clinically significant aberrations in calcium homeostasis. Although calcitonin, released from the thyroid gland C cells, also reduces serum calcium concentration, changes in its serum concentration rarely cause clinically relevant disease.

HYPOCALCEMIC DISORDERS

A normal serum calcium concentration is approximately 8.9–10.2 mg/dL. The normal concentration of ionized calcium is approximately 1.1–1.3 mmol/L. Serum calcium levels in newborns, which are slightly lower than in older children and adults, may be as low as 7 mg/dL in premature infants. Fifty to sixty percent of calcium in the serum is protein-bound and metabolically inactive. Thus, measurement of ionized serum calcium, the metabolically active form, is helpful if serum proteins are low or in conditions such as acidosis that cause abnormal calcium binding to protein.

General Considerations

Hypocalcemia is a consistent feature of conditions such as hypoparathyroidism, PHP, transient neonatal hypoparathyroidism, and severe vitamin D deficiency rickets, and may be present in rare disorders of vitamin D action (receptor defects, Malloy 2010). Causes of rickets are outlined in Table 34–5. Other causes of hypocalcemia include the following:

• Intestinal malabsorption of calcium (may be exacerbated by malabsorption of vitamin D and/or magnesium)

• Chronic renal disease

• Tumor lysis syndrome, rhabdomyolysis (due to cellular destruction that liberates large amounts of intracellular phosphate that complex with serum calcium)

• Activating mutation in the calcium-sensing receptor of the parathyroid glands and kidneys (hypercalciuric hypocalcemia, Hendy 2009)

• Hypoparathyroidism, including typically transient hypoparathyroidism following thyroidectomy

Deficient PTH secretion may be due to deficient parathyroid tissue (DiGeorge syndrome), autoimmunity, or sometimes, magnesium deficiency. Decreased PTH action may be due to magnesium deficiency, vitamin D deficiency, or defects in the PTH receptor (PHP). Occasionally, PTH deficiency is idiopathic. Table 34–6 summarizes the clinical and laboratory characteristics of disorders of PTH secretion and action.

Autoimmune parathyroid destruction with subsequent hypoparathyroidism may be isolated, or associated with other autoimmune disorders in the APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, or APS-1) syndrome. Hypoparathyroidism may also be secondary to manipulation of the blood supply of the parathyroid glands or removal of the parathyroid glands during thyroidectomy. Autosomal dominant hypocalcemia, also called familial hypercalciuric hypocalcemia, is associated with a gain-of-function mutation in the calcium-sensing receptor, which causes a low serum PTH despite hypocalcemia, and excessive urinary loss of calcium. A family history of hypocalcemia may be the clue that differentiates this condition from other causes of hypocalcemia.

Transient neonatal hypoparathyroidism is caused both by a relative deficiency of PTH secretion and PTH action (see Table 34–6). In the early form, associated hypomagnesemia often aggravates hypoparathyroidism due to magnesium’s role in facilitating PTH secretion. The late form of neonatal hypoparathyroidism (after 2 weeks of age) occurs in infants receiving high-phosphate formulas (whole cow’s milk is a well-known example) due to intestinal calcium-phosphate binding, resulting in decreased absorption of intestinal calcium.

Rickets describes characteristic clinical and bony radiologic features associated with hypophosphatemia (see Chapter 11). Vitamin D deficiency, caused by lack of sunlight exposure or dietary deficiency, is the most common cause of rickets. Recently, high rates of occult vitamin D deficiency have formed the basis for the 2008 recommendation by the American Academy of Pediatrics that breast-fed infants receive vitamin D supplementation of at least 400 IU/day. See Table 34–5 for features of other causes of rickets.

Familial hypophosphatemic rickets occurs due to abnormal renal phosphate loss related to abnormal fibroblast growth factor 23 (FGF23) regulation.

Clinical Findings

A. Symptoms and Signs

Prolonged hypocalcemia from any cause is associated with tetany, photophobia, blepharospasm, and diarrhea. Symptoms of tetany include numbness, muscle cramps, twitching of the extremities, carpopedal spasm, and laryngospasm. Tapping the face in front of the ear causes facial spasms (Chvostek sign) and inflation of a sphygmomanometer above systolic blood pressure causes a carpal spasm (Trousseau’s sign). Some patients with hypocalcemia exhibit bizarre behavior, irritability, loss of consciousness, and convulsions. Electrocardiogram may demonstrate prolonged QTc. Headache, vomiting, increased intracranial pressure, and papilledema may occur. In early infancy, respiratory distress may be a presenting finding.

B. Laboratory Findings

Tables 34–5 and 34–6 outline the specific laboratory findings in various causes of hypocalcemia (Shaw, 2009). Magnesium levels may also be low. Measurement of urinary excretion of calcium (calcium-creatinine ratio) can assist in diagnosis and monitoring of therapy in children on calcitriol therapy.

C. Imaging

Soft tissue and basal ganglia calcification may occur in idiopathic hypoparathyroidism and PHP. Various skeletal changes are associated with rickets, including cupped and irregular long bone metaphyses. Torsional deformities can result in genu varum (bowleg). Accentuation of the costochondral junction gives the rachitic rosary appearance seen on the chest wall.

Differential Diagnosis

Tables 34–5 and 34–6 outline the features of disorders associated with hypocalcemia. In individuals with hypoalbuminemia, the total serum calcium may be low and yet the functional serum ionized calcium is normal. Ionized calcium is the test of choice for hypocalcemia in patients with low serum albumin.

Treatment

A. Acute or Severe Tetany

Symptoms are treated acutely by administration of intravenous calcium gluconate or calcium chloride at a dose of 10 mg/kg. Intravenous calcium infusions should not exceed 50 mg/min because of possible cardiac arrhythmia. Cardiac monitoring should be performed during calcium infusion. Rise in serum calcium is limited to about 2–3 hours after an intravenous calcium bolus infusion, therefore the bolus will need to be followed by oral or continuous calcium infusions if hypocalcemia persists.

B. Maintenance Management of Hypoparathyroidism or Chronic Hypocalcemia

The objective of treatment is to maintain the serum calcium and phosphate at near-normal levels without excess urinary calcium excretion.

1. Diet

Calcium supplementation should start at a dose of 50–75 mg of elemental calcium per kilogram per day divided in three to four doses. Supplemental calcium can often be discontinued in patients with rickets after vitamin D therapy has stabilized.

2. Vitamin D supplementation

Ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃) are the most commonly used oral vitamin D preparations. Cholecalciferol is slightly more active than ergocalciferol. Calcitriol (1,25-dihydroxy vitamin D₃) supplementation is recommended for impaired metabolism of dietary vitamin D to 25-OH vitamin D as seen in hepatic dysfunction, or to its active end product, 1,25-dihydroxy vitamin D, or impaired PTH function. Selection and dosage of vitamin D supplements varies with the underlying condition and the response to therapy.

3. Monitoring

Dosage of calcium and vitamin D must be tailored for each patient. Monitoring serum calcium, urine calcium, and serum alkaline phosphatase levels at 1- to 3-month intervals is necessary to ensure adequate therapy and to prevent hypercalcemia, hypercalciuria/nephrocalcinosis and vitamin D toxicity.

The major goals of monitoring in vitamin D deficiency are to ensure: (1) maintenance of serum calcium and phosphorus concentrations within normal ranges, (2) normalization of alkaline phosphatase activity for age, (3) regression of skeletal changes, and (4) maintenance of an age-appropriate urine calcium-creatinine ratio. The urine-creatinine ratio should be less than 0.8 in newborns, 0.3–0.6 in children, and less than 0.25 in adolescents (when using creatinine and calcium measured in milligrams per deciliter).

Monitoring goals are somewhat different in hypophosphatemic rickets. Serum calcium and alkaline phosphatase, and urinary calcium to creatinine ratio should be maintained within normal limits. Monitoring of serum PTH is necessary to ensure that secondary hyperparathyroidism does not develop from excessive phosphate treatment or inadequate calcitriol replacement.

PSEUDOHYPOPARATHYROIDISM (RESISTANCE TO PARATHYROID HORMONE ACTION)

In PHP, PTH production is adequate, but target organs (renal tubule, bone, or both) fail to respond because of receptor resistance. Resistance to PTH action is due to a heterozygous inactivating mutation in the stimulatory G protein subunit associated with the PTH receptor, which leads to impaired signaling. Resistance to other G protein-dependent hormones, such as TSH, GHRH, and follicle-stimulating hormone (FSH)/luteinizing hormone (LH), may also be present.

There are several types of PHP with variable biochemical and phenotypic features (see Table 34–6). Biochemical abnormalities in PHP (hypocalcemia and hyperphosphatemia) are similar to those seen in hypoparathyroidism, but the PTH levels are elevated. PHP may be accompanied by a characteristic phenotype known as Albright hereditary osteodystrophy (AHO), which includes short stature; round, full facies; irregularly shortened fourth metacarpal; a short, thick-set body; delayed and defective dentition; and mild intellectual disability. Corneal and lenticular opacities and ectopic calcification of the basal ganglia and subcutaneous tissues (osteoma cutis) may occur with or without abnormal serum calcium levels. Treatment is the same as for hypoparathyroidism.

Pseudo-pseudohypoparathyroidism (PPHP) describes individuals with the AHO phenotype, but normal calcium homeostasis. PHP and PPHP can occur in the same cohort. Genomic imprinting is probably responsible for the different phenotypic expression of disease. Heterozygous loss of the maternal allele causes PHP while heterozygous loss of the paternal allele causes PPHP.

HYPERCALCEMIC STATES

Hypercalcemia is defined as a serum calcium level greater than 11 mg/dL. Severe hypercalcemia is a level greater than 13.5 mg/dL.

General Considerations

Hypercalcemia is less common in children than in adults and etiology varies by age (McNeilly, 2016). Table 34–7 summarizes the differential diagnosis of childhood hypercalcemia (Lietman 2010).

Hyperparathyroidism is rare in childhood and may be primary or secondary (Belcher, 2013). The most common cause of primary hyperparathyroidism is due to a single parathyroid adenoma. Familial hyperparathyroidism may be an isolated disease, or it may be associated with MEN type 1, or rarely type 2A (Iqbal, 2009). Hypercalcemia of malignancy is associated with solid and hematologic malignancies and is due either to local destruction of bone by tumor or to ectopic secretion of PTH-related protein. When ectopic PTH-related protein is present, calcium is elevated, serum PTH is suppressed, and serum PTH-related protein is elevated. Chronic renal disease with impaired phosphate excretion is the most common secondary cause of hyperparathyroidism (Kemper, 2014).

Clinical Findings

A. Symptoms and Signs

1. Due to hypercalcemia

Manifestations include hypotonicity and muscle weakness; apathy, mood swings, and bizarre behavior; nausea, vomiting, abdominal pain, constipation, and weight loss; hyperextensibility of joints; and hypertension, cardiac irregularities, bradycardia, and shortening of the QT interval. Coma occurs rarely. Calcium deposits occur in the cornea or conjunctiva (band keratopathy) and are detected by slit-lamp examination. Intractable peptic ulcer and pancreatitis occur in adults but rarely in children.

2. Due to Increased calcium and phosphate excretion

Loss of renal concentrating ability causes polyuria, polydipsia, and calcium phosphate deposition in renal parenchyma or as urinary calculi with progressive renal damage.

3. Due to changes in the skeleton

Initial findings include bone pain, osteitis fibrosa cystica, subperiosteal bone absorption in the distal clavicles and phalanges, absence of lamina dura around the teeth, spontaneous fractures, and moth-eaten appearance of the skull on radiographs. Later, there is generalized demineralization.

B. Imaging

Bone changes may be subtle in children. Technetium sestamibi scintigraphy is preferred over conventional procedures (ultrasound, computed tomography, and MRI) for localizing parathyroid tumors.

Treatment

A. Symptomatic

Initial management is vigorous hydration with normal saline and forced calcium diuresis with a loop diuretic such as furosemide (1 mg/kg given every 6 hours). If response is inadequate, glucocorticoids or calcitonin may be used. Bisphosphonates, standard agents for the management of acute hypercalcemia in adults, are being used more often in refractory pediatric hypercalcemia.

B. Chronic

Treatment options vary with the underlying cause. Resection of parathyroid adenoma or subtotal removal of hyperplastic parathyroid glands is the preferred treatment. Postoperatively, hypocalcemia due to the rapid remineralization of chronically calcium-deprived bones may occur. A diet high in calcium and vitamin D is recommended immediately postoperatively and is continued until serum calcium concentrations are normal and stable. Treatment of secondary hyperparathyroidism from chronic renal disease is primarily directed at controlling serum phosphorus levels with phosphate binders and pharmacologic doses of calcitriol are used to suppress PTH secretion. Long-term therapy for hypercalcemia of malignancy is the treatment of the underlying disorder. There has been an increasing role for bisphosphonates in treatment of chronic hypercalcemia, particularly in children with hypercalcemia of immobilization.

FAMILIAL HYPOCALCIURIC HYPERCALCEMIA (FAMILIAL BENIGN HYPERCALCEMIA)

Familial hypocalciuric hypercalcemia is distinguished by low urinary calcium excretion as a result of high renal reabsorption of calcium (Varghese, 2011). PTH is normal or slightly elevated. In most cases, the genetic defect is an inactivating mutation in the membrane-bound calcium-sensing receptor expressed on parathyroid and renal tubule cells. It is inherited as an autosomal dominant trait with high penetrance. There is a low rate of new mutations. Most patients are asymptomatic, and treatment is unnecessary. However, a severe form of symptomatic neonatal hyperparathyroidism may occur in infants homozygous for the receptor mutation.

HYPERVITAMINOSIS D

Vitamin D intoxication is almost always the result of ingestion of excessive amounts of vitamin D (Lietman, 2010). Signs and symptoms of vitamin D-induced hypercalcemia are the same as those in other hypercalcemic conditions. Treatment depends on the severity of hypercalcemia and initial treatment is similar to other hypercalcemic states. However, due to the storage of vitamin D in the adipose tissue, several months of a low-calcium, low-vitamin D diet may also be required.

WILLIAMS SYNDROME

Williams syndrome is an uncommon disorder of infancy characterized by elfin-appearing facies and hypercalcemia in infancy (Lietman, 2010). Other features include failure to thrive, mental and motor retardation, cardiovascular abnormalities (primarily supravalvular aortic stenosis), irritability, purposeless movements, constipation, hypotonia, polyuria, polydipsia, and hypertension. A gregarious and affectionate personality is the rule in children with the syndrome. Hypercalcemia may not appear until several months after birth. Treatment consists of restriction of dietary calcium and vitamin D (Calcilo formula) and, in severe cases, moderate doses of glucocorticoids or even bisphosphonates.

A defect in the metabolism of, or responsiveness to, vitamin D is postulated as the cause of Williams syndrome. Elastin deletions localized to chromosome 7 have been identified in more than 90% of patients and is generally identified by fluorescent in situ hybridization (FISH) analysis. The risk of hypercalcemia generally resolves by age 4.

IMMOBILIZATION HYPERCALCEMIA

Abrupt immobilization, particularly in a rapidly growing adolescent, may cause hypercalcemia and hypercalciuria (Lietman, 2010). Abnormalities often appear 1–3 weeks after immobilization. Medical or dietary intervention may be required in severe cases.

HYPOPHOSPHATASIA

Hypophosphatasia is a rare autosomal recessive condition characterized by deficiency of alkaline phosphatase activity in serum, bone, and tissues, resulting from mutations in the gene for tissue-nonspecific isozyme of alkaline phosphatase (TNSALP) (Whyte, 2012). Enzyme deficiency leads to poor skeletal mineralization with clinical and radiographic features similar to rickets. Severity ranges from severe skeletal deformity and perinatal death to milder skeletal findings (including craniosynostosis), reduced bone mineral density, and motor delays. Serum calcium levels may be elevated. The diagnosis of hypophosphatasia is made by demonstrating elevated urinary phosphoethanolamine associated with low serum alkaline phosphatase. Standard therapy is supportive care; enzyme-replacement therapy shows promise for improved prognosis.

DEVELOPMENT

Sex development is a complex process beginning with the differentiation of the bipotential gonad into either a testis or ovary. In an infant with a Y chromosome, expression of the transcription factor SRY initiates a cascade of gene expression that directs the formation of testes. Without expression of SRY, ovaries develop; however, a 46,XX complement of chromosomes, in addition to several unique genes, is necessary for the development of normal ovaries. Secretion of testosterone and antimüllerian hormone (AMH) by the testes results in the development of male internal ducts (epididymis, seminal vesicle, and vas deferens) and regression of the müllerian ducts, which are the precursors of the female internal genital structures (fallopian tubes, uterus, and vagina) (Figure 34–6).

The external genitalia develop from sexually indifferent structures called the genital tubercle, the urethral folds, and the labioscrotal swellings (Figure 34–7). Development of typical male external genitalia depends on an adequate circulating concentration of testosterone and its metabolite dihydrotestosterone (DHT). Sexual differentiation of the external genitalia is completed at about 12 weeks of gestation.

DISORDERS OF SEXUAL DEVELOPMENT

Disorders of sex development (DSD) can arise from alterations in three main processes: gonadal differentiation, steroidogenesis, or androgen action. Many DSDs will be evident in the newborn period, but some will not manifest until later with abnormal pubertal development. In disorders of gonadal differentiation, the testes or ovaries do not develop normally, which results in either ambiguous genitalia or sex reversal. As an example, individuals with 46,XY complete gonadal dysgenesis do not develop normal gonadal tissue (ie, have streak gonads), and this results in typical female internal and external reproductive structures. XY partial gonadal dysgenesis is associated with incomplete testes development and usually results in a phenotype of ambiguous genitalia. Mutations in genes important for gonadal differentiation have been demonstrated in many patients with both complete and partial gonadal dysgenesis. Mixed gonadal dysgenesis is usually due to presence of both 45,XO and 46,XY cell lines in the same individual. There is typically a testis on one side and a streak gonad on the contralateral side. Ovotesticular DSD occurs when there is both ovarian and testicular tissue. Steroidogenesis refers to steroid hormone biosynthesis and depends on the function of multiple enzymes (Figure 34–8). Enzymatic defects in this pathway can result in decreased or absent testosterone synthesis and in affected XY individuals, there will be reduced or lack of androgen effects resulting in ambiguous genitalia. Since the gonad and adrenal gland share common enzymes of steroid hormone production, some of the enzymatic defects associated with male undervirilization may also affect production of cortisol and aldosterone, leading to cortisol deficiency and salt wasting. Deficiency of 21-hydroxylase, an enzyme in the cortisol and aldosterone pathways, leads to overproduction of adrenal androgens and the most common form of congenital adrenal hyperplasia. In the classic salt-losing form of this disorder, 46,XX infants present with genital ambiguity due to the excess of adrenal androgen production, but have normal uterus and ovaries.

Disorders of androgen action include the diagnosis of androgen insensitivity syndrome (AIS) which is caused by an inactivating mutation in the androgen receptor gene located on the proximal long arm of the X chromosome. In complete AIS (CAIS), there is no androgen action; thus, 46,XY affected individuals have normal appearing female external genitalia with a short vagina, absent müllerian structures and absence or rudimentary wolffian structures. Gonads are located either intra-abdominally or in the inguinal canal. Many of these individuals present when surgery for an inguinal hernia reveals a testis in the hernia sack. With partial AIS (PAIS), the degree of virilization and ambiguity depends on the degree of abnormality in androgen binding.

Evaluation

On physical examination, dysmorphic features and other congenital anomalies should be noted. The genital examination should include measuring the width and length of the stretched phallus and noting the position of the urethral meatus as well as degree of labioscrotal fusion. The normal stretched penile length (SPL) is greater than 2.0 cm in term male infants. The labioscrotal and inguinal regions should be palpated for presence of gonads. Since ovaries and streak gonads do not typically descend, the presence of a palpable gonad is suggestive of a 46,XY or 45X/46,XY karyotype. In all these infants, laboratory studies should be done within the first 24 hours of life and include a FISH for SRY/X-centromere, chromosomal analysis or microarray, electrolytes, LH, FSH, testosterone, and 17-hydroxyprogesterone. Additional laboratory evaluation is usually based on these results. A pelvic ultrasound can be helpful to evaluate for the presence of a uterus; however, ultrasound findings can be unreliable so should be done in an institution which has expertise in pediatric imaging. Many times, laparoscopic examination is necessary to delineate internal structures. It is important that gender assignment be avoided until expert evaluation by a multidisciplinary team is performed. Ideally this team includes pediatric specialists from endocrinology, urology, gynecology, genetics, psychology, and nursing. The team should develop a plan for diagnosis, gender assignment, and treatment options before making any recommendations. Open communications with the parents is essential and their participation in decision-making encouraged.

1. Precocious Puberty in Girls

Precocious puberty is defined as pubertal development occurring below the age limit set for normal onset of puberty. Puberty is considered precocious in girls if the onset of secondary sexual characteristics occurs before age 8 years in Caucasian girls and 7 years for African-American and Hispanic girls. Precocious puberty is more common in girls than in boys. Many girls showing signs of puberty between 6 and 8 years of age have a benign, slowly progressing form that requires no intervention. The age of pubertal onset may be advanced by obesity.

Central (gonadotropin-releasing hormone [GnRH]-dependent) precocious puberty involves activation of the hypothalamic GnRH pulse generator, an increase in gonadotropin secretion, and a resultant increase in production of sex steroids (Table 34–8). The sequence of hormonal and physical events in central precocious puberty is identical to that of normal puberty. Central precocious puberty in girls is generally idiopathic but may be secondary to a central nervous system (CNS) abnormality that disrupts the prepubertal restraint on the GnRH pulse generator. Such CNS abnormalities include, but are not limited to, hypothalamic hamartomas, CNS tumors, cranial irradiation, hydrocephalus, and trauma. Peripheral precocious puberty (GnRH-independent) occurs independent of gonadotropin secretion. In girls, peripheral precocious puberty can be caused by ovarian or adrenal tumors, ovarian cysts, late-onset congenital adrenal hyperplasia, McCune-Albright syndrome, or exposure to exogenous estrogen.

Clinical Findings

A. Symptoms and Signs

Female central precocious puberty usually starts with breast development, followed by pubic hair growth and menarche. However, the order may vary and girls younger than 5 years may not have pubic hair development. Girls with ovarian cysts or tumors generally have signs of estrogen excess such as breast development and possibly vaginal bleeding. Adrenal tumors and CAH produce signs of androgen excess which include pubic hair, axillary hair, acne, and increased body odor. Children with precocious puberty usually have accelerated growth and skeletal maturation, and may temporarily be tall for age. However, because skeletal maturation advances at a more rapid rate than linear growth, final adult stature may be compromised.

B. Laboratory Findings

If the bone age is advanced, further laboratory evaluation is warranted. In central precocious puberty, random FSH and LH concentrations may still be in the prepubertal range. If so, documentation of the maturity of the hypothalamic-pituitary axis depends on demonstrating a pubertal LH response after stimulation with a GnRH agonist. In peripheral precocious puberty, the LH response to GnRH stimulation is suppressed by feedback inhibition of the hypothalamic-pituitary axis by the autonomously secreted gonadal steroids (see Figure 34–1). In girls with an ovarian cyst or tumor, estradiol levels will be markedly elevated. In girls who present with pubic and/or axillary hair but no breast development, androgen levels (testosterone, androstenedione, dehydroepiandrosterone sulfate) and 17-hydroxyprogesterone should be measured.

C. Imaging

One of the first steps in evaluating a child with early pubertal development is obtaining a radiograph of the left hand and wrist to determine skeletal maturity (bone age). When a diagnosis of central precocious puberty is made, an MRI of the brain should be done to evaluate for CNS lesions. In girls whose laboratory tests suggest peripheral precocious puberty, an ultrasound of the ovaries and/or adrenal gland may be indicated.

Treatment

Girls with central precocious puberty can be treated with GnRH analogues that downregulate pituitary GnRH receptors and thus decrease gonadotropin secretion. Currently, the two most common GnRH analogues used are (1) leuprolide, which is given as a monthly intramuscular injection or (2) histrelin subdermal implant, which is replaced annually. With treatment, physical changes of puberty regress or cease to progress and linear growth slows to a prepubertal rate. Projected final heights often increase as a result of slowing of skeletal maturation. After stopping therapy, pubertal progression resumes, and ovulation and pregnancy have been documented.

Treatment of peripheral precocious puberty is dependent on the underlying cause. In a girl with an ovarian cyst, intervention is generally not necessary, as the cyst usually regresses spontaneously. Serial ultrasounds are recommended to document this regression. Surgical resection and possibly chemotherapy are indicated for the rare adrenal or ovarian tumor. Regardless of the cause of precocious puberty or the medical therapy selected, attention to the psychological needs of the patient and family is essential.

2. Benign Variants of Precocious Puberty

Benign premature thelarche (benign early breast development) occurs most commonly in girls younger than 2 years of age. Girls present with isolated breast development without other signs of puberty such as linear growth acceleration and pubic hair development. The breast development is typically present since birth and often waxes and wanes in size. It may be unilateral or bilateral. Treatment is parental reassurance regarding the self-limited nature of the condition. Observation of the child every few months is indicated. Onset of thelarche after age 36 months or in association with other signs of puberty requires evaluation.

Benign premature adrenarche (benign early adrenal maturation) is manifested by early development of pubic hair, axillary hair, acne, and/or body odor. Benign premature adrenarche is characterized by normal linear growth and no or minimal bone age advancement. Laboratory tests (see earlier discussion) will differentiate benign premature adrenarche from late-onset CAH and adrenal tumors. It is recognized that approximately 15% of girls with benign premature adrenarche will go on to develop polycystic ovarian syndrome.

3. Delayed Puberty

Delayed puberty in girls should be evaluated if there are no pubertal signs by age 13 years or menarche by 16 years. Primary amenorrhea refers to the absence of menarche, and secondary amenorrhea refers to the absence of menses for at least 6 months after regular menses have been established. The most common cause of delayed puberty is constitutional growth delay (Table 34–9). This growth pattern, characterized by short stature, normal growth velocity, and a delay in skeletal maturation, is described in detail earlier in this chapter. The timing of puberty in children with constitutional growth delay is commensurate to the bone age, not the chronologic age. Girls may also have delayed puberty from any condition that delays growth and skeletal maturation, such as hypothyroidism and GHD.

Primary hypogonadism in girls refers to a primary abnormality of the ovaries. The most common diagnosis in this category is Turner syndrome, in which the lack of or an abnormal second X chromosome leads to early loss of oocytes and accelerated stromal fibrosis. Other types of primary ovarian insufficiency include 46,XY gonadal dysgenesis and 46,XX gonadal dysgenesis, galactosemia, autoimmune ovarian failure, radiation, and chemotherapy. Premutation carriers for fragile X syndrome are also at increased risk of premature ovarian failure.

Central hypogonadism refers to a hypothalamic or pituitary deficiency of GnRH or FSH/LH, respectively. Central hypogonadism can be functional (reversible), caused by stress, undernutrition, prolactinemia, excessive exercise, or chronic illness. Permanent central hypogonadism is typically associated with conditions that cause multiple pituitary hormone deficiencies, such as congenital hypopituitarism, CNS tumors, or cranial irradiation. Isolated gonadotropin deficiency is rare but may occur in Kallmann syndrome, which is also characterized by hyposmia or anosmia. There are many genes that have been implicated in both isolated gonadotropin deficiency and Kallmann syndrome. In either primary or central hypogonadism, signs of adrenarche are generally present.

Delayed menarche or secondary amenorrhea may result from primary ovarian failure or central hypogonadism, or may be the consequence of hyperandrogenism, anatomic obstruction precluding menstrual outflow, or müllerian agenesis.

Clinical Evaluation

The history should ascertain whether and when puberty commenced, level of exercise, nutritional intake, stressors, sense of smell, symptoms of chronic illness, and family history of delayed puberty. Past growth records should be assessed to determine if height and weight velocity have been appropriate. Physical examination includes body proportions, breast and genital development, and stigmata of Turner syndrome. Pelvic examination or pelvic ultrasonography should be considered, especially in girls with primary amenorrhea.

A bone age radiograph should be obtained first. If the bone age is lower than that consistent with pubertal onset (< 12 years in girls), evaluations should focus on finding the cause of the bone age delay. If short stature and normal growth velocity are present, constitutional growth delay is likely. If growth rate is abnormal, evaluation for causes of growth delay is warranted. Measurement of FSH and LH may not be helpful in the setting of delayed bone age since prepubertal levels are normally low.

If the patient has attained a bone age of more than 12 years and there are minimal or no signs of puberty on physical examination, FSH and LH levels will distinguish between primary ovarian failure (elevated FSH/LH) and central hypogonadism (low FSH/LH). If gonadotropins are elevated, a karyotype should be performed to evaluate for Turner syndrome. Central hypogonadism is characterized by low gonadotropin levels, and evaluation is geared toward determining if the hypogonadism is functional or permanent. Laboratory tests should be directed toward identifying chronic disease and hyperprolactinemia. Cranial MRI may be helpful.

In girls with adequate breast development and amenorrhea, a progesterone challenge may be helpful to determine if sufficient estrogen is being produced and to evaluate for anatomical defects. Girls who are producing estrogen have a withdrawal bleed after 5–10 days of oral progesterone, whereas those who are estrogen-deficient or have an anatomical defect have little or no bleeding. The most common cause of amenorrhea in girls with sufficient estrogen is polycystic ovarian syndrome. Girls who are estrogen-deficient should be evaluated similarly to those who have delayed puberty.

Treatment

Replacement therapy in hypogonadal girls begins with estrogen alone at the lowest available dosage. Oral preparations such as estradiol or topical estrogen patches are used. Estrogen doses are gradually increased every 6 months and then 18–24 months later, progesterone is added either cyclically or continuously. Eventually, the patient may change over to an estrogen-progestin combined pill or patch if desired. Progesterone therapy is needed to counteract the effects of estrogen on the uterus, as unopposed estrogen promotes endometrial hyperplasia. Estrogen is also necessary to promote bone mineralization and prevent osteoporosis.

4. Secondary Amenorrhea

See discussion of amenorrhea in Chapter 4.

1. General Considerations

Polycystic ovarian syndrome (PCOS) is one of the most common menstrual disorders in women, estimated to affect 10%–15% of all reproductive age women. The underlying pathology of PCOS is not well understood. Many girls with PCOS will have a history of early adrenarche. The diagnosis cannot formally be made until at least 1 year post-menarche or with primary amenorrhea, due to the normal duration of time required for girls to establish regular menstrual cycles. Many girls with PCOS are obese, and this is contributing to an increased prevalence of the disease, but PCOS is also present in girls without obesity. Adolescents with PCOS typically present for cosmetic concerns or menstrual irregularities. However, PCOS is associated with many comorbidities and it is important to provide comprehensive screening and care.

2. Clinical Findings

PCOS should be considered in adolescents who have (1) menstrual abnormalities including: (a) oligomenorrhea of < 8 menses a year 2 years following menarche, (b) severe oligomenorrhea: > 90 days between cycle at least a year post-menarche, (c) primary amenorrhea ≥ 15 years, or (d) primary amenorrhea ≥ 2 years after breast development; and (2) clinical signs and symptoms of hyperandrogenism such as hirsutism, cystic acne, androgenic alopecia, and/or biochemical hyperandrogenism. PCOS is a diagnosis of exclusion and other causes of irregular menses such a primary ovarian failure, prolactinoma, thyroid dysfunction, hypothalamic hypogonadotropic hypogonadism as seen in those who are underweight, ovarian tumor or pituitary mass and causes of hyperandrogenism such as adrenal tumors, ovarian tumors, or congenital adrenal hyperplasia should be ruled out with laboratory testing. The physical exam should be comprehensive and assess for severity of acne, hirsutism as scored by the Ferriman-Gallwey scale, alopecia, acanthosis nigricans, skin tags, pilonidal cysts, hidradenitis, thyroid size, airway and tonsil size, liver size, peripheral edema, striea size, and color and clitoral enlargement. Ovarian ultrasound is currently not recommended for the diagnosis of PCOS until 8 years post-menarche due to the large variability of normal ovaries in adolescent girls. Uterine ultrasound can be used to determine structural abnormalities causing amenorrhea, thickness of the endometrium in cases of failure to initiate a menstrual bleed following a short course of Provera or to monitor for large cysts causing ovarian pain.

Once a diagnosis of PCOS is established, girls also need to be screened for associated co-morbidities. Adolescents with PCOS have an increased risk of developing insulin resistance and type 2 diabetes, and a 75 g 2 hour oral glucose tolerance should be performed, or alternatively a hemoglobin A1C test at diagnosis and then every 1–2 years. Fasting lipids should be measured at diagnosis and then per American Academy of Pediatrics guidelines. Up to 50% of obese girls with PCOS have nonalcoholic fatty liver disease, and transaminases should be checked at diagnosis, and liver size assessed by exam. The risk of hypertension is increased, and blood pressure should be checked at every appointment with an appropriate sized cuff. If symptoms of obstructive sleep apnea are present, overnight polysomnography should be performed. All girls should be screened for anxiety and depression on a routine basis.

3. Treatment

The treatment for PCOS should be comprehensive, personalized for each individual, and ideally delivered via a coordinated multidisciplinary approach. All girls, even those of normal weight are encouraged to maintain a healthy lifestyle, with moderate to vigorous activity 3–5 days a week and a healthy diet. To induce weight loss, diets may need to be very low calorie (1200–1500 kcal/day) and exercise may need to be daily. Monophasic combined oral contraceptives, with 30–35 mcg of estradiol and a third- or fourth-generation nonandrogenic progestin are used to regulate menses, decrease acne, hirsutism, and alopecia. Other methods of delivery including combined estradiol and progesterone patches or vaginal rings can also be used, although they are less reliable for contraception in individuals greater than 200 pounds. Implantable and uterine progestins can be utilized to prevent endometrial hyperplasia, although due to the risk of weight gain and depression, injectable progesterone should be avoided. Cyclic oral progesterone, at a dose of 10 mg daily for 10 days can be utilized to initiate menses every 3 months in those that do not desire to take oral contraceptives. Metformin, at a dose of 1000 mg twice a day can be used to treat insulin resistance and hyperglycemia, and can induce modest improvements in menstrual regularity. The extended release form can be prescribed at 2000 mg once a day in those with gastric intolerance to the regular formulation. Typical acne treatments should be used, and for hirsutism treatments include spironolactone up to 200 mg a day, eflornithine cream, electrolysis, and laser hair treatment. Topical minoxidil can reduce androgenic alopecia. Standard therapies for obstructive sleep apnea, hyperlipidemia, hypertension, and psychological disturbances should be utilized as needed. The use of weight loss medications should be considered in older obese adolescents in conjunction with lifestyle therapies. Patients should be seen every 3–6 months, pending the complexity of their medical needs.

1. Precocious Puberty in Boys

Puberty is considered precocious in boys if secondary sexual characteristics appear before age 9 years. While the frequency of central precocious puberty is much lower in boys than girls, boys are much more likely to have an associated CNS abnormality (see Table 34–8) and require medical evaluation. In addition, several types of gonadotropin-independent (peripheral) precocious puberty occur in boys (see Table 34–8).

Clinical Findings

A. Symptoms and Signs

Appearance of pubic hair is the most common presenting sign of puberty in boys, since increased growth velocity occurs later in the process than in girls. Examination of the testes is a critical component of the evaluation of a boy with suspected precocious puberty. Testicular size differentiates central precocity, in which the testes enlarge (> 2 cm in the longitudinal axis or > 4 mL using Prader beads), from gonadotropin-independent causes, in which the testes usually remain small. In some cases of gonadotropin-independent precocious puberty, such as familial male precocious puberty and HCG-mediated precocious puberty, there may be some testicular enlargement, but usually less than expected for the degree of virilization. Tumors of the testis are associated with either asymmetrical or unilateral testicular enlargement.

B. Laboratory Findings

Testosterone concentrations are usually elevated in precocious puberty but do not differentiate the source. Basal high-sensitivity serum LH and FSH concentrations will be in the pubertal range in boys with central precocious puberty, but suppressed in peripheral, gonadotropin-independent precocity. GnRH-analogue (leuprolide) stimulation testing can also distinguish central from gonadotropin-independent puberty, but is often not needed in boys because increased testicular volume is usually a reliable physical sign of central puberty. In boys with peripheral precocious puberty caused by congenital adrenal hyperplasia (CAH) plasma adrenal androgens and 17-hydroxyprogesterone will be elevated. Serum β-HCG concentrations signify the presence of an HCG-producing tumor (eg, CNS dysgerminoma or hepatoma) in boys who present with precocious puberty and testicular enlargement but suppressed gonadotropins. Genetic testing may be helpful in diagnosing CAH or familial male precocious puberty (due to mutations in the LH receptor).

C. Imaging

A radiograph of the left hand to assess epiphyseal maturation (bone age) is often useful in evaluating precocious puberty. In all boys with central precocious puberty, cranial MRI should be obtained to evaluate for a CNS abnormality. If testing suggests peripheral precocious puberty and laboratory studies are not consistent with CAH, imaging may be useful to detect hepatic, adrenal, and testicular tumors.

Treatment

Treatment of central precocious puberty in boys entails treatment of the underlying cause and the use of GnRH analogues. Boys with McCune-Albright syndrome or familial male precocious puberty are treated with agents that block steroid synthesis (eg, ketoconazole) or with a combination of antiandrogens (eg, spironolactone) and aromatase inhibitors (eg, anastrozole or letrozole) that block the conversion of testosterone to estrogen.

2. Delayed Puberty

Boys should be evaluated for delayed puberty if they have no secondary sexual characteristics by 14 years of age or if more than 5 years have elapsed since the first signs of puberty without completion of genital growth.

By far the most common cause of delayed puberty in boys is constitutional growth delay, a normal variant of growth described in detail earlier in this chapter. True hypogonadism in boys may be primary due to absence, malfunction, or destruction of testicular tissue; or central, due to pituitary or hypothalamic insufficiency.

Primary testicular insufficiency may be due to anorchia; Klinefelter syndrome (47,XXY) or other sex chromosome anomalies; enzymatic defects in testosterone synthesis; or inflammation or destruction of the testes following infection (eg, mumps), autoimmune disorders, radiation, trauma, or tumor.

Central hypogonadism may accompany multiple pituitary hormone deficiency or may be due to isolated or complete gonadotropin deficiency. The etiologies of central hypogonadism in boys is the same as girls (see Table 34–9).

Clinical Evaluation

The history should focus on whether and when puberty started, history of cryptorchidism, hypospadias, or micropenis, growth pattern, symptoms of chronic illness, sense of smell, and family history of delayed puberty. Physical examination should include growth parameters, pubertal stage, and testicular location, size, and consistency. Testes less than 2 cm in length, or less than 4 mL using Prader beads, are prepubertal; symmetric testes more than 2.5 cm or more than 4 mL indicate onset of puberty.

A radiograph of the left hand and wrist to assess bone age should be the first step in evaluating delayed puberty. If bone age is delayed relative to chronological age and growth velocity is normal for a prepubertal boy, constitutional growth delay is the most likely diagnosis.

Laboratory evaluation may include measurement of LH and FSH levels (if bone age is > 12 years) with elevated gonadotropins indicating primary hypogonadism or testicular failure. Low gonadotropins are not specific but may suggest the possibility of central hypogonadism and further evaluation look for pituitary hormone deficiencies, chronic disease, undernutrition, hyperprolactinemia, or CNS abnormalities. Inhibin B is sometimes useful in differentiating between constitutional delay (normal concentrations) and idiopathic hypogonadotropic hypogonadism (lower concentrations), although there can be significant overlap in these conditions.

Treatment

Boys with delayed puberty who are troubled by their stature and/or prepubertal appearance may be offered a 4- to 6-month course of low-dose depot testosterone (50–100 mg/mo given intramuscularly) to promote virilization and possibly “jump-start” their endogenous development. In adolescent boys with permanent hypogonadism, testosterone treatment will need to be gradually increased over 3–4 years to adult dosing. Topical testosterone gel applied daily is an alternative to injections but often is too potent in commercially available concentrations to use in early puberty. Other formulations of testosterone are not widely used in adolescents.

3. Cryptorchidism

Cryptorchidism (undescended testis) affects 2%–4% of full-term male newborns and up to 30% of premature infants. Cryptorchidism can occur in an isolated fashion or associated with other findings. Often the cause is unknown, however abnormalities in the hypothalamic-pituitary-gonadal axis, intrinsic testicular development defects, and androgen biosynthesis or receptor defects can result in cryptorchidism.

Infertility and testicular malignancy are major risks of untreated cryptorchidism. Histologic changes occur as early as age 6 months in children with undescended testes. Fertility is impaired by approximately 33% and 66% after unilateral and bilateral cryptorchidism, respectively. The cancer risk for adults after cryptorchidism in childhood is reported to be 5–10 times greater than normal. After 6 months of age, spontaneous descent occurs only very rarely. Consequently, intervention is typically considered beginning at this time.

Clinical Findings

Exam should focus on whether testes can be palpated in the scrotum or inguinal canal, appearance of the genitalia, and any midline defects. To prevent retraction of the testis during exam, two hands are required. One hand milks the testes from the deep inguinal ring to the scrotum. The second hand lies over the scrotum to hold the testis. Examination in the squatting position for older children or in a warm bath can be helpful. Ultrasonography, CT, and MRI may detect testes in the inguinal region, but these studies are not completely reliable in finding abdominal testes.

In the mini-puberty period of infancy between 1 and 4 months of age, measurement of LH, FSH, and testosterone can assess the HPG axis. After this time, inhibin B and/or an HCG stimulation test can be done to confirm the presence or absence of functional abdominal testes.

Differential Diagnosis

Various disorders of sexual development can present with cryptorchidism. A karyotype can identify a virilized 46,XX individual (CAH), mixed gonadal dysgenesis (45,X/46,XY), and 47,XXY/Klinefelter syndrome, all of which can be associated with unilateral or bilateral cryptorchidism. The diagnosis of bilateral cryptorchidism in an apparently normal male newborn should never be made until the possibility that the child is a fully virilized female with potentially fatal salt-losing CAH has been considered.

Treatment

Surgical orchidopexy should be performed if descent has not occurred by 6–12 months of age. The recommended timing of surgical intervention is based on the assumption that early surgery will allow normal germ cell development and decrease the risk for future infertility and cancer. However, in some cases, a primary abnormality of the testis may be responsible for both the undescent and future risks. Therapy with HCG 250–1000 IU twice weekly for 5 weeks has been used to induce descent of the testis but has a low success rate.

4. Gynecomastia

Gynecomastia is a common, self-limited condition that occurs in up to 75% of normal pubertal boys. Adolescent gynecomastia typically resolves within 2 years but may not totally resolve if the degree of gynecomastia is extreme (> 2 cm of tissue). Gynecomastia is more common in obese boys, possibly due to adipose aromatization of testosterone to estrogen. Gynecomastia may also occur in male hypogonadism, such as Klinefelter syndrome, and as a side effect of some medications. Medical therapy using antiestrogens and/or aromatase inhibitors may be beneficial if initiated early when there is active stimulation of the mammary glands, but given most pubertal gynecomastia will self-resolve pharmacologic management is rarely pursued. Surgical intervention should be considered for prolonged and/or severe cases (see Chapter 4).

The adult adrenal cortex consists of three zones responsible for synthesis of different steroids from the precursor, cholesterol (see Figure 34–8):

• Outermost zona glomerulosa—aldosterone.

• Middle zona fasciculata—cortisol and small amounts of mineralocorticoids.

• Innermost zona reticularis—androgens.

The predominant regulator of mineralocorticoid (primarily aldosterone) production and secretion is the volume- and sodium-sensitive renin-angiotensin-aldosterone system. Mineralocorticoids promote sodium retention and stimulate potassium excretion in the distal renal tubule.

Glucocorticoid production, primarily cortisol, is under the control of pituitary adrenocorticotropic hormone (ACTH; see Figure 34–1 and Table 34–1), which is in turn regulated by hypothalamic corticotropin-releasing hormone (CRH). ACTH concentration is greatest during the early morning hours with a smaller peak in the late afternoon and a nadir at night. The pattern of serum cortisol concentration follows this pattern with a lag of a few hours. In the absence of cortisol feedback, there is dramatic CRH and ACTH hypersecretion.

Glucocorticoids are critical for gene expression in a many cell types. Glucocorticoids also help maintain blood pressure by promoting peripheral vascular tone and sodium and water retention. In excess, glucocorticoids are both catabolic and antianabolic; they promote the release of amino acids from muscle and increase gluconeogenesis while decreasing incorporation of amino acids into muscle protein. They also antagonize insulin activity and facilitate lipolysis.

At the onset of puberty, production of androgens (dehydroepiandrosterone and androstenedione) increases and is an important contributor to pubertal development in both sexes. The adrenal gland is the major source of androgen in females.

ADRENOCORTICAL INSUFFICIENCY

Adrenal insufficiency may be primary—due to disorders of the adrenal gland itself, or central/secondary—due to disorders of CRH and/or ACTH secretion. Primary adrenal insufficiency impairs the production of all adrenal steroids, whereas secondary adrenal insufficiency should not affect production of mineralocorticoids or androgens as these are not regulated by ACTH. The causes of primary and secondary adrenal insufficiency are listed in Table 34–10.

Secondary adrenal insufficiency may be isolated ACTH deficiency or combined with other pituitary hormone deficiencies.

Clinical Findings

A. Symptoms and Signs

1. Acute form (adrenal crisis)

Nausea, vomiting, abdominal pain; dehydration; fever (sometimes followed by hypothermia); weakness; hypoglycemia; hypotension and circulatory collapse; confusion and coma. Hyponatremia and hyperkalemia are seen in primary adrenal insufficiency. Acute illness, surgery, trauma, or hyperthermia may precipitate an adrenal crisis in patients with adrenal insufficiency.

2. Chronic form

Fatigue, hypotension, weakness, weight loss or failure to gain weight, vomiting and dehydration, recurrent hypoglycemia. In primary adrenal insufficiency, salt craving and hyponatremia and/or hyperkalemia can be seen. Diffuse tanning occurs with increased pigmentation over pressure points, scars, and mucous membranes in primary adrenal insufficiency due to melanocyte-stimulating activity of alternate products of hypersecreted pro-opiomelanocortin, the parent molecule of ACTH.

B. Laboratory Findings

1. Suggestive of adrenocortical insufficiency

• Primary adrenal insufficiency

  • Decreased—serum sodium, serum bicarbonate, serum glucose, blood pH, and blood volume.

  • Increased—serum potassium, urea nitrogen levels.

  • Urinary sodium and the ratio of urinary sodium to potassium inappropriate for the degree of hyponatremia.

• Central adrenal insufficiency—serum sodium levels may be mildly decreased as a result of impaired water excretion but true salt-wasting is not present (mineralocorticoid function should remain intact).

• Eosinophilia and moderate lymphopenia occur in both forms of insufficiency.

2. Confirmatory tests

• Primary adrenal insufficiency—plasma cortisol less than 18 mcg/dL 30 and 60 minutes after 250 mcg of cosyntropin (high-dose stimulation test) given intravenously and failure of aldosterone to rise above baseline

• Central adrenal insufficiency—plasma cortisol less than 18 mcg/dL 30 and 60 minutes after 1 mcg of cosyntropin given intravenously (low-dose stimulation)

Elevated in primary adrenal failure and low/low-normal in central adrenal insufficiency

Decreased

After administration of ovine CRH, serum concentrations of ACTH and cortisol are measured. Localization of the site of impairment is possible based on careful interpretation of results. The CRH test has not been widely used in pediatrics.

Differential Diagnosis

Acute adrenal insufficiency must be differentiated from sepsis, diabetic coma, CNS disturbances, dehydration and acute poisoning. In the neonatal period, adrenal insufficiency may be clinically indistinguishable from respiratory distress, intracranial hemorrhage, or sepsis. Chronic adrenocortical insufficiency must be differentiated from anorexia nervosa, depression, certain muscular disorders (myasthenia gravis), salt-losing nephropathy, and chronic debilitating infections.

Treatment

A. Acute Insufficiency (Adrenal Crisis)

1. Hydrocortisone sodium succinate

Hydrocortisone sodium succinate (50 mg/m² intravenously over 2–5 minutes or intramuscularly) is given initially followed by 12.5 mg/m², every 4–6 hours until stabilization is achieved and oral therapy can be tolerated. Cortisol replacement is critical because pressor agents may be ineffective with cortisol insufficiency.

2. Fluids and electrolytes

In primary adrenal insufficiency, 5%–10% glucose in normal saline, 10–20 mL/kg intravenously, is given over the first hour and repeated if necessary to reestablish vascular volume. Normal saline is continued thereafter at 1.5–2 times maintenance fluid requirements until volume and electrolytes have normalized. In central adrenal insufficiency, routine fluid management is generally adequate after initial restoration of vascular volume and institution of cortisol replacement.

3. Fludrocortisone

Treatment with fludrocortisone, a mineralocorticoid agonist, is not required acutely, as hydrocortisone in stress doses has adequate mineralocorticoid action. When oral intake is tolerated, fludrocortisone, is started, 0.05–0.15 mg daily, and continued every 12–24 hours for primary adrenal insufficiency.

B. Maintenance Therapy

1. Glucocorticoids

A maintenance dosage of 6–10 mg/m²/day of hydrocortisone (or equivalent) is given orally in two or three divided doses. To prevent acute adrenal crises, the dosage of all glucocorticoids is increased to 30–50 mg/m²/day during intercurrent illnesses or other times of stress (fever > 101.5°F, trauma, surgery, or systemic illness) and should also be increased during significant diarrhea due to reduced absorption. Families should be encouraged to give stress doses of hydrocortisone if they have concerns, as brief exposure to stress doses of hydrocortisone will not have adverse effects. Rarely, families become overly anxious and give stress doses frequently. This should be avoided as it can contribute to obesity, growth retardation, and other cushingoid features.

2. Mineralocorticoids

In primary adrenal insufficiency, fludrocortisone is given, 0.05–0.15 mg orally daily as a single dose or in two divided doses. Periodic monitoring of blood pressure is recommended to avoid overdosing.

3. Salt

Children should be given ready access to table salt. In the infant, supplementation of breast milk or formula with 3–5 mEq Na⁺/kg/day is generally required until table foods are introduced.

Course & Prognosis

If treated appropriately, the prognosis of adrenal insufficiency is good however spontaneous recovery is unlikely unless the etiology was transient (exogenous glucocorticoid exposure, eg). If adrenal crisis is not recognized and promptly treated with pharmacologic glucocorticoids, the course of acute adrenal insufficiency is rapid and death may occur within a few hours, particularly in infants. Regular care with an endocrinologist is required to evaluate management and adjust dosing to ensure adequate replacement while avoiding overdosing that could lead to impaired growth, hypertension, and Cushingoid features.

CONGENITAL ADRENAL HYPERPLASIAS

General Considerations

Autosomal recessive mutations in the enzymes of adrenal steroidogenesis cause impaired cortisol biosynthesis with increased ACTH secretion. ACTH excess subsequently results in adrenal hyperplasia with increased production of adrenal hormone precursors that are metabolized through the unblocked androgen pathway. Increased pigmentation, especially of the scrotum, labia majora, and nipples, is common due to excessive ACTH secretion. CAH is most commonly (> 90% of patients) the result of homozygous or compound heterozygous mutations in the cytochrome P-450 C21 (CYP21A2) gene causing 21-hydroxylase deficiency (see Figure 34–8). The defective gene is present in 1:250–1:100 people and the worldwide incidence of the disorder is 1:15,000, with increased incidence in certain ethnic groups. In its severe form, excess adrenal androgen production starting in the first trimester of fetal development causes virilization of the female fetus and life-threatening hypovolemic, hyponatremic shock (adrenal crisis) in the newborn, if untreated. There are also other enzyme defects that less commonly result in CAH. The clinical syndromes associated with these defects are shown in Figure 34–8 and Table 34–11.

Prenatal diagnosis is now possible and newborn screening by measurement of serum 17-hydroxyprogesterone has been established in all 50 US states and many other countries worldwide.

In nonclassic presentations of 21-hydroxylase deficiency, affected individuals have a normal phenotype at birth but develop virilization during later childhood, adolescence, or early adulthood. Hormonal studies are characteristic of 21-hydroxylase deficiency, with cosyntropin stimulated 17-OHP levels intermediate between those of nonaffected individuals and those with the classic form of the disease. Individuals with the nonclassic form of the disease may be asymptomatic or only mildly symptomatic, but they can carry a severe CYP21A2 mutation resulting in offspring with the classic form.

Clinical Findings in 21-Hydroxylase Deficiency

A. Symptoms and Signs

1. In females

Abnormality of the external genitalia varies from mild enlargement of the clitoris to complete fusion of the labioscrotal folds, forming an empty scrotum, a penile urethra, a penile shaft, and clitoral enlargement sufficient to form a normal-sized glans (see Figure 34–7). Signs of adrenal insufficiency (salt loss) typically appear 5–14 days after birth. With milder enzyme defects, clinically apparent salt loss may not occur and virilization predominates with accelerated growth and skeletal maturation. Pubic hair appears early, acne may be excessive, and the voice may deepen. Excessive pigmentation may develop. Isosexual central precocious puberty may occur if treatment is not initiated before the bone age is significantly advanced. Final adult height is often compromised.

2. In males

The male infant usually appears normal at birth but may present with salt-losing crisis in the first weeks of life if treatment is not initiated. In milder forms, salt-losing crises may not occur and virilization predominates, with enlargement of the penis and increased pigmentation, as well as other symptoms and signs similar to those of affected females. The testes are not enlarged unless there are rare adrenal rests in the testes producing asymmetrical enlargement. In some rare enzyme defects, ambiguous genitalia may be present due to impaired androgen production (see Table 34–11).

B. Laboratory Findings

1. Blood

Hormonal studies are essential for accurate diagnosis. Findings characteristic of the enzyme deficiencies are shown in Table 34–11.

2. Genetic studies

Rapid assessment of genetic sex should be obtained in any newborn with ambiguous genitalia since 21-hydroxylase deficiency is the most common cause of ambiguity in females.

C. Imaging

Imaging is generally not required to make the diagnosis of CAH. Ultrasonography, CT scanning, and MRI may be useful in defining pelvic anatomy or to exclude an adrenal tumor.

Treatment

A. Medical Treatment

Treatment goals in CAH are to provide the smallest dose of glucocorticoid that will adequately suppress excess androgen precursors and produce normalization of growth velocity and skeletal maturation; excessive glucocorticoids cause the undesirable side effects of Cushing syndrome. Mineralocorticoid replacement sustains normal electrolyte homeostasis, but excessive mineralocorticoids cause hypertension and hypokalemia.

1. Glucocorticoids

Supraphysiologic doses of hydrocortisone are often needed to suppress androgen excess in CAH. Initially, parenteral or oral hydrocortisone (30–50 mg/m²/day) is provided until suppression of abnormal adrenal steroidogenesis has been accomplished, as evidenced by normalization of serum 17-hydroxyprogesterone. Subsequently, patients are placed on maintenance doses of 10–15 mg/m²/day in three divided doses. Dosage is adjusted to maintain normal growth rate and skeletal maturation. Serum 17-hydroxyprogesterone and androstenedione are usually used to monitor therapy; however, no one test is universally accepted.

2. Mineralocorticoids

Fludrocortisone, 0.05–0.15 mg/day, is given orally once a day or in two divided doses. Periodic monitoring of blood pressure and plasma renin activity are recommended to avoid overdosing.

B. Surgical Treatment

For affected females, consultation with a urologist or gynecologist experienced in female genital reconstruction should be arranged as soon as possible during infancy.

Course & Prognosis

When initiated in early infancy, treatment with glucocorticoids permits normal growth, development, and sexual maturation. If not adequately controlled, CAH results in sexual precocity and masculinization throughout childhood. Affected individuals will be tall as children but short as adults because of rapid skeletal maturation and premature closure of the epiphyses. If treatment is delayed or inadequate, true central precocious puberty may occur in males and females.

Patient education stressing lifelong therapy is important to ensure compliance in adolescence and later life. Virilization and multiple surgical genital reconstructions may be associated with risk of psychosexual disturbances in female patients and ongoing psychological evaluation and support is a critical component of care.

ADRENOCORTICAL HYPERFUNCTION

General Considerations

Cushing syndrome may result from excessive autonomous secretion of adrenal steroids (adrenal adenoma or carcinoma), excess pituitary ACTH secretion (Cushing disease), ectopic ACTH or CRH secretion, or chronic exposure to exogenous glucocorticoids. In children younger than 12 years, Cushing syndrome is usually iatrogenic. It is less commonly due to adrenal tumor, adrenal hyperplasia, pituitary adenoma, or extrapituitary ACTH-producing tumor.

Clinical Findings

A. Symptoms and Signs

1. Excess glucocorticoid

Adiposity, most marked on the face, neck, and trunk—a fat pad (buffalo hump) in the interscapular area is characteristic but not diagnostic; fatigue; plethoric facies; purplish striae; easy bruising; osteoporosis and back pain; hypertension and glucose intolerance; proximal muscle wasting and weakness; retardation of growth and skeletal maturation.

2. Excess mineralocorticoid

Hypokalemia and mild hypernatremia, increased blood volume, edema, hypertension.

3. Excess androgen

Hirsutism, acne, virilization, and menstrual irregularities.

B. Diagnosis of Cushing Syndrome

1. Salivary cortisol

elevated salivary cortisol obtained at midnight is a noninvasive and highly specific and sensitive test for hypercortisolism.

2. 24-Hour urinary-free cortisol excretion

elevated 24-hour urinary free cortisol/creatinine suggests Cushing Syndrome.

3. Low-dose (15 mcg/kg) dexamethasone suppression test

dexamethasone (15mcg/kg, max 1mg) is given at midnight followed by measurement of fasting plasma cortisol and ACTH at 8 AM the following morning. Failure to suppress cortisol < 1.8 ug/dL suggests Cushing Syndrome.

C. Establishing the Cause of Cushing Syndrome

1. ACTH concentration

decreased ACTH values (< 5pg/mL) suggest an adrenal cause. Intermediate ACTH values (5–29 pg/mL) are indeterminant and warrant further investigation. Elevated ACTH values (> 29 pg/mL) suggest an ACTH-dependent (pituitary or ectopic) cause. ACTH.

2. High-dose (8 mg) dexamethasone testing

high-dose dexamethasone testing may help to determine ACTH-dependent Cushing syndrome from ACTH-independent Cushing syndrome.

D. Imaging

Pituitary imaging may demonstrate a pituitary adenoma. Adrenal imaging by CT scan may demonstrate adenoma or bilateral hyperplasia. MRI and nuclear medicine studies of the adrenals may be useful in complex cases. Skeletal maturation is usually delayed.

Differential Diagnosis

Children with exogenous obesity accompanied by striae and hypertension are often suspected of having Cushing syndrome. However, children with Cushing syndrome have a poor growth velocity, relatively short stature, and delayed skeletal maturation, while those with exogenous obesity usually have a normal or slightly increased growth velocity, normal to tall stature, and advanced skeletal maturation. The color of the striae (purplish in Cushing syndrome, pink in obesity) and the distribution of the obesity may assist in differentiation. The urinary-free cortisol excretion (in milligrams per gram of creatinine) may be mildly elevated in obesity, but midnight salivary cortisol is normal and cortisol secretion is suppressed by low-dose dexamethasone suppression test.

Treatment

In all cases of primary adrenal hyperfunction due to tumor, surgical removal is indicated if possible. Glucocorticoids should be administered parenterally in pharmacologic doses during and after surgery until the patient is stable. Supplemental oral glucocorticoids, potassium, salt, and mineralocorticoids may be necessary until the suppressed contralateral adrenal gland recovers, sometimes over a period of several months. Similarly, pituitary adenomas and ectopic sources of ACTH or CRH are generally treated surgically. Recurrent adenomas may respond to irradiation.

PRIMARY HYPERALDOSTERONISM

Primary hyperaldosteronism may be caused by an adrenal adenoma or adrenal hyperplasia. It is characterized by paresthesias, tetany, weakness, periodic paralysis; nocturnal enuresis; hypokalemia, hypernatremia, metabolic alkalosis; hypertension; glucose intolerance; elevated plasma and urinary aldosterone; and suppressed plasma renin activity.

Primary hyperaldosteronism is rare in pediatrics. However, there are three recognized genetic causes (types I–III). Type I (glucocorticoid remediable hyperaldosteronism) is due to a hybrid of the genes encoding 11β-hydroxylase and aldosterone synthase. Type III results from mutations in the KCNJ5 gene encoding a K⁺ channel. Somatic mutations of this gene are also seen in later onset hyperaldosteronism. The cause for type II is unknown.

Treatment is with glucocorticoids (type I), spironolactone (type II), or subtotal or total adrenalectomy for hyperplasia or tumor.

USES OF GLUCOCORTICOIDS & ADRENOCORTICOTROPIC HORMONE IN TREATMENT OF NONENDOCRINE DISEASES

Glucocorticoids are used for their anti-inflammatory and immunosuppressive properties in a variety of conditions in childhood. Pharmacologic doses are necessary to achieve these effects, and side effects are common. Numerous synthetic preparations possessing variable ratios of glucocorticoid to mineralocorticoid activity are available (Table 34–12).

When prolonged use of pharmacologic doses of glucocorticoids is necessary, clinical manifestations of Cushing syndrome are common. Side effects may occur with the use of synthetic exogenous agents by any route, including inhalation and topical administration, or with the use of ACTH. Alternate-day therapy lessens the incidence and severity of some of the side effects (Table 34–13).

Tapering of Pharmacologic Doses of Steroids

Prolonged use of pharmacologic doses of glucocorticoids causes suppression of ACTH secretion and consequent adrenal atrophy; the abrupt discontinuation of glucocorticoids may result in adrenal insufficiency. ACTH secretion generally does not restart until the administered steroid has been given in subphysiologic doses (< 6 mg/m²/day orally) for several weeks.

If pharmacologic glucocorticoid therapy has been given for less than 10–14 days, the drug can be discontinued abruptly because adrenal suppression will be short-lived. However, it is advisable to educate the patient and family about the signs and symptoms of adrenal insufficiency in case problems arise.

If tapering is not required for the underlying disease, the dosage can be safely decreased to the physiologic range. Although a rapid decrease in dose to the physiologic range will not lead to frank adrenal insufficiency (because adequate exogenous cortisol is being provided), some patients may experience a steroid withdrawal syndrome, characterized by malaise, insomnia, fatigue, and loss of appetite. These symptoms may necessitate a two- or three-step decrease in dose to the physiologic range.

Once a physiologic equivalent dose (8–10 mg/m²/day hydrocortisone or equivalent) is achieved and the patient’s underlying disease is stable, the dose can continue to be tapered. There is no clinical evidence to support any particular regimen of glucocorticoid tapering. Patient age, frailty, concomitant illness, and duration of glucocorticoid should all be taken into account when creating a taper regimen. If patients become symptomatic during the taper, the dose should be increased back to the last asymptomatic dose and maintain that dose for two to four weeks. Then the taper can continue.

It is advisable to continue giving stress doses of glucocorticoids when appropriate until recovery of the response to stress has been documented. After basal physiologic adrenal function returns, the adrenal reserve or capacity to respond to stress and infection can be estimated by the low-dose ACTH stimulation test, in which 1 mcg of synthetic ACTH (cosyntropin) is administered intravenously. Plasma cortisol is measured 30 and 60 minutes after the infusion. A plasma cortisol concentration greater than 18 mg/dL indicates a satisfactory adrenal reserve. Even if the results of testing are normal, careful monitoring and the use of stress doses of glucocorticoids should be considered during severe illnesses and surgery.

ADRENAL MEDULLA PHEOCHROMOCYTOMA

Pheochromocytoma is an uncommon tumor, but up to 10% of reported cases occur in pediatric patients. The tumor can be located wherever chromaffin tissue (adrenal medulla, sympathetic ganglia, or carotid body) is present. It may be multiple, recurrent, and sometimes malignant. Familial forms include pheochromocytomas associated with the dominantly inherited neurofibromatosis type 1, MEN type 2, and von Hippel-Lindau syndromes, as well as mutations of the succinate dehydrogenase genes. Neuroblastomas, ganglioneuromas, and other neural crest tumors, as well as carcinoid tumors, may secrete pressor amines and mimic pheochromocytoma.

The symptoms of pheochromocytoma are caused by excessive secretion of epinephrine or norepinephrine: headache; sweating; tachycardia, hypertension, vasomotor instability (flushing and postural hypotension); anxiety; dizziness, weakness; nausea, vomiting, diarrhea; dilated pupils, blurred vision; abdominal and precordial pain.

Laboratory diagnosis is possible in more than 90% of cases. Serum and urine catecholamines are elevated, but abnormalities may be limited to periods of symptomatology or paroxysm. Plasma-free metanephrine is the most sensitive and specific test, though phenoxybenzamine, tricyclic antidepressants, and β-adrenoreceptor blockers can cause false-positive results. A level three times the normal range is diagnostic. Intermediate values may require additional testing with serum and urine catecholamines. After demonstrating a tumor biochemically, imaging methods including CT or MRI are used to localize the tumor and nuclear medicine using functional ligands such as (123)I-MIBG, [¹⁸F]DA positron emission tomography scanning, and somatostatin receptor scintigraphy (with either [¹²³I]Tyr3-octreotide or [¹¹¹In] DTPA-octreotide) are useful in further diagnostic evaluation.

Laparoscopic tumor removal is the treatment of choice; however, the procedure must be undertaken with great caution and with the patient properly stabilized. Oral phenoxybenzamine or intravenous phentolamine is used preoperatively. Profound hypotension may occur as the tumor is removed but may be controlled with an infusion of norepinephrine, which may have to be continued for 1–2 days.

Unless irreversible secondary vascular changes have occurred, complete relief of symptoms is to be expected after recovery from removal of a benign tumor. However, prognosis is poor in patients with metastases, which occur more commonly with large, extra-adrenal pheochromocytomas.