++
The best estimate of incidence of GHD in the US population is
often cited as being about 1:3480. However, acquired, idiopathic,
isolated GHD may be overdiagnosed. Growth hormone (GH)-treated patients
with GHD (as defined by a stimulated GH level of < 10 ng/mL)
account for about 60% of all treated patients of whom 78% have “idiopathic” GHD and
22% have “acquired” or “organic” (neoplasms,
trauma, inflammation, miscellaneous) causes of GHD.
++
Around 300 patients with inherited abnormalities of the GH receptor
have been identified. Potentially, a larger group of individuals
with heterozygous abnormalities of the GH receptor will be added
to this group with abnormalities such as defects of GH receptor
signaling (JAK-STAT) and defects of the insulin-like growth factor
I (IGF-I) gene.
+++
Differential Diagnosis
of Growth Hormone Deficiency (Hypopituitarism)
++
The causes of hypopituitarism include disorders of the pituitary
gland and hypothalamic disorders that impair the release of growth
hormone-releasing hormone (GHRH), as listed in Table
523-1.
++
+++
Hypothalamic
Dysfunction
++
Idiopathic hypopituitarism with growth failure
due to growth hormone deficiency (GHD) may appear at the end of
the first year after birth. This disorder has been postulated to
be due to brith complications because as many as 70% of children
with idiopathic hypopituitarism have histories of some form of perinatal
insult, such as hypoxia from maternal bleeding, breech delivery,
or asphyxia during the birth process. However, in at least 30% of
these patients, abnormalities of the pituitary stalk, an ectopic
posterior pituitary gland, or anterior pituitary hypoplasia are
demonstrated with imaging studies. Therefore, it seems more likely
that the perinatal difficulties in GHD children are a consequence,
rather than a cause, of the hypopituitarism. These children are
able to secrete growth hormone (GH) in response to the injection
of growth hormone-releasing hormone (GHRH), and can secrete thyroid-stimulating
hormone (TSH) in response to thyrotropin-releasing hormone (TRH).
Deficiency of GH may also be associated with a variety of midline
central nervous system and facial developmental defects, including
holoprosencephaly, cleft lip, and cleft palate. Hypopituitarism
also can occur in association with hypotelorism or single upper
central incisor.
++
Septooptic dysplasia is a form of midfacial
central nervous system hypoplasia in which GH deficiency and other
pituitary hormone deficiencies are associated with small optic disc,
nystagmus, blindness, and often absence or underdevelopment of the septum pellucidum. There is an increased
incidence in offspring of young mothers, in first-born children,
in areas of high unemployment, and in babies exposed to intrauterine
medications, smoking, alcohol, and diabetes. Mutations of HESX1,
a paired-like homeodomain gene expressed early in pituitary and
forebrain development, are associated with familial forms of septooptic
dysplasia.
+++
Genetic Causes
of Growth Hormone Deficiency
++
Inherited genetic defects are associated with growth hormone
deficiency (GHD) and hypopituitarism (Table 523-2);
as many as 3% to 30% of children with GHD have
an affected parent, sibling, or child. A variety of coding defects
for transcription factors led to a failure of development of the
pituitary cells.
++
++
Abnormalities of human PROP1 result in multiple
pituitary hormone deficiencies (MPHDs), characterized by variable
and often age-dependent degrees of deficiency of growth hormone
(GH), prolactin, thyroid-stimulating hormone (TSH), follicle-stimulating
hormone (FSH), leuteinizing hormone (LH), and, occasionally, adrenocorticotrophic
hormone (ACTH). Gonadotropin abnormalities are particularly variable
such that approximately 30% of patients have spontaneous
pubertal development, including menarche, before ultimately developing
hypogonadotropic hypogonadism. Pituitary size varies among patients
and through life so that it may be very large and then involute
leaving an empty sella. ACTH deficiency may not develop until the
fourth or fifth decade of life. Multiple PROP1 (chromosome
5q35, OMIM601538) abnormalities have been identified and include
missense, frameshift, and splicing mutations. There does not appear
to be strong correlation between phenotype and genotype. Large-scale screening
of patients with MPHDs has found 54% with PROP1 mutations,
but there appears to be substantial geographic variation in associated
genetic defects.
++
Specific mutations, especially deletions, in the gene encoding
GH, some with abnormalities that produce a bioinactive GH, have
been described. No examples of mutations of the gene encoding growth
hormone-releasing hormone (GHRH) have been identified, but multiple
kindreds with homozygous mutations of the GHRH-receptor gene have
been identified; these patients have marked short stature, but lack
other features of GHD, such as microphallus, truncal obesity, and
hypoglycemia.
++
There are as many as 4000 pediatric cancer survivors who have
growth hormone deficiency (GHD) resulting from a broad range of
cancer treatments. Following cranial irradiation, GHD may evolve
over years; thus, diagnosis may require serial testing. Some patients
with auxology suggestive of GHD may have insulin-like growth factor
I (IGF-I) and/or insulin-like growth factor binding protein
3 (IGFBP-3) levels below the normal range on repeated tests, but
growth hormone (GH) responses in provocation tests remain above
the “cut-off” level. Such children do not have
classical GHD, but nonetheless may have an abnormality of the GH/IGF
axis and may benefit from GH treatment.
++
Radiation may impair both hypothalamic and pituitary function;
however, in the dosing range usually given to children with malignancy,
hypothalamic damage is more common. Low doses typically cause isolated
GHD, and higher doses may cause multiple pituitary deficiencies. The
majority of long-term survivors develop GHD with the adverse effect
of radiotherapy directly related to the biologically effective dose
to the hypothalamus. Within 5 years of radiation, nearly 100% of
children receiving Å 30 Gy over 3 weeks to the hypothalamic-pituitary
axis have subnormal GH responses to provocative tests, whereas GHD
may not become apparent for a decade or more after lower doses (18-24
Gy). Even when serum GH responses to provocative testing are normal,
spontaneous GH secretion may be blunted at x-ray doses as low as
18 to 24 GY.
++
Poor linear growth from decreased GH secretion may be exacerbated
by the impact of radiation itself, with inadequate pubertal acceleration of
spinal growth. Surprisingly, cranial radiation can also result in
precocious puberty, especially in children irradiated at young ages,
causing early epiphyseal fusion. Sexual precocity appears to occur
more frequently with low doses of radiation, and gonadotropin deficiency
is likely at high doses. Treatment with gonadotropin-releasing hormone
(GnRH) analogs may be necessary to suppress the hypothalamic-pituitary gonadal
axis in an attempt to attain normal final height.
++
Bone marrow transplantation (BMT) for patients with inborn errors
of metabolism, aplastic anemias, and malignancies requires preparative
regimens that include total lymphoid or total body radiation, often with
chemotherapy, and sometimes including cranial radiation. In children
who had cranial radiation followed by high-dose chemotherapy and
total body radiation as preparative regimens, growth failure is almost
inevitable 2 to 5 years after BMT.
++
Craniopharyngiomas are the most common neoplastic cause of pituitary
insufficiency in children. This tumor is a congenital malformation
present at birth and gradually grows over the ensuing years. About
75% of craniopharyngiomas arise in the suprasellar region,
the remainder resembling pituitary adenomas. Most often, symptoms
of headaches, vomiting, visual disturbances, symptoms of diabetes
insipidus, and a change in sensorium result from the central nervous
system involvement by the tumor. Fifty percent to 80% of
patients have abnormalities of at least one anterior pituitary hormone
at diagnosis. Many children or adolescents have evidence of growth
arrest that may have begun near infancy and/or pubertal
delay. If the tumor invades the hypothalamus, signs of impaired vegetative
function, including poikilothermia, hypersomnia, and obesity, can
occur. Because nearly 90% of patients have suprasellar
or intrasellar calcification, plain radiographs of the skull can
be useful in diagnosis. MRI is the most sensitive diagnostic technique,
allowing identification of cystic and solid components and delineation
of anatomic relationships necessary for a rational operative approach.
Surgical excision, when possible, is the preferred treatment. When
complete excision of the tumor is not possible, drainage of the
cyst followed by radiation therapy is recommended. Transsphenoidal
decompression of the cyst combined with radiation therapy is most
efficacious in the management of large craniopharyngioma. The metabolic
syndrome with evidence of insulin insensitivity and increased body
mass index (BMI) is common and a predictor of potential major long-term
morbidity. The long-term childhood and adolescent consequences of
craniopharyngioma are substantial with many quality of life issues exacerbating
the hypopituitarism. Hypothalamic gliomas, often associated with
neurofibromatosis, and germinomas can cause pituitary insufficiency
and many of the neurologic signs of craniopharyngioma. Microadenoma
of the pituitary can occur with Cushing syndrome (see Chapter 535) and can cause hypopituitarism by compressing adjacent
normal pituitary tissue. Following transsphenoidal resection, those
with a macroadenoma have about a 50% incidence of hypopituitarism,
whereas those with microadenomas have normal pituitary function;
long-term cure rates are 55% to 65% for both tumor
sizes.
+++
Other Acquired
Conditions
++
Decreased growth and impaired pubertal maturation may be seen
in up to 60% of children and adolescents who have suffered
mild to severe head injury. Growth hormone (GH)
secretory defects are seen in psychosocial dwarfism,
and extreme form of “failure to thrive” due to
emotional deprivation. After the children spend a brief period in
a supportive environment, pituitary function improves remarkably,
and linear growth is accelerated. Empty sella syndrome is
an uncommon disorder among children. It occurs when the diaphragma
sellae does not surround the pituitary stalk tightly. The result
is herniation of the arachnoid into the pituitary fossa and compression of
normal pituitary tissue onto the walls of the sella turcica. The
sella turcica can be expanded, and intrasellar hypodensity may be
apparent by CT. Many patients with empty sella syndrome have no
symptoms or signs of pituitary dysfunction but some do have associated
pituitary hypofunction. The prevalence of empty sella syndrome increases
among patients with pituitary adenoma. Localized (hypothalamus, pituitary)
or generalized proliferation of mononuclear macrophages (histiocytes)
characterizes Langerhans cell histiocytosis, a diverse disorder
occurring at all ages, with peak incidence at ages 1 to 4 years
(see Chapter 463). Approximately 50% to
75% of patients with one of these disorders, Hand-Schüller-Christian,
have diabetes insipidus, But growth hormone deficiency (GHD) is
rare.
+++
Clinical Presentation
++
The clinical presentation of hypopituitarism with growth hormone
deficiency (GHD) varies, depending on the age at presentation. Typical
features are shown in Table 523-3. In the
newborn, diagnosis can be challenging. The presence of micropenis in a male newborn should always lead
to an evaluation of the growth hormone (GH)/insulin-like
growth factor (IGF) axis. Head MRI is essential when the diagnosis
is suspected because it will identify developmental abnormalities
of the hypothalamic-pituitary area, and the results are available
sooner than other laboratory data. A GH level must be measured in
the presence of neonatal hypoglycemia occurring in the absence of
a metabolic disorder such as hyperammonemia or carnitine deficiency
syndromes (see Chapter 545). A level of less
than 20 ng/mL (in contrast to 10 ng/mL in older
children) in a polyclonal radioimmunoassay (RIA) suggests neonatal
GHD. An insulin-like growth factor binding protein 3 (IGFBP-3) level is
of value for the diagnosis of neonatal GHD, but insulin-like growth
factor I (IGF-I) levels are rarely helpful.
++
++
Most patients with idiopathic hypopituitarism without neonatal
findings manifest poor growth by the end of the first year of life.
Growth rates are slow during childhood, with rates of less than
3 to 4 cm/year being common. Onset of growth failure after
a period of normal growth suggests the presence of an intrasellar
or suprasellar tumor, or some other acquired defect. Among patients
with early-onset disease, episodes of hypoglycemia are common, usually
after periods of fasting, before breakfast, or during illnesses.
There is a 10% incidence of hypoglycemic seizures and a
20% incidence of hypoglycemia without clinical findings.
Children with hypopituitarism tend to be overweight for height and
have prominent subcutaneous deposits of abdominal fat (Fig.
523-1). Many affected patients do not undergo puberty at the
appropriate age because of concurrent gonadotropin deficiency. Because
adrenal secretion of mineralocorticoids is not dependent on pituitary
adrenocorticotrophic hormone (ACTH), children with hypopituitarism
rarely have an electrolyte imbalance. Most children show no clinical
signs of thyroid hormone deficiency, although serum thyroxine concentrations
may be less than normal. Diabetes insipidus is rare among patients
with idiopathic hypopituitarism. When present, it suggests the presence
of a tumor or another structural hypothalamic lesion (eg, septo-optic
dysplasia or infundibular dysgenesis).
++
+++
Treatment of Hypopituitarism
++
Therapy for hypopituitarism includes replacement of all deficient
hormones. Growth hormone (GH) therapy is described in detail later
in this chapter. Most children with hypopituitarism do not have
clinical hypothyroidism, but in those who do, growth responses may
be attenuated. Some, however, may have serum T4 concentrations less
than normal. Others may have a decline in serum T4 level once GH
therapy is started. This may attenuate the growth response. Replacement
doses of levothyroxine are indicated with the goal of achieving
free T4 levels in the upper part of the normal range. Clinical signs
of hypoadrenalism are uncommon among children with hypopituitarism,
so administration of glucocorticoids is not generally indicated
unless the patient has syncope, postural hypotension, attacks of
hypoglycemia, or laboratory evidence of pituitary-adrenal axis hypofunction.
Because glucocorticoid excess attenuates growth, the dose is usually
limited to 5 to 10 mg cortisol per square meter of body surface
area per day by mouth. Four to six times this dosage is needed during
periods of stress. Diabetes insipidus often occurs after operations
on the region of the pituitary gland and hypothalamus. Management
using desmopressin is discussed in Chapter 525.
Long-acting testosterone enanthate is administered intramuscularly
to boys with hypopituitarism who have no signs of puberty by 14
years of age; beginning with a dosage of 50 mg a month, the dosage
is gradually increased over several years to 200 mg every 2 weeks.
This androgen often markedly enhances the growth response to GH.
Girls who need estrogen replacement are given conjugated oral estrogens (0.3–0.6
mg daily) or transdermal estradiol (eg, Vivelle dots). After 9 to
12 months of continuous estrogen therapy, cycling with a synthetic
progestin is begun, and the dosage of estradiol is gradually increased.
+++
Treatment of
Growth Hormone Deficiency in Hypopituitarism
++
The growth response to growth hormone (GH) of children with hypopituitarism
is a function of the logarithm of the GH dose. The currently used
starting dose is 0.03 to 0.05 mg/kg/d given subcutaneously
on a daily basis, with the mean American dose being 0.3 mg/kg/week.
Children with growth hormone deficiency (GHD) typically increase
their growth rate from 3 to 4 cm/year before treatment
to a mean of 8.0 to 11.0 cm/year during the first year
of therapy. As treatment continues, growth rate declines somewhat,
so that after 3 to 4 years of therapy, it may be average for age
and maturational status. In general, children with the most profound GHD
respond best to GH.
++
The best results of treatment are achieved by children who are
treated earlier and never have the psychologic consequences of short
stature. Growth response is inversely correlated with age of treatment
onset. Short-term studies of patients treated prior to age 3 years
show marked early catch-up, with a mean height gain of 3 standard
deviation score (SDS) after 4 years of therapy, allowing most children
to reach the normal height range by mid-childhood. In a group of
25 children treated prior to 12 months of age, adult height also
matched the target height despite low dosage and less frequent administration.
Thus, although GH therapy is available, long-term studies still show
that most patients fail to reach their genetic target heights. Evaluation
of adult heights in 121 patients with childhood GHD treated in the
Genentech GH research trials indicates a mean adult height in both
male and female patients of –0.7 SDS, with 106 being within
2 SDS for normal adult Americans.1 Even in these
closely followed patients, however, a –0.4 to –0.6
SDS difference from mid-parental target height still occurred. The
achievement of the genetic target is possible, however, because
a Swedish subgroup (in the Kabi Pharmacia International Growth Study [KIGS] database)
of consistently treated patients reached a median final height SDS
of –0.32, which was equivalent to the mid-parental target height.
By multiple regression analysis, factors found to correlate with
enhanced adult height were baseline height; younger age at onset
of treatment; longer treatment duration, especially during prepubertal years;
and a greater growth velocity during the first year of treatment
(eFigs. 523.1 and 523.2).
Increased height velocity and subsequent superior adult height outcome,
although with considerable overlap, were demonstrated in children
with GHD with differing GH-receptor alleles. Although the development
of recombinant GH has solved the problem of supply experienced in
the pituitary GH era, delays in diagnosis and initiation of therapy
may still compromise adult height.
++
++
++
High-dose GH therapy during puberty has been used to increase
adult height of GH-deficient patients. GH secretion increases by
two- to fourfold during the pubertal growth spurt, with dramatic
concomitant increases in serum insulinlike growth factor I (IGF-I)
levels. Pubertal growth normally accounts for approximately 17% of
adult male height and 12% of adult female height. Administration
of substantial pubertal GH doses (0.1 vs. 0.043 mg/kg/d)
led to a 4.6 cm increase in near-final height without more rapid
acceleration of skeletal maturation.
++
The use of higher doses of GH, the ability to treat until growth
cessation, early initiation of treatment, progressive weight-related
dose increments with attention to compliance with daily administration,
and appropriate thyroid hormone and glucocorticoid replacement therapy
are important factors in these adult height outcomes. As final height
correlates with height at the onset of puberty in the GH-deficient patients,
every effort must be made to enhance growth velocity during prepuberty.
Attempts at modifying growth during pubertal years with robust GH
dosing, slowing the pubertal process with gonadotropin-releasing
hormone agonists, or blocking estrogen production with aromatase
inhibitors to slow skeletal maturation have had modest success,
but require further research prior to routine use.
++
Changes in levels of the GH-dependent peptides, IGF-I, and insulin-like
growth factor binding protein 3 (IGFBP-3), acid labile subunit (ALS)
as well as of leptin, correlate with growth responses. Measurement
of these may give added information on the growth-promoting and
fat-mobilizing actions of GH, as well as of the spectrum of childhood
responsivity to exogenous GH. Specifically, modifying the GH dose
based on frequent monitoring of IGF-I levels, combined with documentation
of the growth response, seems reasonable and may enhance growth
outcomes by greater individualization of the treatment program.
Safety monitoring should include 6 to 12 monthly assessment of IGF-I
and IGFBP-3 values, and perhaps annual measurement of fasting glucose/insulin
ratios.
++
If a child does not respond to GH therapy, the diagnosis of GHD
is reconsidered, and the possibility of a problem that impairs the
GH response is considered. A suboptimal response can be due to (1)
most important, by poor compliance; (2) improper preparation of
GH for administration or incorrect injection techniques; (3) subclinical hypothyroidism;
(4) coexisting systemic disease; (5) excessive glucocorticoid therapy;
(6) prior radiation of the spine; (7) epiphyseal fusion; and (8)
anti-GH antibodies. Although 10% to 20% of recipients
of recombinant GH develop anti-GH antibodies, growth attenuation
is rarely due to such antibodies. GH resistance syndromes involving
abnormalities of structure or function of the GH receptor exist
on an inherited or acquired basis and cause failure of IGF generation with
consequent growth impairment. The most common situation in which
GH-mediated IGF production is impaired is in malnutrition or chronic
illness. In these settings, although the anabolic actions of GH
may seem to have merit, the efficacy is extremely variable.
++
GH treatment of children has few side effects. Glucose intolerance
among treated patients is extremely rare. Concern had been raised
that GH treatment may predispose patients to leukemia, but no relation between
GH and leukemia has been established. Slipped capital femoral epiphysis,
pseudotumor cerebri, and gynecomastia are rare adverse effects of
GH treatment. The latter two are reversible with cessation of therapy
and then reinitiation of treatment with slowly progressive dosing.
+++
Growth Hormone Therapy
in Other Disorders
++
The US Food and Drug Administration currently approves growth
hormone (GH) treatment for children with Turner syndrome, chronic
renal insufficiency, short children who were babies with intrauterine growth
retardation, Prader-Willi syndrome, Noonan syndrome, and idiopathic
short stature. It is certainly apparent that many children do not
have the classic criteria of growth hormone deficiency (GHD), but they
and other specific groups may benefit from GH therapy of their extreme
short stature.
+++
Cranial Radiation/Chemotherapy
++
Children that underwent cranial radiation with documented GHD
and growth failure are candidates for exogenous GH treatment, there
is no evidence for enhanced relapses of the primary neoplasm in
patients treated with GH. Unfortunately, the response to GH is very
variable. Spinal growth impairment, inadequate or delayed treatment,
and sexual precocity may limit linear growth. Chemotherapy regimens
by themselves may impair final adult height, although not nearly
to the extent seen after radiation.
++
Although growth hormone (GH) secretion and serum insulin-like
growth factor I (IGF-I) and IGF-II levels usually are normal among
these children, serum level of insulin-like growth factor binding
proteins (IGFBPs) often are increased. Growth factor binding proteins (GFBPs)
inhibit the action of IGF and, in turn, growth. In nephrotic syndrome,
however, serum levels of IGF-I and IGFBP-3 are low because of urinary
losses. Chronic glucocorticoid therapy can exacerbates growth retardation
by diminishing GH release and blunting the action of IGF-I at growth
plates. GH treatment of children with renal failure is effective
in accelerating linear growth, likely by increasing the molar ratio
of IGF peptides to IGFBPs and thereby overcoming the inhibitory
action of IGFBPs.
+++
Children with
a History of Intrauterine Growth Retardation
++
Short children with a history of intrauterine growth retardation
(IUGR) who are very short during early to middle childhood years
are able to approximate the growth velocity of their peers with
administration of growth hormone (GH) therapy. However, many questions
regarding the long-term efficacy of GH therapy on final height remain.
Younger, smaller, and lighter children grow best, with the greatest catch-up
growth occurring during the prepubertal years. In a report from
a long-term Dutch small for gestational age (SGA) treatment trial (mean
duration of therapy being 8 years), mean height reached the parental
target, with 91% of children within the normal range. More
provocatively, intelligence quotient, behavior, and self-perception
scores increased significantly and approximated those of normal
Dutch children. The complexity of the metabolic derangements in
the SGA population demands that long-term follow-up of treated children
be undertaken to determine whether cardiovascular risk factors will
also appear despite their earlier thin habitus.
++
Growth hormone treatment increases growth, at least initially,
in patients with thalassemia. In a long study (average duration
59 months) starting with young (7.2 years) patients, an increased growth
velocity was maintained throughout the treatment period; when treatment
was initiated at an older age (13.6 years), however, final height
was not improved.
++
The growth hormone (GH)-insulin-like growth factor (IGF) axis
shows evidence for some degree of acquired GH insensitivity with
lowered mean IGF-I and elevated GH levels.2-14 Short-term
treatment of prepubertal children who have cystic fibrosis (CF)
with GH results in an anabolic effect, with greater growth velocity,
nitrogen retention, and increased protein and decreased fat stores.15-17 Pulmonary
function improved in most patients. A 4-year longitudinal study
using the National CF Foundation Registry found that improved nutrition
status and growth were associated with a slower age-related decrement
of pulmonary function.18 GH treatment may prove to have
a role in CF therapy.19-24
+++
Idiopathic Short
Stature
++
Controlled studies have demonstrated clear gains of height among
idiopathic short stature (ISS) children. A meta-analysis looking
at an aggregate group of 1089 children suggested efficacy of treatment.
Data from two large trials showed a cumulative gain of 7.3 cm in
the group treated with 0.37 mg/kg/week over the
placebo-treated children. Concerns had been raised that growth hormone
(GH) treatment might accelerate pubertal onset and progression,
resulting in failure to improve height standard deviation score
(SDS) for bone age, thereby offsetting the positive responses observed
during early years of GH treatment of ISS, but this has not been
observed. Taken together, these data show that GH treatment of prepubertal
children with ISS does increase growth velocity and final height.
In two recent studies of GH-treated ISS children, no evidence of
increased adverse events relative to other GH-treated groups was
noted. In view of the current limitations of diagnostic testing
to discriminate between GH deficiency and the less classical syndromes
of primary insulin-like growth factor (IGF) deficiency, it is likely
that some cases of “partial” GHD or GH insensitivity
may not be diagnosed using traditional criteria. Further therapeutic
trials of GH for ISS to adult height are required. Appropriate evaluation
should include thorough analysis of the GH-IGF axis (with growth
hormone-binding protein [GHBP] levels, serum IGF-I
and insulin-like growth factor binding protein 3 [IGFBP-3] concentrations,
and, in some cases, IGF responses to GH treatment), before labeling
a short child as “normal.” Proper assessment of pretreatment
growth velocity should be over a minimum of a 6-month period and
preferably for 12 months.
++
Decisions concerning therapy should be individualized, with careful
attention to the needs and expectations of the child and family.
In the otherwise normal child with severe short stature (at least
2.25 standard deviations [SDs] below the mean
for age) and a failure to show convincing evidence for spontaneous
catch-up growth, a trial of GH therapy should be
discussed with the patient and family. This discussion should include
an assessment of normal growth patterns, familial growth patterns,
and predicted pubertal and statural development. The inconveniences,
discomforts, and potential risks of GH treatment should be fully
described. It is the physician’s responsibility to ensure
that expectations of the child and the parents are realistic in regard
to short-term growth and ultimate height. Where appropriate, counseling
and psychologic support should be provided. If a trial of GH therapy
is desired, treatment should be for a minimum of 6 months with the
US Food and Drug Administration (FDA)-approved dosage of 0.37 mg/kg/week,
and therapy with GH should be continued beyond 6 months only if
growth is accelerated (defined as an increase in the height velocity
of at least 2 cm/year). Documentation of the efficacy of
treatment requires continuous monitoring, both in terms of growth
and in measurement of the GH-dependent peptides. Growth acceleration
with GH treatment does not relieve the physician of seeking an underlying
etiology for the child’s growth retardation. Appropriate
studies should be repeated, when indicated. Treatment must be carefully
monitored for side effects of GH treatment, and continued psychologic
support should be provided for the child and family. This includes
guiding the patient through puberty and providing posttreatment
follow-up.
++
The use of biosynthetic IGF-I for treatment of children with
ISS has been suggested, but should be viewed as experimental.