88: Common Multiple Congenital Anomaly Syndromes

A congenital anomaly is defined as a structural defect, present at birth and different from the norm. These anomalies can be further divided into major anomalies that require medical and surgical care (eg, congenital heart defect, cleft palate, meningomyelocele) and minor anomalies that do not have medical significance (eg, single palmar crease, epicanthal folds, fifth digit clinodactyly). Anomalies themselves can be classified based on the developmental process involved in their formation. Well-defined types of anomalies include malformations, deformations, disruptions, dysplasias, syndromes, associations, and sequences (Table 89–1). It is also important to understand that these may not be entirely mutually exclusive. Table 89–1 provides an overview of congenital anomalies that are associated with congenital heart disease, and Table 89–2 reviews the teratogens associated with some of these lesions.

Among newborns, ∼1–3% have more than one major congenital anomaly recognized at birth. These infants often have longer hospital stays and have increased mortality rates. Malformations can cause >20% of neonatal deaths.

In the management of multiple congenital anomaly (MCA) syndromes, the neonatologist must deal with complex clinical issues calling for a wide range of diagnostic skills. Without a correct diagnosis of MCA syndrome, many available forms of therapy go underused and others may be tried, although they will be relatively ineffective. Furthermore, unrealistic counseling may be given about prognosis and recurrence risk. Only a few common MCA syndromes are life-threatening in the neonatal period. It is important to note, however, that malformations are the most common cause of death at this critical point in the life span. Table 88–2 lists symptoms and signs that should alert the clinician to the possibility of cryptogenic malformations or disorders. Obviously, if overt malformations are present, an MCA syndrome will be immediately recognized and diagnostic efforts will shortly follow. However, if external features of the disorder are subtle or nonspecific and the usual procedures associated with intensive newborn support have been started, findings may go unrecognized early. Each manifestation listed in Table 88–2 is more common in infants with MCA syndromes. Underlying etiologies for MCA syndromes include chromosomal abnormalities, monogenic disorders, multifactorial disorders, and unknown. The diagnostic approach to MCA syndromes in neonates is no different from that in older children. Because so many of these children are intubated with multiple lines and tubes, detailed assessment of physical characteristics can be challenging. Clinical photographs are essential, especially when a clinical geneticist is not available locally. If specialists in these fields are not available, a telephone call to a university medical center for expert advice is often useful. If the infant is critically ill and suspicion for a MCA syndrome is present, looking for other major malformations is important (eg, echocardiogram, renal/abdominal ultrasound, brain imaging). The basis for diagnosis of an MCA syndrome in a neonate involves a combination of defining the physical manifestations and diagnostic genetic testing. Diagnostic problems can also occur because immediate efforts tend to emphasize therapy. Nevertheless, diagnosis will often facilitate or guide therapy more efficiently.

1. Comparative genomic hybridization (CGH) or chromosomal microarray analysis (CMA). A new but now well-established cytogenetic technique that can be used to detect chromosomal deletions or duplications. CGH/CMA is a fluorescent technique that compares a reference standard DNA to the patient's DNA. Depending on the laboratory and specific platform used, comparisons are made at hundreds to thousands of regions across the entire genome to assess for copy number differences between the 2 samples. CGH/CMA assesses for common microdeletion and microduplication regions, subtelomeric regions, and pericentromeric regions. This test is not only capable of diagnosing described chromosomal abnormalities, but it can also detect novel changes. Recently CGH/CMA testing has replaced high-resolution karyotyping as first-tier testing for infants with MCA.

2. High-resolution karyotype. This test typically involves the analysis of chromosomes obtained from white blood cells present in a peripheral blood sample and is unaffected by a red blood cell transfusion. This process can take up to 2 weeks for completion. Differences in chromosomal number, large chromosomal deletions or duplications, and translocations can be detected with this test. This test remains the standard for confirming a well-recognized clinical phenotype (eg, Down syndrome), but has been replaced by CGH/CMA as the first-line test for infants with MCA.

3. Fluorescent in situ hybridization (FISH). A cytogenetic technique in which a probe can be used to detect specific DNA sequences. FISH can be performed on preparations that require the culturing and synchronization of cells to detect small chromosomal or submicroscopic deletions. This process is faster than high-resolution karyotyping, but it still can take several days to weeks to complete. FISH also can be done on an interphase or unsynchronized sample. Typically interphase FISH is done to assess for forms of chromosomal aneuploidy. FISH probes can be used to assess for the copy number of a given chromosome. Most commercial laboratories offer a panel to assess for copies of chromosomes 13, 18, 21, X, and Y. This can be done on an interphase sample and a result given within 48 hours from reaching the laboratory. This test can be very important in trying quickly to confirm a diagnosis in a critically ill infant with trisomy 13, 18, or 21 or Turner syndrome. In addition to interphase FISH, a complete high-resolution karyotype must be done to assess for a possible translocation.

For MCA syndromes, counseling is complex and requires a great deal of sensitivity. First, it is important to have a secure diagnosis, if one is possible. The next step is to establish the parents' understanding of the entire situation and what they have been told by other professionals. Be sure you know what questions the parents want answers to before the factual counseling begins. Do not give excessive details relative to the facts and try to avoid specific predictions, particularly regarding timing and the presence or absence of certain problems relative to the future. Leave some degree of hope, but be honestly realistic, particularly if the parents clearly demand it. Assume frequent follow-up counseling sessions, and outline a long-term program for the child's care and evaluations. Recurrence risk figures and the availability of prenatal diagnosis for subsequent pregnancies are mandatory areas to cover. Remember: You may well view the child's problems much differently than the parents do. Consequently, work with the family from their perspective.

The most common MCA syndromes diagnosed in the neonatal period are chromosomal.

1. Trisomy 21 (Down syndrome)

   1. Incidence. Trisomy 21 is by far the most common MCA syndrome, occurring in about 1 in 650 live births.

   2. Neonatal mortality. Quite small and mostly due to severe cardiac anomalies or congenital leukemias.

   3. Physical findings. Findings include hypotonia, a poor or absent Moro reflex, flat facial profile, upslanting palpebral fissures, Brushfield spots, anomalous auricles, joint hyperextensibility, excess nuchal skin, fifth-digit brachydactyly/clinodactyly, and a single transverse palmar crease.

   4. Associated anomalies. Include congenital heart defects (∼50%), most commonly an atrioventricular canal defect or ventricular septal defect. Major gastrointestinal malformations include Hirschsprung disease, duodenal or esophageal atresia, imperforate anus, and renal and urinary tract anomalies.

2. Trisomy 18 (Edward syndrome)

   1. Incidence. Approximately 1 in 5000–7000 live births. There is a 4:1 female-to-male sex ratio.

   2. Neonatal mortality. Mean life expectancy is 48 days. More than 90% of infants die in the first 6 months. Survival beyond the first year is rare.

   3. Physical findings. Consist of prenatal and postnatal growth deficiency, decreased subcutaneous fat, initial hypotonia followed by hypertonia, microcephaly, dolichocephaly with a prominent occiput, micrognathia, malformed auricles, short sternum with widely spaced nipples, overlapping digits with hypoplastic nails, and clubbed or rocker-bottom feet.

   4. Associated anomalies. Congenital heart disease is typically present (95% incidence) and is usually complex. Less frequent anomalies include cryptorchidism, horseshoe kidney, and umbilical or inguinal hernia.

3. Trisomy 13 (Patau syndrome)

   1. Incidence. Approximately 1 in 12,000 live births.

   2. Neonatal mortality. Mean life expectancy of 130 days. Forty-five percent of infants die in the first month. Survival beyond the first year is rare.

   3. Physical findings. Consist of low birthweight, microcephaly with sloping forehead, scalp cutis aplasia, microphthalmia, cleft lip and palate, dysplastic ears, redundant nuchal skin, postaxial polydactyly, and overlapping and flexed fingers with hyperconvex nails.

   4. Associated anomalies. Congenital heart disease is typically present (95% incidence) and usually complex. Renal abnormalities are common and can include polycystic kidneys, hydronephrosis, hydroureters, or horseshoe kidney. Holoprosencephaly, cryptorchidism, a single umbilical artery, and inguinal or umbilical hernias are common.

4. Monosomy X (Turner syndrome)

   1. Incidence. Approximately 1 in 2500 live-born females.

   2. Neonatal mortality. Turner syndrome is usually compatible with survival if the child reaches term. Approximately 98–99% of Turner syndrome fetuses are spontaneously aborted.

   3. Physical findings. Consist of epicanthal folds, prominent ears, micrognathia, low posterior hairline, excess nuchal skin, webbed neck, broad chest with wide-spaced nipples, hypoplastic nails, peripheral lymphedema of the hands and feet, and pigmented nevi.

   4. Associated anomalies. Include congenital heart defects, typically a bicuspid aortic valve or aortic coarctation, horseshoe kidney, and gonadal dysgenesis.

5. 22q11.2 Deletion syndrome (DiGeorge syndrome, velocardiofacial syndrome). It is now understood that the phenotypes of DiGeorge syndrome (congenital heart disease, hypocalcemia, and immunodeficiency), velocardiofacial syndrome (velopharyngeal incompetence, congenital heart disease, and characteristic facial features), and conotruncal anomaly facial syndrome are all encompassed by and result from the chromosome 22q11.2 deletion.

   1. Incidence. Approximately 1 in 5000 live births.

   2. Neonatal mortality. Neonatal deaths occur in <10% of cases and are almost exclusively due to cardiac defects.

   3. Physical findings. Consist of a range of malformations including:

      1. Congenital heart disease (∼75%). Typically conotruncal malformations including tetralogy of Fallot, interrupted aortic arch, ventricular septal defects, or truncus arteriosus.

      2. Palatal abnormalities (∼70%). Typically velopharyngeal incompetence, submucosal cleft palate, and cleft palate.

      3. Immune function (∼75%). Typically immunodeficiency occurs as a result of thymic hypoplasia and secondary T-cell abnormalities.

      4. Craniofacial features. Typically include microcephaly, malar flattening, mandibular retrusion, overfolded or squared-off helices, prominent nasal root, bulbous nasal tip, hooded eyelids, and hypertelorism. However, some neonates offer no clues to their underlying diagnosis based on their facial features, especially persons of African American heritage.

   4. Associated anomalies. Include hypocalcemia (∼50%), significant feeding problems (∼30%), renal anomalies (∼33%), hearing loss (both conductive and sensorineural), and hyperextensibility of hands and fingers.

6. William syndrome (7p11.23 deletion)

   1. Incidence. Approximately 1 in 7500 live births.

   2. Neonatal mortality. Quite small and mostly due to severe cardiac anomalies.

   3. Physical findings. Consist of a flat midface, medial eyebrow flare, short palpebral fissures, epicanthal folds, depressed nasal bridge, anteverted nostrils, long philtrum, thick lips, and blue iridae with a stellate pattern.

   4. Associated anomalies. Include congenital heart defects (∼80%), inguinal or umbilical hernias, hypercalcemia, and feeding difficulties.

1. Oligohydramnios sequence (Potter sequence)

   1. Incidence. Approximately 1 in 3000–9000 live births.

   2. Neonatal mortality. Almost all of these infants die.

   3. Pathophysiology. The initial malformations in this sequence are varied, but all lead to oligohydramnios. Primary malformations can include bilateral renal agenesis, severe polycystic kidneys, or a urinary tract obstruction. The resultant oligohydramnios then results in deformations and disruptions including compression deformities of the face and limbs, pulmonary hypoplasia with pneumothoraces, wrinkled skin, and growth restriction. Absent abdominal musculature (prune belly) and cryptorchidism may also be present.

   4. Associated anomalies. Include congenital heart defects, esophageal and duodenal atresia, imperforate anus, sirenomelia, hypoplastic nails, Pierre Robin sequence, large fontanelles, wide sutures, flexion contractures, and clubfeet.

2. Amniotic rupture sequence (Amniotic band syndrome)

   1. Incidence. Approximately 1 in 8000–11,000 live births.

   2. Neonatal mortality. Variable based on affected tissues and organs.

   3. Pathophysiology. The effects of early amnion rupture with entanglement of body parts in bands or strands of amnion is the primary event. The resulting biomechanical forces can lead to disruptions, deformations, and malformations. Viscera that are normally outside the fetus in early embryonic development may be hindered in their return, giving rise to omphalocele and other anomalies.

   4. Physical findings. Examination of the placenta and amniotic membranes is diagnostic. Aberrant bands or strands are noted, and remnants of the amnion may be rolled up in the umbilical cord.

      1. Extremities. Anomalies of the extremities include congenital amputations, constrictions, and distal swellings (Plate 2).

      2. Craniofacies. Craniofacial anomalies include microcephaly, encephaloceles, and facial clefts.

      3. Viscera. Visceral anomalies include omphaloceles, ectopia cordis, thoracoschisis, and abdominoschisis.

3. Arthrogryposis (multiple joint contractures)

   1. Incidence. Approximately 1 in 8000 live births.

   2. Neonatal mortality. Variable based on etiology.

   3. Pathophysiology. Arthrogryposis can result secondarily from varied abnormalities in the developing fetus. Factors that lead to reduced movement including primary neurologic, muscular, or orthopedic problems can all lead to arthrogryposis. Joint contractures can also be secondary to factors that are extrinsic to the developing fetus, such as fetal crowding and constraint. Neurologic abnormalities include meningomyelocele, prenatal spasticity, anencephaly, and hydranencephaly. Muscle abnormalities include muscle agenesis and fetal myopathies. Orthopedic abnormalities include synostosis, joint laxity with dislocations, and aberrant soft tissue fixations.

   4. Clinical presentation. The newborn infant is affected by a combination of joint contractures, joint extensions, and joint dislocations. Those with arthrogryposis of central nervous system origin are at increased risk for aspiration and inadequate respiratory movement.

4. Pierre Robin sequence. This sequence can occur in isolation or as part of a larger MCA syndrome. The most common associated syndrome is Stickler syndrome.

   1. Incidence. Approximately 1 in 8500 live births.

   2. Neonatal mortality. Small and mostly due to severe upper airway obstruction at birth.

   3. Pathophysiology. The primary event of this sequence is hypoplasia of the mandible, which results in secondary glossoptosis. The glossoptosis then leads to both upper airway obstruction and the development of a cleft palate.

   4. Clinical presentation. Infants have micrognathia or a receding chin with a cleft palate. Respiratory distress can occur as a result of upper airway obstruction. Low-set ears may also be present.

   5. Management. In mild cases, prone positioning can prevent airway obstruction. In more severe cases, temporary measures for glossoptosis and prevention of airway obstruction include nasal pharyngeal airway, nasal esophageal intubation, lip-tongue adhesion, mandibular distraction, laryngeal mask airway, and tracheostomy. Gastric tube feedings are common due to oral feedings causing respiratory distress.

1. VATER/VACTERL association. These conditions are closely related MCA associations. VATER is an acronym that stands for vertebral defects, anal atresia, tracheoesophageal fistula, and radial or renal dysplasia. VACTERL is an acronym that stands for vertebral defects, anal atresia, cardiac malformations, tracheoesophageal fistula, renal dysplasia and limb abnormalities.

   1. Incidence. Approximately 1 in 5000 live births.

   2. Neonatal mortality. Small and mostly due to severe cardiac or renal anomalies.

   3. Clinical presentation. Aside from the defects described in the acronyms, other features of these disorders include a single umbilical artery and prenatal growth deficiency.

2. CHARGE syndrome. CHARGE is an acronym that stands for coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies. CHARGE is an autosomal dominant disorder that results from mutations in the CDH7 gene.

   1. Incidence. Approximately 1 in 8500–10,000 live births.

   2. Neonatal mortality. Variable based on the degree of upper airway obstruction and congenital heart disease. Feeding difficulties are a major cause of morbidity in all age groups.

   3. Physical findings. The major features of CHARGE syndrome include unilateral or bilateral coloboma of the iris, retina, choroid, and or discs with or without microphthalmos (80–90%); cardiovascular malformations including conotruncal defects (75–85%); unilateral or bilateral choanal atresia or stenosis (50–60%); and developmental delay and hypotonia (∼100%); growth deficiency is typically postnatal with or without growth hormone deficiency (70–80%). Genital abnormalities include cryptorchidism in males and hypogonadotropic hypogonadism in both males and females. Ear anomalies are both external with anomalous auricles and internal with ossicular malformations, Mondini defect of the cochlea, and absent or hypoplastic semicircular canals.

   4. Associated anomalies. Include cranial nerve dysfunction resulting in hyposomia or anosmia, unilateral or bilateral facial palsy (40%) and/or swallowing problems (70–90%), and tracheoesophageal fistula (15–20%).

3. Beckwith-Wiedemann syndrome (BWS)

   1. Incidence. Approximately 1 in 13,000 live births.

   2. Neonatal mortality. Infants have ∼20% mortality rate, mainly caused by complications of prematurity.

   3. Physical findings. Perinatal findings include polyhydramnios, premature birth, macroglossia, linear ear creases, and macrosomia. Hemihyperplasia may be present at birth but can develop over time. Neonatal hypoglycemia is often present and clinically important. Anterior abdominal wall defects, including omphalocele and umbilical hernia, are common.

   4. Associated anomalies. Include renal anomalies and an increased risk of mortality associated with Wilms tumor and hepatoblastoma. The estimated risk for tumor development in children with BWS is 7.5%. This increased risk for neoplasia seems to be concentrated in the first 8 years of life. Tumor development is uncommon in affected individuals >8 years of age.

1. Fetal alcohol syndrome (FAS). The incidence is estimated to be 1–2 per 1000 live births. Features include prenatal and postnatal growth deficiency, irritability in infancy, microcephaly, short palpebral fissures, smooth philtrum with thin and smooth upper lip, joint anomalies, and congenital cardiac defects. Brain development and function are the most serious consequences of prenatal alcohol exposure.

2. Fetal hydantoin (Dilantin) syndrome. When taken during pregnancy, it results in a 2- to 3-fold increased risk for congenital malformations. Approximately 5–10% of exposed fetuses manifest the embryopathy. Features include mild to moderate prenatal growth deficiency, microcephaly, wide anterior fontanelle, low-set hairline, hirsutism, hypertelorism, strabismus, broad, depressed nasal bridge, cleft lip and palate, digit and nail hypoplasia, and umbilical and inguinal hernias. Similar craniofacial features are also associated with prenatal exposure to carbamazepine, Mysoline, and phenobarbital.

3. Fetal valproate syndrome was described when an association was made between maternal ingestion of valproic acid and neural tube defects. Additional anomalies of fetal valproate syndrome include narrow bifrontal diameter, epicanthal folds; telecanthus; midface hypoplasia; broad, low nasal bridge with a short nose; long philtrum; micrognathia; long, thin fingers; congenital heart defects; genitourinary anomalies; and clubfeet.

4. Fetal Accutane (isotretinoin) syndrome. Caused by the maternal use of isotretinoin, an active metabolite of vitamin A, for severe cystic acne. An estimated 25% of fetuses exposed to isotretinoin have a major malformation. Fetal anomalies include congenital heart defects, hydrocephalus, microcephaly, cranial nerve deficits, microtia, and a cleft palate. Pregnancy should wait until 2 years posttreatment with isotretinoin. Ingestion of large amounts of vitamin A may result in the same adverse effects to the fetus.

5. Diabetic embryopathy. Children born to insulin-dependent diabetic mothers have a 2- to 3-fold risk for congenital malformations. The cardiovascular, genitourinary, and central nervous systems are the most frequently affected systems. Cardiovascular anomalies include ventricular septal defect, transposition of great arteries, single umbilical artery, and situs inversus. Anomalies of the genitourinary system consist of renal agenesis and hypospadias, and anomalies of the central nervous system include spina bifida and anencephaly.

6. Infants of mothers with myotonic dystrophy vary in their clinical presentation from mild hypotonia and feeding problems to severe respiratory insufficiency causing death. Other abnormalities include a history of polyhydramnios and decreased fetal movement, multiple joint contractures, clubfeet, and facial weakness. The mutation identified to be the cause of myotonic dystrophy is a trinucleotide-containing cytosine-thymidine-guanosine that undergoes expansion in females with each transmission from an affected mother to a child. The severity of symptoms and onset of disease increases with transmission of this disorder to family members in subsequent generations.

7. Infectious (prenatal) diseases. Infectious diseases such as toxoplasmosis, rubella, and, cytomegalovirus can result in anomalies including microcephaly, macrocephaly, hydrocephalus, and congenital heart defects. Toxoplasmosis is the most common cause of congenital infections, with an occurrence rate of 0.5–2.5% of all live births. (See Chapter 142.)