Numerous genetic conditions are evident and diagnosable during the neonatal period because of a specific pattern of clinical features often present on infant physical examination. This chapter reviews several of the more frequently observed genetic dysmorphic conditions neonatal practitioners are most likely to encounter in a newborn (apart from the common trisomies that are addressed separately in this textbook), which include: Turner syndrome (TS), 22q11.2 deletion syndrome, CHARGE (coloboma, heart defect, atresia choanae [also known as choanal atresia], retarded growth and development, genital abnormality, and ear abnormality) syndrome, and VACTERL (vertebral, anal, cardiac, tracheoesophageal, renal, and limb) association.
As several genetic syndromes and 1 association are discussed in this chapter, it is reasonable to define both entities. The term syndrome derives from the Greek and means “concurrence” or “along with, together.” Thus, a genetic syndrome refers to a pattern of congenital anomalies that can be explained by a common genetic or developmental cause. Syndromes often include developmental abnormalities and increased risk of recurrence in families. An association is a collection of physical findings and is considered a nonrandom occurrence; it is known not be a polytypic defect, sequence, or syndrome.1 Associations are generally not associated with an increased risk of recurrence.1
Identification of a specific genetic diagnosis during the immediate newborn period is helpful for appropriate medical management, as well as to provide the infant’s family with prognostic information and accurate recurrence risk information.
CLINICAL GENETICS EVALUATION
Physical examination of the neonate is essential in providing diagnostic accuracy as well as focusing differential diagnoses. The genetic dysmorphology evaluation is a careful physical examination of the infant in a head-to-toe manner, taking note of any facial or body asymmetries, malformations, or deformations that may be present externally. This also involves measuring and plotting the growth parameters (length, weight, and head circumference) on appropriate curves for gestational age, such that entities of microcephaly or microsomia are not neglected.
The neonatal head is evaluated by assessing the head shape, size of the anterior and posterior fontanelles, and cranial sutures. Close attention is paid to possible sutural ridging or unusual head shape that is distinct from transient postnatal vertex molding. Careful evaluation of the scalp is performed to uncover lesions such as cutis aplasia congenita or unusual hair patterning that may indicate an underlying cerebral malformation. Facial asymmetry or cranial nerve palsy is best visualized while the infant is crying. Presence of facial asymmetry is often seen in association with syndromes such as CHARGE or 22q11.2 deletion syndrome and thus is of significant diagnostic value.
Evaluation of the eyes with an ophthalmoscope is warranted such that red reflexes can be visualized and irides can be closely examined for the presence of colobomas, which tend to be located inferonasally. Certain ophthalmic anomalies, such as iris Brushfield spots (observed in Down syndrome), retinal coloboma, optic nerve hypoplasia, and abnormal retinal pigmentation are not easily visualized by this methodology and require formal ophthalmology evaluation for detection.
Ears are analyzed for any unusual appearance of the concha, ear positioning, presence of preauricular pits or tags, or malformations such as microtia. The palate and lips are visualized for evidence of clefting, with close attention paid to the uvula to assess if there is a bifid formation or circumferential zona pellucida that could indicate a submucous cleft palate. An infant with frequent nasal regurgitation of feedings may have a submucous cleft or velopharyngeal insufficiency.
Nuchal skin redundancy with a low posterior hairline may be present in association with certain chromosome abnormalities, single-gene disorders, or in infants with complex congenital cardiac defects. If nuchal webbing is noted, close evaluation for limb edema indicating in utero lymphatic obstruction is also helpful diagnostically.
Examination of the limbs, hands, fingers, feet, toes, and palmar and plantar creases provides further insight as well as careful consideration for syndactyly, polydactyly, joint contractures, and limb positioning. Knowledge of a cardiac murmur, abdominal wall defects, hepatosplenomegaly, genitourinary anomalies, sacral dimple, or neural tube defects are essential and will guide the genetic diagnostic workup appropriately.
COMMON DYSMOPRHIC SYNDROMES
Turner syndrome is a genetic condition caused by absence of all (monosomy) or part (partial monosomy) of the second X chromosome; thus, it only affects females. This multisystemic disorder has variable phenotypic severity, and in milder cases, this diagnosis may be overlooked during infancy, without detection until childhood or adolescence once short stature and pubertal delay are recognized.2
Turner syndrome has a birth prevalence of 1 in 2000 to 5000 female live births; however, the majority of 45,X concept uses spontaneously abort during the first trimester of pregnancy. TS-affected fetuses that survive into the second trimester are often recognized to have increased nuchal fold and lymphedema on prenatal ultrasound.3 At birth, affected neonates may present with a constellation of features of a variable phenotypic spectrum. Congenital cardiac defects may often be the sole manifesting feature. Abnormalities of the left outflow tract, such as bicuspid aortic valve, and coarctation of the aorta are commonly observed. Nuchal webbing, low posterior hairline, residual edema of the dorsum of the hands and plantar surfaces of the feet, and a shield-shaped chest with widely spaced nipples may be identified via careful newborn physical examination. The severity of these findings tends to depend on the degree of in utero lymphedema during embryologic development. Thus, mildly affected females may be diagnostically challenging.
A number of different diagnostic tests can be performed on the female infant suspected to have TS: chromosome analysis from peripheral blood; echocardiogram to evaluate for congenital cardiac defects; and renal ultrasound to look for structural anomalies of the kidney or abnormalities of the renal collecting system.3 Furthermore, careful hip examination for congenital hip dysplasia and newborn hearing screen prior to discharge are recommended (Table 109-1).
Table 109-1Diagnostic Testing for Genetic Dysmorphic Conditions Encountered in the Neonatal Period ||Download (.pdf) Table 109-1Diagnostic Testing for Genetic Dysmorphic Conditions Encountered in the Neonatal Period
|Condition ||Diagnostic Testing ||Additional Studies/Imaging |
|Turner syndrome ||Chromosome analysis ||Echocardiogram |
| ||Renal ultrasound |
|Evaluate for hip dysplasia |
|22q11.2 Deletion syndrome ||FISH for 22q11.2 microdeletion ||Echocardiogram |
| ||Renal ultrasound |
|Immune workup |
|T-cell subsets or flow cytometry |
|Serum calcium level |
|Hearing screen |
|CHARGE syndrome ||CT of the temporal bones ||Ophthalmology evaluation |
| ||CHD7 full gene sequencing ||Echocardiogram |
| || ||Renal ultrasound |
|VACTERL association ||Diagnosis of exclusion ||Spine and extremity films |
| ||Renal ultrasound |
|Ophthalmology evaluation |
|Evaluate for tracheoesophageal fistula |
Structural chromosome abnormalities such as isochromosome X, ring X, as well as deletions of a portion of the short arm (Xp) or long arm (Xq) have also been reported in females with TS.2 A smaller percentage of females may exhibit mosaicism (45,X/46,XX or 45,X/46,XY). Presence of Y chromosome material warrants prophylactic gonadectomy secondary to increased risk for gonadoblastoma or dysgerminoma.2 This illustrates the importance of chromosome analysis not only for confirmation of the diagnosis, but also to aid in further medical management and accuracy of recurrence risk in cases with structural rearrangements.
22q11.2 Deletion Syndrome
The 22q11.2 deletion syndrome is an autosomal dominant condition considered to be 1 of the most common microdeletion syndromes, with a prevalence of 1 in approximately 2000–4000 live births. This syndrome is also known in the medical literature as velocardiofacial syndrome, as well as DiGeorge syndrome in the subset of patients possessing both the microdeletion and immune deficiency. The microdeletion consists of a very small region, often undetectable by routine karyotype, and involves the 22q11.2 region of the long arm of chromosome 22. This disorder has a wide spectrum of clinical findings; a vast number of congenital anomalies have been observed in association with this condition.
More than 35 genes are present within the 22q11.2 critical region. Haploinsufficiency of this locus can cause malformation of the fourth branchial artery, which is a precursor for the right ventricle and cardiac outflow tract formation during embryogenesis.4 Furthermore, malformation of the third and fourth branchial pouches may compromise development of the parathyroid, thymus, and craniofacial structures in the fetus.
Knowledge of malformations of certain embryologic structures in the affected fetus facilitates our understanding of common clinical features observed in this condition. Cardiac anomalies, palatal abnormality, thymic and parathyroid hypoplasia/aplasia, and craniofacial anomalies are typically observed. Conotruncal cardiac anomalies, such as tetralogy of Fallot, interrupted aortic arch, truncus arteriosus, and ventricular septal defects, are commonly seen. Cleft palate, submucous cleft palate, velopharyngeal incompetence, or hypotonia of velopharyngeal musculature may cause feeding difficulties, such as severe dysphagia and reflux during infancy.10
Certain blood cell counts and chemistries may also be abnormal. Immunodeficiency (reduced T-cell count) and hypocalcemia may be present secondary to hypoplasia or aplasia of the thymus and parathyroid glands, respectively. Hypocalcemia is typically most evident and serious during the neonatal period and tends to normalize with age. However, hypocalcemia may recur later in childhood, especially during illness or puberty.
Craniofacial anomalies are variable in appearance and severity and may include hooded eyelids; ocular hypertelorism; ear abnormalities (overfolded or squared off helices, cupped protuberant ears, associated pits or tags); and asymmetric crying facies. In the absence of a congenital cardiac defect or the presence of minimal or atypical phenotype, diagnosis during infancy may not be made.1 Table 109-1 lists the appropriate workup for an infant suspected to have this condition.
Fluorescence in situ hybridization (FISH) for the 22q11.2 region on peripheral blood metaphases is the gold standard diagnostic test (Figure 109-1). Of note, comparative genomic hybridization (array CGH) is also capable of detecting this particular microdeletion. In infants, a thorough physical examination, echocardiogram, and measurement of serum calcium level are warranted if a diagnosis of 22q11.2 deletion syndrome is suspected. Immunodeficiency workup may be initialized once FISH confirmation of the diagnosis is made. Ninety percent of 22q11.2 deletion syndrome cases are de novo occurrences; however, it is generally recommended that both parents of a patient with 22q11.2 deletion syndrome be tested as well to provide the most accurate information on risk of recurrence.
Fluorescence in situ hybridization (FISH) positive for 22q11.2 microdeletion. This image represents a peripheral blood metaphase cell with FISH for the 22q11.2 microdeletion. Only 1 orange signal for the TUPLE1 probe (specific for the DiGeorge region) is noted, indicating deletion of the q11.2 region on 1 chromosome 22. There are 2 green control probe signals, indicating that 2 chromosome 22s are present. This patient has a confirmed 22q11.2 microdeletion, consistent with 22q11.2 deletion syndrome. (Used with permission of Touran M. Zadeh, MD, Genetics Center, Orange, California.)
CHARGE Syndrome is 1 of the most common multiple-anomaly conditions that may be encountered by neonatologists and clinicians. CHARGE is an acronym for the cardinal features typically observed in association with this condition: coloboma, congenital heart defects, choanal atresia, retardation of growth and development, genital abnormalities, ear abnormalities and deafness. This is an autosomal dominant condition, with most cases arising in a de novo manner (ie, unaffected parents). Neonates with CHARGE may have life-threatening complications, especially if more than 1 of these 3 features is present: bilateral choanal atresia, tracheoesophageal fistula, or cyanotic congenital cardiac defect.5, 9
Neonates with CHARGE syndrome may have normal growth parameters at birth, with observation of decreased linear growth by late infancy. The inability to pass a nasogastric tube during the immediate newborn period should alert the clinician to the presence of choanal atresia, and the possibility of CHARGE syndrome must be considered.1 The clinical examination can thus be refocused to the heart, eyes, and other potentially involved organ systems accordingly. Imaging of the nasal passages via computed tomography (CT) is helpful in elucidating the quality of blockage. Bilateral choanal atresia is considered a medical emergency requiring surgical intervention.
As CHARGE syndrome affects multiple organ systems, further evaluation of the eyes, heart, and genitourinary system is warranted. Colobomas are present in up to 90% of patients with this condition and may be located in the iris or retinas (affecting the optic nerve or macula). Thus, a formal dilated ophthalmologic evaluation is necessary. Cardiac defects, predominantly conotruncal anomalies, are present in 75%–85% of infants with CHARGE syndrome. Genitourinary anomalies consisting of microphallus, hypospadias, and cryptorchidism in males and hypoplasia of the external female genitalia may be present.5 In addition, affected females may have atresia of the uterus, cervix, and vagina in a minority of cases.1 Renal abnormalities, including duplex kidneys, renal agenesis/hypoplasia, and vesicouretral reflux (VUR), have been reported in up to 40% of infants with CHARGE syndrome.
A consistent feature in approximately 90% of infants with CHARGE syndrome is abnormalities of the semicircular canals.5 This finding is more specific and accurate than the currently available molecular genetic testing, which involves full gene sequencing of the CHD7 gene (with only a 60% mutation detection rate). Thus, if CHARGE syndrome is suspected, a CT scan of the temporal bones to look for middle and inner ear bony defects is diagnostically more sensitive and valuable than molecular genetic testing from blood. Furthermore, external ear anomalies may be asymmetric and present as short, protruding, lop or cup-shaped, and simple helices with hypoplastic lobules.1
As this is a variable condition, a clinical diagnosis of CHARGE syndrome may be challenging and is dependent on the method in which affected neonates are ascertained. Definite CHARGE syndrome is considered if neonates have the following 4 features: ocular coloboma, choanal atresia/stenosis, cranial nerve dysfunction, and a characteristic CHARGE-appearing ear and inner ear anomalies. Probable/possible CHARGE syndrome is suspected if the neonate has 2 major characteristics as just listed and several minor characteristics (genital hypoplasia, cardiovascular anomalies, orofacial cleft, tracheoesophageal fistula, or distinctive facial features).5 If CHARGE is suspected, a genetic evaluation is warranted as well as an appropriate evaluation of the previously mentioned organ systems (Table 109-1) to provide the family with the most accurate diagnosis as well as risk of recurrence.
In contrast to the other syndromes mentioned in this chapter, VACTERL is an association without an identifiable molecular cause. Another name for this condition is VATER association, which is an acronym for the multisystemic features typically observed: vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial and renal dysplasia. The CL has been added more recently to include cardiac and limb defects (as observed in VACTERL). Both VACTERL association and CHARGE syndrome may have overlapping phenotypic features. However, careful physical examination and workup can usually distinguish between these 2 distinct entities.
Neonates with VACTERL do not have dysmorphic features or abnormalities in linear growth. Furthermore, neurocognitive impairment is also not typically observed in patients with VACTERL.6 A careful physical examination and appropriate imaging modalities are appropriate assessment tools. Vertebral defects can be visualized on anterior-posterior and lateral complete spine radiographs; anomalies include hemivertebrae, segmentation defects, absent vertebrae, and sacral dysgenesis.6 Anal atresia or stenosis requires immediate surgical intervention, and a range of cardiac anomalies have been described. Renal agenesis, reflux, and ureteropelvic junction (UPJ) obstruction can be observed on ultrasound imaging.
Limb defects tend to involve the upper more than the lower extremities, with radial bones more affected than ulnar bones. Thumb anomalies, including thumb aplasia or hypoplasia, rudimentary thumbs, and preaxial polydactyly, have all been reported.1 The upper extremity findings can be similar to that observed in Fanconi anemia and Townes-Brocks syndrome and several other genetic conditions.6
Fanconi anemia is a genetic condition that can present with multiple physical anomalies during the neonatal period. Most commonly observed manifestations include thumb anomalies and multisystemic involvement, including the eyes, kidneys and urinary tract, ears, and heart, along with hypogonadism and developmental delay. Bone marrow failure is not usually present until 6 to 8 years of age.7 Townes-Brocks is characterized by a clinical triad of features consisting of abnormal-appearing ears, imperforate anus, and thumb anomalies.8 These 2 genetic syndromes have an increased risk of recurrence compared to an association, which is generally sporadic in nature.
For diagnostic purposes, x-rays of the upper extremities may be helpful, along with echocardiogram, renal ultrasound, spine films, and ophthalmology evaluation if VACTERL is being considered (Table 109-1). Chromosome breakage studies may be pursued to ensure that a diagnosis of Fanconi anemia is not overlooked. Furthermore, molecular genetic testing for Townes-Brocks syndrome is available clinically with a good mutation detection rate.1
VACTERL association is considered a diagnosis of exclusion that should not be made until 1 year of age. Thus, appropriate genetic workup for other syndromes with similar clinical features is necessary prior to assigning this diagnosis.
Knowledge of common dysmorphic genetic conditions that often present during the neonatal period is helpful in appropriate medical management and prognosis. Distinction between an isolated malformation, association, or a genetic syndrome also provides further information for the family as well as a more accurate recurrence risk. A genetics evaluation should be considered in any newborn with multiple congenital anomalies.1
L. Neonatal presentations of CHARGE syndrome and VATER/VACTERL association. NeoReviews. 2008;9:e299–e304.
ML. American Academy of Pediatrics clinical report on health supervision for children with Turner syndrome. Pediatrics
KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 2211.2 deletion syndrome. Lancet
CA. Charge syndrome. In: Cassidy
JE, eds. Management of Genetic Syndromes. 3rd ed. Hoboken, NJ: Wiley-Blackwell; 2010:157–168.
BD. VACTERL/VATER association. Orphanet J Rare Dis. 2010;6:56.
EH. 22q11.2 deletion syndrome. In: GeneReviews
. 2005. http://www.genetests.org