Digeorge Syndrome, Takao Syndrome, Shprintzen syndrome (velocardiofacial)

The infant described in the vignette has a number of features of DiGeorge syndrome. DiGeorge syndrome results from abnormal cervical neural crest migration into the derivatives of the third and fourth pharyngeal arches and pouches during early embryogenesis. The pattern of malformations includes hypoplasia or aplasia of the thymus and parathyroid glands and structural abnormalities of the great vessels. The defects lead to the classic clinical manifestations of deficient cellular immunity due to T-cell dysfunction, causing increased susceptibility to infection; hypocalcemia due to absent parathyroid hormone, resulting in hypocalcemic seizures; and aortic arch abnormalities. Some affected infants also have facial dysmorphic features, which can include hypertelorism, short palpebral fissures, short philtrum, micrognathia, and ear abnormalities.

Most patients who have DiGeorge syndrome are found to have partial monosomy for the proximal long arm of chromosome 22 due to microdeletion of 22q11.2. This microdeletion can be detected by fluorescent in situ hybridization (FISH) using a molecular probe specific for the region. Although the deletion occasionally is evident on routine chromosome analysis, the FISH study is much more sensitive. Most cases represent de novo deletion events, although familial cases have been described.

The 22q11.2 deletion is associated with a variety of other phenotypes, including the Shprintzen syndrome (velocardiofacial syndrome), Takao syndrome, and isolated outflow tract defects of the heart (eg, tetralogy of Fallot, truncus arteriosus, interrupted aortic arch). In  general, Takao syndrome is diagnosed when the patient primarily has cardiac disease, with normal T-cell and parathyroid function. Shprintzen (velocardiofacial) syndrome denotes those patients who have the features of DiGeorge syndrome plus craniofacial and palatal abnormalities. Of interest, all three phenotypes can be evident in a single family in  which a heritable chromosome 22 deletion is present. It has been suggested that this constellation of related syndromes that have the common etiologic factor of a chromosome 22 deletion should be termed CATCH22 for Cardiac abnormality, Abnormal facies, T-cell deficit, Cleft palate, and Hypocalcemia resulting from 22q11 deletion. In general, the diagnosis of DiGeorge syndrome requires a neonatal presentation of thymic hypoplasia and hypocalcemia; Shprintzen syndrome requires the presence of nasal speech due to palatal insufficiency.

Because deafness is not a major feature of DiGeorge syndrome, obtaining brainstem auditory evoked potentials is not indicated. The etiology of the seizure in the infant described in the vignette is hypocalcemia, and electroencephalography would not provide additional useful information for management, which should include administration of calcium. Hypothyroidism usually is not evident in the newborn period, and thyroid function is preserved in DiGeorge syndrome.

References:
Burn J, Wilson DI, Cross I, et al. The clinical significance of 22q11
deletion. In: Clark EB, Markwald RR, Takao A, eds. Developmental
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Burn J. Closing time for CATCH22. J Med Genet. 1999;36:737-738
DeSilva D, Duffty P, Booth P, Auchterlonie I, Morrison N, Dean JC.
Family studies in chromosome 22q11 deletion: further demonstration of
phenotypic heterogeneity. Clin Dysmorphol. 1995;4:294-303
Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features
associated with interstitial chromosome 22q11 deletions: a European
collaborative study. J Med Genet. 1997;34:798-804
Stevens CA, Carey JC, Shigeoka AO. DiGeorge anomaly and
velocardiofacial syndrome. Pediatrics. 1990;85:526-530