The 22q11 Deletion Syndromes (DiGeorge, Shprintzen, Takao)

Generally...

The contiguous gene deletion syndromes comprise a group of disorders defined by characteristic dysmorphisms or behaviors in association with a submicroscopic chromosome deletion that is detected using fluorescence in situ hybridization (FISH) or microarray technologies. In each case, the deleted segment contains multiple genes that play varying roles in producing a particular phenotype. Angelman, Beckwith-Wiedemann, Wolf-Hirschhorn (4p-), Prader-Willi, and 22q11 deletion syndromes are among the best delineated contiguous gene deletion syndromes.

22q11 Deletion Syndrome (the long arm of chromosome 22 at band 11), which occurs in approximately 1 in 4,000 births, is the most common of the contiguous gene deletion syndromes. 22q11 deletion syndrome should be suspected in any child who has a conotruncal heart defect (eg, tetralogy of Fallot, double-outlet right ventricle, truncus arteriosus), especially if accompanied by developmental delay, dysmorphic features, or recurrent upper respiratory tract infections. Testing for the condition involves sending blood for FISH (it must be specified that the region of interest is 22q11) or for microarray analysis, assuming the array covers the 22q11 region. DiGeorge, Takao and Shprintzen syndromes are all manifestations of the submicroscopic deletions in the 22q11 region.

DiGeorge syndrome (Mnemonic: CATCH 22)

• abnormal cervical neural crest migration into the derivatives of the third and fourth branchia/pharyngeal arches and pouches during early embryogenesis.
• hypoplasia or aplasia of the thymus and parathyroid glands and structural abnormalities of the great vessels.
• Deficient cellular immunity decreased mature T cells and decreased CD4+ cells
• chrom 22q11 microdeletions; 75% de novo;  25% inherited
• Inheritance: embryonologic defects, catch 22 syndromes
• Infants present with: hypocalcemia (seizure), absent T-cells and failure to thrive
• Clinical Features:
  • some affected infants also have facial dysmorphic features, which can include hypertelorism, short palpebral fissures, short philtrum, micrognathia, and ear abnormalities.
  • Due to variable degree of thymic hypoplasia, there is a wide spectrum of immunodeficiency. May be relatively asymptomatic or may be susceptible to opportunistic pathogens including fungi, viruses, P. jiroveci, GVHD; 15% also have impaired humoral immunity
  • absence of parathyroid glands -> hypoparathyroid (decr Ca) -> hypocalcemic seizures
  • absence of thymus, problems with cellular immunity -> infections
  • facial abnormalities (soft dysmorphic features): hypertelorism, ear anomalies, short palpebral fissures, short philtrum
  • Aortic arch abnormalities: congenital heart dz (what are the two most common?)
  • In general, the immune defect improves with age, and many children produce normal numbers of functional T lymphocytes by the end of the 2nd year of life.
• Cardiac anomalies: 2 most common: interrupted aortic arch  (often w/ VSD) and persistent truncus arteriosus (cono-truncal abnormalities), also TOF.
• CNS abnormalities occur in 1/3: arhinencephaly, lissencephaly, simple gyral pattern, microcephaly
• thyroid function is preserved in DiGeorge syndrome.
• Dx by FISH
• Other labs: decreased CD3 lymphocytes, decreased CD4 cell ct, may have decreased in vitro T cell proliferative responses
• Therapy: thymus graft w/wo bone marrow transplantation for most severe immune deficiencies

Takao syndrome

• like digeorge, but no thymic aplasia or parathyroid dysfunction
• primarily cardiac dz

Shprintzen (velocardiofacial):

• like digeorge
• plus craniofacial (prominent nose with squared nasal root, abundant scalp hair, deficient malar area, long face, retruded mandible)
• plus palatal abnormalities (nasal speech)
• small stature/microsomia, slender/hyperextensible fingers.
• CHD including VSD.
• Mild intellectual impairment
• Autosomal dominant.

Isolated outflow tract defects of the heart also occur

• eg, tetralogy of Fallot, truncus arteriosus, interrupted aortic arch)

Mnemonic: CATCH 22

CHLA board review course 2005
Baraitser and Winter, 1996. Color Atlas of Congenital Malformation Syndromes