DiGeorge Syndrome Clinical Presentation

The most common reason to suspect chromosome 22q11.2 deletion syndrome is a cardiac anomaly, especially a conotruncal one. Neonatal hypocalcemia should also raise suspicion for this syndrome, especially if the hypocalcemia or heart defect is coupled with cleft palate, which is frequently observed in affected individuals. The characteristic facies of this syndrome are often subtle in infancy and not fully manifested until the child is older; therefore, they are not a common indication for a genetic investigation. The distinctive facial features may even be absent or very subtle in people of African-American or other nonwhite descent. Developmental delay may be mild in infancy or may go unnoticed until the child reaches school age. Additional abnormalities of every organ system have been reported,^[10] although, individually, are rare. Details of the common symptoms/anomalies follow.

Cardiac and vascular features

Congenital heart defects are observed in 74-80% of patients. A higher incidence is noted in cases diagnosed during infancy because of the symptomatic nature of the heart lesion. Any conotruncal heart defect can occur. In infancy, tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch are more common; ventricular septal defect (VSD), pulmonary atresia plus VSD, and other conotruncal defects are seen in cases diagnosed after age 2 years. Rare cardiac anomalies include vascular ring anomaly, transposition of great arteries with VSD, coarctation of the aorta,atrial septal defect (ASD), pulmonary stenosis, hypoplastic left heart, and patent ductus arteriosus.

Some patients have vascular anomalies, and those who need pharyngeal surgery should be specifically checked for anomalies of the carotid arteries.

Craniofacial features

Characteristic facies are easier to recognize in white children and consist of a high and broad nasal bridge, long face, narrow palpebral fissures, and micrognathia. Microcephaly and asymmetric crying face may be present. Facial features become more pronounced as the children grow into the second decade.

Hypernasal voice indicates velopharyngeal incompetence (VPI) and is more common than an overt cleft of the secondary palate. VPI may be caused by a submucous cleft palate. An overt cleft palate does improve the chances of an earlier diagnosis.

Poor sucking and nasal regurgitation due to VPI or a submucous cleft palate may be present. The swallowing problem usually resolves by the end of the first year, leaving the child with hypernasal speech as the major remaining manifestation.

Recurrent episodes of otitis media may be observed. Conductive or sensorineural hearing loss (or both) may be present.

Recurrent infections

Recurrent infections secondary to immune deficiency may be observed. The overall incidence of immune dysfunction is 77%.^[10]

The characteristic immunodeficiency is a mild-to-moderate defect in T-cell lineage as a consequence of thymic hypoplasia. Naïve T-cell production is usually reduced. Only a small fraction of patients present with marked impairment of T-cell function associated with complete absence of thymus and T cells and severe systemic infections consistent with severe combined immunodeficiency (SCID) phenotype. T-cell functions and numbers that improve with age may be attributed to homeostatic T-cell proliferation secondary to limited T-cell production.

Variable secondary humoral defects, including hypogammaglobulinemia and selective antibody deficiency, may be present.

Impaired T-cell production may predispose patients with 22q11.2 deletion to autoimmune diseases. In a cohort of 195 patients with chromosome 22q11.2 deletion syndrome, various autoimmune diseases, including juvenile rheumatoid arthritis (JRA), idiopathic thrombocytopenic purpura (ITP), and autoimmune hemolytic anemia (AHA), were each more prevalent than in the age-matched general population.^[11] No specific pattern of autoimmune diseases appears to be associated with 22q11.2 deletion.

Hypocalcemia

Hypocalcemia due to hypoparathyroidism can cause seizures. The incidence of hypocalcemia varies widely, from 17-60%. This is frequently a self-limiting problem, and approximately 50% of patients are no longer needing calcium supplementation by age 1 year.

Developmental delay/learning difficulties

Developmental delay and learning difficulties are observed in 70-90% of patients. In infancy, developmental milestones are achieved later than expected for age. Delayed language acquisition is often seen in older children.

A frequent pattern of disability is observed,^[12] consisting of a low performance intelligence quotient (IQ) compared with verbal IQ, which creates problems with nonverbal learning, abstract reasoning, and math. In school-aged children, full-scale IQ scores can range from average to low average to mild mental retardation. The incidence of mild mental retardation is approximately 30%. Brain anomalies like polymicrogyria and enlarged Sylvian fissures have rarely been noted.

Behavioral abnormalities

Various behavioral abnormalities, including attention deficit disorder, shyness, disinhibition, and autism spectrum disorders, have been reported. The incidence of psychoses such as depression, bipolar disorders, schizophrenia, and anxiety is increased,^[13] and some report their prevalence to be about 10%.

In one longitudinal study,^[13] 20% of VCFS children in mid adolescence had significant prodromal psychotic symptoms. In their sample, weaker executive functioning and verbal abilities and high levels of odd/eccentric and anxious behaviors in childhood best predicted prodromal psychotic symptoms in adolescence.

Other findings

Kidney and renal pelvis duplications can occur.

There is considerable variability in individual physical findings and in the organ systems that may be involved.

Patients usually have characteristic facies, which become more pronounced as the child grows into the second decade. These are more commonly and easily recognized in white children. Retrognathia or micrognathia, long face, high and broad nasal bridge, and narrow palpebral fissures are common features, as shown in the image below.

Although VPI is more common, a cleft of soft palate or a bifid uvula (associated with a submucous cleft palate) may be present.

Other frequent facial features include small teeth, asymmetric crying face, and down-turned mouth, as shown in the image below.

Heart murmur and other cardiac findings may be present, depending on the nature of the cardiac lesion.

Long tapering fingers may be present.

Short stature may occur; decrease in the rate of linear growth may suggest rarely seen growth hormone deficiency.

GI anomalies like esophageal atresia and anal atresia or stenosis may be present.

Polydactyly and scoliosis due to vertebral anomalies have been seen in rare cases.

Occurrence is sporadic in 85% of cases. Approximately 7% of cases are inherited as dominant, and less than 1% of cases are due to chromosomal rearrangements. The hereditary cases show no predilection in inheritance from the mother or the father. An affected person has a 50% chance of transmitting the condition to his or her child. Wide intrafamily and interfamily variability in clinical manifestations is seen.

Remember that not all patients with DiGeorge syndrome (DGS) have the 22q11.2 microdeletion. Patients with other chromosomal anomalies, such as those with deletion of band 4q, 10p, or 17p; infants of mothers with diabetes; and patients with fetal alcohol syndrome, may show signs of DGS. Chromosome 10p13-p14 deletion is often referred to as DGS2.