What is new with 22q? An update from the 22q and You Center at the Children's Hospital of Philadelphia

Abstract

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by recurrent, chromosome-specific, low copy repeat (LCR)-mediated copy-number losses of chromosome 22q11. The Children's Hospital of Philadelphia has been involved in the clinical care of individuals with what is now known as 22q11.2DS since our initial report of the association with DiGeorge syndrome in 1982. We reviewed the medical records on our continuously growing longitudinal cohort of 1,421 patients with molecularly confirmed 22q11.2DS from 1992 to 2018. Most individuals are Caucasian and older than 8 years. The mean age at diagnosis was 3.9 years. The majority of patients (85%) had typical LCR22A-LCR22D deletions, and only 7% of these typical deletions were inherited from a parent harboring the deletion constitutionally. However, 6% of individuals harbored other nested deletions that would not be identified by traditional 22q11.2 FISH, thus requiring an orthogonal technology to diagnose. Major medical problems included immune dysfunction or allergies (77%), palatal abnormalities (67%), congenital heart disease (64%), gastrointestinal difficulties (65%), endocrine dysfunction (>50%), scoliosis (50%), renal anomalies (16%), and airway abnormalities. Median full-scale intelligence quotient was 76, with no significant difference between individuals with and without congenital heart disease or hypocalcemia. Characteristic dysmorphic facial features were present in most individuals, but dermatoglyphic patterns of our cohort are similar to normal controls. This is the largest longitudinal study of patients with 22q11.2DS, helping to further describe the condition and aid in diagnosis and management. Further surveillance will likely elucidate additional clinically relevant findings as they age.

Keywords: 22q11.2; DiGeorge; genomic disorder; multidisciplinary; syndrome.

Figure 1.

Dermatoglyphics of Patients with 22q11.2 Deletion Syndrome. U = ulnar loop. W = whorl. A = arch. R = radial arch. The proportion of each letter indicates the fraction of individuals exhibiting that dermatoglyphic for a given finger position. The height of the Y axis indicates the information content of a given dermatoglyphic at a given position. A. Dermatoglyphics of 529 patients with 22q11.2 deletion syndrome. B. Dermatoglyphics of 720 healthy Caucasian individuals from Plato et al, 1975.

Figure 2.

Age at Diagnosis of 22q11.2 Deletion Syndrome The black line indicates the age at diagnosis for all individuals with available data in the cohort. The red line indicates the same data for the subset of individuals with a cardiac diagnosis. The blue line indicates the time course for individuals without cardiac disease.

Figure 3.

Developmental Trajectory of Individuals with 22q11.2 Deletion Syndrome. A. Age at Attainment of Gross Motor Milestones. The black solid line indicates the time course of attainment of sitting independently by our cohort. The dashed black line indicates the median age of sitting independently. The blue solid line indicates the time course of walking independently. The dashed blue line indicates the median age of walking independently. B. Age at Attainment of Language Milestones. The black solid line indicates the time course of attainment of first words. The dashed black line indicates the median age of first words. The blue solid line indicates the time course of making simple phrases. The dashed blue line indicates the median age of attainment of simple phrases. C. Gross Motor Milestone Delays Associated with Congenital Heart Disease. The solid lines indicate the time course of attainment of sitting independently stratified by the presence (blue line) or absence (red line) of congenital heart disease. Individuals with heart disease sat a median of 1 month slower. The dashed lines indicate the age of walking independently. Individuals with heart disease walked independently a median of 3 months slower. D. Intelligence Quotient Distribution of Individuals with 22q11.2 Deletion Syndrome (N=361).