Chromosome 22q11.2 deletion syndrome and DiGeorge syndrome

Chromosome 22q11.2 deletion syndrome is the most common microdeletion syndrome in humans. The effects are protean and highly variable, making a unified approach difficult. Nevertheless, commonalities have been identified and white papers with recommended evaluations and anticipatory guidance have been published. This review will cover the immune system in detail and discuss both the primary features and the secondary features related to thymic hypoplasia. A brief discussion of the other organ system involvement will be provided for context. The immune system, percolating throughout the body can impact the function of other organs through allergy or autoimmune disease affecting organs in deleterious manners. Our work has shown that the primary effect of thymic hypoplasia is to restrict T cell production. Subsequent homeostatic proliferation and perhaps other factors drive a Th2 polarization, most obvious in adulthood. This contributes to atopic risk in this population. Thymic hypoplasia also contributes to low regulatory T cells and this may be part of the overall increased risk of autoimmunity. Collectively, the effects are complex and often age‐dependent. Future goals of improving thymic function or augmenting thymic volume may offer a direct intervention to ameliorate infections, atopy, and autoimmunity.     

Obesity in adults with 22q11.2 deletion syndrome

PurposeTo characterize the prevalence of and contributing factors to adult obesity in the most common recurrent copy-number variation (CNV), 22q11.2 deletion, given that other rare CNVs are known to have obesity phenotypes.MethodsIn 207 adults with 22q11.2 deletion syndrome (22q11.2DS), we used available height and weight measurements to calculate body mass index (BMI) and recorded associated factors that could play a role in obesity. We used the maximum BMI per subject and logistic regression to test a model predicting obesity class.ResultsThe prevalence of obesity (BMI ≥30) in 22q11.2DS (n = 90, 43.5%; at median age of 26.7 years) was significantly greater than for Canadian norms (odds ratio (OR) 2.30, 95% confidence interval (CI) = 1.74–3.02, P < 0.0001), even after excluding individuals with a history of antipsychotic use. The regression model was significant (P < 0.0001). Psychotropic medication use and age, but not sex or presence of intellectual disability, were associated with higher obesity level. Ten (4.8%) individuals were diagnosed with type 2 diabetes at a median age of 39.5 years; the prevalence was higher in those with obesity (P < 0.01).ConclusionThe results suggest that adult obesity is related to the 22q11.2 deletion. The findings expand the potential genetic causes of obesity and have important implications for management of 22q11.2DS.     

Parathyroid hormone reserve in 22q11.2 deletion syndrome

ObjectiveWe hypothesized that most patients with 22q11.2 deletion and a history of hypocalcemia have inadequate parathyroid function, manifested by intact parathyroid hormone levels below normal. We aimed to evaluate intact parathyroid hormone levels both during normocalcemia and at hypocalcemia, in this population.Study DesignRetrospective chart review of 103 patients with 22q11.2 deletion born since 1997 and cared for at the Children's Hospital of Philadelphia. Calcium and intact parathyroid hormone drawn simultaneously were recorded, along with clinical presentation at hypocalcemia.ResultsForty-seven simultaneous Ca/intact parathyroid hormone values were available. Seventy-nine percent of calcium levels and 81% of parathyroid hormone levels were within normal range. There were 19 patients with a history of symptomatic hypocalcemia, for whom any available simultaneous Ca/parathyroid hormone levels, before, during, or after hypocalcemia were analyzed. In this subgroup, 59% of calcium and 76% of parathyroid hormone levels were normal. None had an intact parathyroid hormone of >39.2 pg/mL at hypocalcemia. Seventy-three percent of hypocalcemic events had a precipitating stressor.ConclusionsHypoparathyroidism in 22q11.2 deletion is mild, manifesting as a phenomenon of decreased parathyroid hormone reserve. Subjects are normocalcemic most of the time, but are unable to mount elevated intact parathyroid hormone levels, and therefore unable to correct hypocalcemia, in response to stressors.     

Mosaicism del(22)(q11.2q11.2)/dup(22)(q11.2q11.2) in a patient with features of 22q11.2 deletion syndrome

The chromosome 22q11 region is prone to rearrangements, including deletions and duplications, due to the presence of multiple low copy repeats (LCRs). DiGeorge/velo-cardio-facial syndrome is the most common microdeletion syndrome with more than 90% of patients having a common 3-Mb deletion of 22q11.2 secondary to non-homologous recombination of flanking LCRs. Meiotic reciprocal events caused by LCR-mediated rearrangement should theoretically lead to an equal number of deletions and duplications. Duplications of this region, however, have been infrequently reported and vary in size from 3 to 6 Mb. This discrepancy may be explained by the difficulty in detecting the duplication and the variable, sometimes quite mild phenotype. This newly described 22q duplication syndrome is characterized by palatal defects, cognitive deficits, minor ear anomalies, and characteristic facial features. We report on a male with truncus arteriosus and an interrupted aortic arch, immunodeficiency, and hypocalcemia. The patient is mosaic for two abnormal cell lines: a deletion [del(22)(q11.2q11.2)] found in 11 cells and a duplication [dup(22)(q11.2q11.2)] found in 9 cells. Molecular cytogenetic analysis in our patient revealed a 1.5 Mb deletion/duplication, the first duplication reported of this size. Deletion/duplication mosaicism, which is rare, has been reported in a number of cases involving many different chromosome segments. We present the clinical phenotype of our patient in comparison to the phenotypes seen in patients with the 22q11.2 deletion or duplication alone. We propose that this rearrangement arose by a mitotic event involving unequal crossover in an early mitotic division facilitated by LCRs.     

22q11.2 deletion syndrome and congenital heart disease

The 22q11.2 deletion syndrome has an estimated prevalence of 1 in 4–6,000 livebirths. The phenotype varies widely; the most common features include: facial dysmorphia, hypocalcemia, palate and speech disorders, feeding and gastrointestinal disorders, immunodeficiency, recurrent infections, neurodevelopmental and psychiatric disorders, and congenital heart disease. Approximately 60–80% of patients have a cardiac malformation most commonly including a subset of conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B), conoventricular and/or atrial septal defects, and aortic arch anomalies. Cardiac patients with a 22q11.2 deletion do not generally experience higher mortality upon surgical intervention but suffer more peri‐operative complications than their non‐syndromic counterparts. New guidelines suggest screening for a 22q11.2 deletion in the patient with tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, conoventricular septal defects as well as those with an isolated aortic arch anomaly. Early identification of a 22q11.2 deletion in the neonate or infant when other syndromic features may not be apparent allows for timely parental screening for reproductive counseling and anticipatory evaluation of cardiac and noncardiac features. Screening the at‐risk child or adult allows for important age‐specific clinical, neurodevelopmental, psychiatric, and reproductive issues to be addressed.     

Antibody deficiency in adults with 22q11.2 deletion syndrome

There are limited data on immunological disorders, infection profile, and autoimmunity among adults with the 22q11.2 deletion syndrome (22q11.2DS) in the literature. To expand this knowledge base, we evaluated immunoglobulin levels, lymphocyte subsets, and T-cell function in 26 adults, consecutively referred to our 22q11.2DS multidisciplinary team. Their medical records were also reviewed with respect to frequency and severity of infections and autoimmune disorders. Six patients had low immunoglobulin levels; among these patients, one had a combined IgA and IgG1 deficiency, one had an isolated IgG3 deficiency, and four had a profound antibody deficiency comparable to common variable immunodeficiency (CVID). Three of the patients with profound antibody deficiency showed signs of reduced T-cell function measured as a low response to mitogen and/or antigen stimulation. The four patients with profound antibody deficiency suffered from more severe infections than the rest of the patient group. Three of them also had a history of both immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AHA). Our results suggest that a subgroup of individuals with 22q11.2DS can develop a severe antibody deficiency associated with lower respiratory tract infections and autoimmune conditions. Early diagnosis of hypogammaglobulinemia among these individuals is important in order to provide optimal treatment. We therefore recommend an immunological evaluation and follow-up among adults with 22q11.2DS who have a history of autoimmune conditions or recurrent infections.     

Palatal evaluation and treatment in 22q11.2 deletion syndrome

Palatal involvement occurs commonly in patients with 22q11.2 Deletion Syndrome (22qDS), and includes palatal clefting and velopharyngeal dysfunction in the absence of overt or submucous clefts. The reported incidence and distribution of palatal abnormalities vary in the literature. The aim of this article is to revisit the incidence and presenting features of palatal abnormalities in a large cohort of patients with 22qDS, summarize the surgical treatments performed in this cohort, and provide an overview of surgical treatment protocols and management guidelines for palatal abnormalities in this syndrome. Charts of 1,121 patients seen through the 22q and You Center at the Children's Hospital of Philadelphia were reviewed for palatal status, demographic factors, deletion size, and corrective surgical procedures. Statistical analysis was performed using Pearson's chi‐squared test to identify differences between gender, deletion size, and palatal abnormality. Of the patients with complete evaluations, 67% were found to have a palatal abnormality. The most common finding was velopharyngeal dysfunction in 55.2% of patients, and in 33.3% of patients, this occurred in the absence of palatal clefting. There was no significant difference in the incidence of palatal abnormalities by gender; however, a difference was noted among race (p < 0.01) and deletion sizes (p < 0.01). For example, Caucasian and Asian patients presented with a much higher prevalence of palatal abnormalities, and conversely those with nested deletions presented with a much lower rate of palatal defects. Overall, 26.9% of patients underwent palatal surgery, and the most common indication was velopharyngeal dysfunction. Palatal abnormalities are a hallmark feature of 22q11.2 Deletion Syndrome; understanding the incidence, presenting features, and treatment protocols are essential for practitioners counseling and treating families affected with this disorder.     

Immunologic reconstitution in 22q deletion (DiGeorge) syndrome

Adoptive transfer of mature T cells (ATMTC) through bone marrow (BM) transplantation, first attempted over 20 years ago, has recently emerged as a successful therapy for complete 22q deletion syndrome (22qDS). This provides a potential option to thymic transplantation (TT) for immune reconstitution in 22qDS. Compared to thymic transplant, ATMTC is an easier procedure to accomplish and is available at more centers. However, there are differences in the nature of the T-cell reconstitution that results. Predictably, more naïve T cells and recent thymic emigrants are present in patients treated with thymus transplant. There are no significant differences in mortality between the two procedures, but the number of patients is too limited to conclude that the procedures are equally effective. Adoptive transfer should be pursued as a reasonable treatment for 22qDS patients requiring immune reconstitution when thymus transplant is not available.     

Sclerocornea associated with the chromosome 22q11.2 deletion syndrome

Reported ocular findings in the 22q11.2 deletion syndrome (which encompasses the phenotypes of DiGeorge, velocardiofacial, and Takao (conotruncal-anomaly-face) syndromes) have included posterior embryotoxon (prominent, anteriorly displaced Schwalbe's line at the corneal limbus or edge), retinal vascular tortuosity, eyelid hooding, strabismus, and astigmatism. We present seven 22q11.2 patients from multiple centers with sclerocornea, an eye finding previously unreported in the literature. Four boys and three girls were identified with sclerocornea, systemic DGS/VCFS findings, and fluorescence in situ hybridization (FISH)-confirmed microdeletion at chromosome 22q11.2. FISH diagnosis was perinatal in six patients but at 2 years of age in one child. Sclerocornea was bilateral in five patients. Findings included descemetocele (five eyes), microophthalmos (one eye), iridocorneal adhesions (one bilateral case), and severe anterior segment dysgenesis (one eye). Two patients underwent bilateral corneal transplantation; another two were scheduled for possible unilateral transplant. Sclerocornea is a static congenital condition in which the cornea is opaque and vascularized and resembles the sclera. The novel finding of sclerocornea suggests that a genetic locus at 22q11.2 may be involved in anterior segment embryogenesis. In most of our patients, the diagnostic process was underway, but in one patient 22q11.2 deletion was not suspected until after the child had already been undergoing treatment for sclerocornea for 2 years. Sclerocornea should be added to the clinical manifestations of the 22q11.2 deletion syndrome. Ophthalmologists diagnosing sclerocornea in children with systemic findings suggestive of 22q11.2 deletion should ensure appropriate genetic referral.     

Prenatal and postnatal diagnosis of 22q11.2 deletion syndrome

Microdeletion of chromosome 22q11.2, the most common human deletion syndrome encompasses a wide spectrum of abnormalities. Many clinical or ultrasonographic findings may support deletion studies, either in utero or in the post-natal period. The objective of our study was to evaluate the circumstances of 22q11.2 deletion diagnosis in a single centre of genetics during a 12 years period. Testing for 22q11.2 deletion was performed in 883 cases. Congenital heart defect was the most common reason for referral. An antenatal 22q11.2 microdeletion was detected in 8 fetuses (4.7%) among 169 pregnancies, all presenting conotruncal anomalies. In one case prenatal diagnosis led to the identification of the deletion in the mildly affected father and had negative impact on the family. During the same period, postnatal 22q11.2 DS was diagnosed in 81 out of 714 patients aged from birth to 42 years (11.3%) (p = 0.02). A CHD was present in 37 (45.7%). This figure is significantly lower than the 75% commonly reported. These results suggest that deletion studies could be justifiable in fetuses with non-cardiac prenatal sonographic findings that have been reported in association with 22q11.2 DS. However, as most of these malformations are rather common and non specific, systematic 22q11.2 testing is not justifiable. In such cases, careful cardiac and thymus examination could provide additional clues for 22q11.2 testing. In addition parents should be given accurate information before antenatal or postnatal testing, including the wide variability of the clinical phenotype, the impossibility to establish a precise prognosis concerning psychomotor development and psychiatric risks.     

Selective IgM deficiency and 22q11.2 deletion syndrome.

BACKGROUND: The 22q11.2 deletion syndrome is a common chromosomal disorder with highly variable phenotypic expression and immunologic defects. Humoral immunity is mostly unaffected, but selective IgA deficiency occurs in up to 13% of patients. Selective IgM deficiency associated with 22q11.2 deletion has been reported in 1 patient. OBJECTIVE: To describe another 2 patients with 22q11.2 deletion syndrome and IgM deficiency. METHODS: Patient 1 was a 6-year-old boy with recurrent otitis media, sinopulmonary infections, wheezing, and speech delay. His serum IgM level was 18 mg/dL, and his IgA and IgG levels were normal. Antibody titers to protein and carbohydrate antigens were protective. Workup for velopharyngeal insufficiency resulted in the diagnosis of 22q11.2 deletion syndrome 3 years later. Patient 2 was a 14-year-old girl diagnosed as having 22q11.2 deletion at 9 years of age after presenting with neonatal seizures, atrial and ventricular septal defects, recurrent otitis media, mental retardation, and asthma. Her serum IgM level was 11 mg/dL, with normal IgG and IgA levels. Antibody titers to protein and carbohydrate antigens were protective. Patient 3 was a previously described 15-year-old girl with persistently draining ears, 22q11.2 deletion, and an IgM level less than 6 mg/dL. Her clinical and laboratory features are summarized. RESULTS: Results of further testing on the patients, including lymphocyte enumeration, were normal. The literature is reviewed regarding decreased IgM levels in 22q11.2 deletion syndrome. CONCLUSIONS: Fluorescence in situ hybridization analysis for chromosome 22q11.2 deletion should be considered in patients with selective IgM deficiency, especially if concurrent chronic otitis media, developmental delay, velopharyngeal insufficiency, or dysmorphic features are present.