Inv dup(22), del(22)(q11) and r(22) in the father of a child with DiGeorge syndrome

We here report a unique inherited case of DiGeorge syndrome. The asymptomatic father had a mosaic karyotype with a 21q11 deletion in three different cell lines. In two of the cell lines there was an additional supernumerary inv dup(22) or an r(22), respectively. In the third cell line the del(22) was the sole anomaly. FISH analysis showed that both the inv dup(22) and the r(22) included the DGS region. We hypothesize that an inter-chromosomal recombination between inverted repeats, together with a recombination between sister chromatids during meiosis I, gave rise to a deletion of 22q11 as well as an inv dup(22) containing the DGS region. The inv dup(22) was later rearranged into a ring chromosome during mitosis which was subsequently lost during cell division, thereby resulting in three different cell lines. This is the first case reported with an inv dup(22) and a del(22)(q11) in the same cell line. Our findings support a related mechanism in the formation of these two rearrangements mediated by low-copy repeats.     

Type I diabetes mellitus in a patient with chromosome 22q11.2 deletion syndrome

We describe a patient with type I diabetes, clinical findings consistent with velocardiofacial syndrome, and a chromosome 22q11.2 deletion. A nine-year-old boy presented with a history of polyuria, polydipsia, weight loss, hyperglycemia, ketosis, serum insulin antibodies, and a low C-peptide level. He had distinctive facial features, learning disabilities, short stature, and a history of glottic web and clubfoot. Although a normal karyotype was obtained, fluorescence in situ hybridization (FISH) revealed a submicroscopic deletion in the DiGeorge/velocardiofacial syndrome critical region at 22q11.2. His maternal half-brother also carried a chromosome 22q11.2 deletion. His mother has similar facial features and hypoparathyroidism. Autoimmune problems associated with chromosome 22q11.2 deletions have been reported. We suggest that the defects in immune regulation due to T-cell deficiency in chromosome 22q11.2 deletion syndrome may predispose to autoimmune disorders, including type I diabetes mellitus.     

Hemophagocytic lymphohistiocytosis in a patient with deletion of 22q11.2

We report on a new patient with deletion of 22q11 associated with hemophagocytic lymphohistiocytosis and a fatal outcome. She had minor facial anomalies and cardiac malformation corresponding to those described in del (22q11) syndrome, normal T and B cell function and NK activity; bone marrow aspiration showed active erythrophagocytosis. Our case in addition to two other children reported previously suggest that such a rare association between lymphocyte-macrophage activation and deletion of 22q11 may be more frequent than previously recognized. Am. J. Med. Genet. 87:329–330, 1999. © 1999 Wiley-Liss, Inc.     

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.     

Mosaicism for a tandem duplication dup(1)(q12q22) in an 18 year old female.

The clinical features and cytogenetic results of an 18 year old mentally handicapped female found to be a mosaic for a tandem duplication of chromosome 1 (46,XX,dup(1)(q12q22)/46,XX) are reported. The case is compared with the three previously described cases and possible mechanisms for the origin of the duplication are discussed. This patient was not found to have features of Proteus syndrome which was previously reported in a subject mosaic for a tandem duplication involving chromosome (1)(q11q25).     

Source monitoring for actions in adolescents with 22q11.2 deletion syndrome (22q11DS)

BACKGROUND: Source monitoring consists in identifying the origin of mental events. Recent research suggests that confusions over internally generated mental events may represent a cognitive marker for increased proneness to psychotic symptoms and disorders. We have examined source monitoring for actions in adolescents with the 22q11.2 deletion syndrome (22q11DS), a neurogenetic disease associated with high rates of schizophrenia during adulthood, and expected to observe source monitoring deficits in comparison to IQ-matched and typically developing controls. METHOD: Eighteen adolescents with 22q11DS, 17 adolescents matched for age and IQ, and also 17 adolescents matched for age participated in this study. Our adapted action monitoring paradigm asked subjects to visualize a series of actions in three different conditions: (1) visualize themselves performing the action; (2) visualize the experimenter performing the action; or (3) simply repeat the action statements without visualization of the action performer. RESULTS: The adolescents with 22q11DS performed adequately in terms of recognition (hits), but in comparison to both control groups, they committed more source confusions on correctly recognized items. Further examination revealed that the adolescents were more likely to demonstrate confusions between exterior sources in which the self was not involved. CONCLUSIONS: Source monitoring deficits can be observed in adolescents with 22q11DS, a syndrome putting them at high risk for developing schizophrenia. These deficits are discussed in terms of early cognitive processes associated with genetic risk for schizophrenia.     

17p11.2p12 triplication and del(17)q11.2q12 in a severely affected child with dup(17)p11.2p12 syndrome

Multiple congenital anomalies/mental retardation syndromes due to genomic rearrangements involving chromosome 17p11.2 include deletion resulting in Smith-Magenis syndrome and a reciprocal duplication of the same region resulting in the 17p11.2 duplication syndrome. We present the clinical and molecular analysis of an 8-year-old male with a dup(17p11.2p12) who was evaluated for unusual severity of the phenotype. Fluorescent in situ hybridization (FISH) analysis not only confirmed the 17p duplication but also identified an approximately 25% mosaicism for tetrasomy 17p11.2p12. Whole-genome array comparative genomic hybridization (aCGH) was performed to identify other genomic rearrangements possibly contributing to the severe phenotype and the unusual features in the patient. The 17p duplication was determined by FISH and aCGH to encompass approximately 7.5 Mb, from COX10 to KCNJ12. An approximately 830 Kb deletion of 17q11.2q12, including exon 1 of an amiloride-sensitive cation channel neuronal gene, ACCN1, was also identified by aCGH; breakpoints of the deletion were confirmed by FISH. Sequencing the non-deleted allele of ACCN1 did not show any mutations. Western analysis of human tissue-specific proteins revealed that ACCN1 is expressed not only in the brain as previously reported but also in all tissues examined, including heart, liver, kidneys, and spleen. The large-sized 17p11.2p12 duplication, partial triplication of the same region, and the 17q11.2q12 deletion create a complex chromosome 17 rearrangement that has not been previously identified. This is the first case of triplication reported for this chromosome. Our study emphasizes the utility of whole-genome analysis for known cases with deletion/duplication syndromes with unusual or severe phenotypes.     

Early language measures associated with later psychosis features in 22q11.2 deletion syndrome

The 22q11.2 deletion syndrome (22q11DS) is associated with impaired cognitive functions and increased risk for schizophrenia spectrum disorders. Speech and language deficits are prominent, with evidence of decline anteceding emergence of psychosis. There is paucity of data examining language function in children with 22q11DS with follow‐up assessment of psychosis spectrum (PS) symptoms. We examined the association between early language measures, obtained clinically, and PS status, obtained on average 10.1 years later, in 166 youths with 22q11DS, with repeated language testing in 48. Participants were administered the Preschool Language Scale (receptive/expressive), and/or, for school aged children, the Clinical Evaluation of Language Fundamentals (receptive/expressive), and age appropriate IQ tests. The structured interview for prodromal syndromes (SIPS) assessed PS symptoms. We found that performance on all preschool measures showed age associated decline, and males performed more poorly on core composite (receptive/expressive) and receptive language measures. For language assessment later in childhood, poorer performance was consistently associated with subsequent PS status. Furthermore, steeper age‐related decline was seen in the PS group across language measures and marginally for full‐scale IQ. These findings suggest that while preschool language testing is useful in characterizing performance decline in individuals with 22q11DS, it does not robustly differentiate those with subsequent PS from those without. However, language testing in the school age population can help identify individuals with 22q11DS who are at risk for psychosis. Such data are needed for elucidating a lifespan trajectory for affected individuals and may help understand pathways to psychosis applicable to the general population.     

A patient with dup(10p)del(8q) and Pendred syndrome

We report on a severely retarded girl with multiple congenital anomalies. Chromosome studies showed a der (8) chromosome with dup(10p) and deficiency for a small distal segment of 8q. Her father proved to be carrier of a de novo balanced translocation between chromosome 8q and 10p. At 1 year the patient was also found to have the Pendred syndrome, an autosomal recessive defect in thyroid organification. The concurrence of chromosome anomalies and single gene disorders might not be too rare, but can be easily overlooked. Yet there are important consequences for genetic counseling. Moreover, recognition of these concurrences may help gene mapping.     

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.     

Duplication of (12)(pter-q13.3) combined with deletion of (22)(pter-q11.2) in a patient with features of both chromosome aberrations

We report a patient with multiple dysmorphic signs and congenital malformations, representing a combination of clinical features of duplication (12p) and deletion (22)(q11.2) syndromes. The girl had overgrowth at birth, showed abnormal cranio-facial findings, cleft uvula, a complex conotruncal heart defect, a polycystic right kidney, and an umbilical hernia. She died at the age of 6 months of cardio-respiratory failure. Cytogenetic examination demonstrated a derivative chromosome 12 replacing one of the two chromosomes 22. The paternal karyotype was normal 46,XY while the mother's karyotype was 46,XX,rcp(12;22)(q13.2;q11.2). According to the published data, all patients with deletion 22q11.2 combined with other unbalanced chromosomal aberration have a more severe clinical expression than those with interstitial deletions.     

Chromosome 22q11.2 deletion in a boy with Opitz (G/BBB) syndrome

This report is on a 14-month-old boy with manifestations of Opitz (G/BBB) syndrome in whom a 22q11.2 deletion was found. Deletion analysis was requested because of some findings in this patient reminiscent of velocardiofacial (VCF) syndrome. The extent of aspiration and of respiratory symptoms in this child is not usually seen in VCF syndrome. Opitz syndrome maps to at least two loci, one on Xp, the other on 22q11.2. © 1996 Wiley-Liss, Inc.