Severe craniosynostosis in an infant with deletion 22q11.2 syndrome

We report a male infant with 22q11.2 deletion syndrome and very severe multi‐sutural craniosynostosis associated with increased intracranial pressure, marked displacement of brain structures, and extensive erosion of the skull. While uni‐ or bi‐sultural craniosynostosis is a recognized (though relatively uncommon) feature of 22q11 deletion syndrome, a severe multi‐sutural presentation of this nature has never been reported. SNP Microarray was otherwise normal and the patient did not have common mutations in FGFR2, FGFR3, or TWIST associated with craniosynostosis. While markedly variable expressivity is an acknowledged feature of deletion 22q11 syndrome, herein we also consider and discuss the possibility that this infant may have been additionally affected with an undiagnosed single gene disorder. © 2012 Wiley Periodicals, Inc.     

Laryngeal atresia type III (glottic web) with 22q11.2 microdeletion: Report of three patients

The clinical manifestations of patients with a 22q11.2 deletion are highly variable and mainly include developmental defects of structures derived from the third and fourth pharyngeal pouches. Laryngeal atresia has occasionally been reported in DiGeorge syndrome as well as in velo-cardio-facial syndrome. We observed three patients with type III laryngeal atresia (glottic web) and 22q11.2 microdeletion. One patient showed a “classical” 22q11.2 deletion phenotype with clinical overlap with DiGeorge and velo-cardio-facial syndromes. However, the pattern of congenital anomalies of the two others was less specific, heart defects and minor anomalies being the only outstanding clinical manifestations suspicious for monosomy 22q11.2. Our findings suggest that laryngeal atresia represents an additional malformation which should prompt investigation of 22q11.2 deletion, especially in combination with congenital heart defects. Am. J. Med. Genet. 70:130–133, 1997. © 1997 Wiley-Liss, Inc.     

Behavior in preschool children with the 22q11.2 deletion syndrome

Children with the 22q11.2 deletion syndrome (22q11DS) are at an increased risk of psychiatric problems from pre‐adolescence; little is known, however, about behavioral problems at a preschool age and the relationship between speech and behavior in this group. Parents of 90 children (aged 1.42–5.99 years) with 22q11DS filled out the Child Behavior Checklist, documenting behaviors including speech problems. Their profiles were compared with those of a comparison group consisting of 33 children with nonsyndromic orofacial clefts without 22q11DS, since both children with 22q11DS and children with clefts are expected to have speech problems. In the 22q11DS group, data on intelligence was acquired by means of formal tests. Parents of children with 22q11DS reported significantly higher mean scores on withdrawn behavior, affective problems and pervasive developmental problems compared to children with nonsyndromic clefts. Approximately 30% of children with 22q11DS had a score above the 97th percentile on at least one of the behavior subscales, indicating psychopathology. In children with 22q11DS, the reported behavioral problems were not associated with speech problems. Behavioral problems were found in 30% of young children with 22q11DS and were unlikely to be caused by speech problems. Within the 22q11DS group, behavioral problems were not related to the degree of cognitive impairment. This shows that many children with 22q11DS, known to be at an increased risk of psychiatric problems from pre‐adolescence, already show behavioral problems before the age of 6 years. © 2012 Wiley Periodicals, Inc.     

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.     

Wilms tumor in a patient with 22q11.2 microdeletion

22q11.2 deletion syndrome is the most common microdeletion syndrome. Wilms tumor is one of the most common solid tumors in childhood yet 22q11.2 deletion and Wilms tumor only once have been reported in the same patient. Here we describe a young patient with subtle clinical findings suggestive of 22q11.2 at the time of diagnosis who subsequently developed Wilms tumor. We assert the importance of a low threshold for screening for 22q11.2 deletion and the associated phenotypes and maintaining vigilance in screening for common primary malignancies in patients with known 22q11.2 deletion.     

The internet is parents' main source of information about psychiatric manifestations of 22q11.2 deletion syndrome (22q11.2DS)

With advances in laboratory technology, an increasing number of potentially pathogenic CNVs is recognised. The phenotypic effects of some CNVs are well characterised, however, it remains unclear how much information reaches the parents of affected children and by what route. The 22q11.2 deletion syndrome (del22q11.2) is caused by the deletion of approximately 40 genes from the long arm of chromosome 22 and was first described in 1955 [1]. Our study reports the extent to which parents of an affected child are aware of the various manifestation of the condition and describes how they first learned about these potential problems.     

Chromosome 22q11.2 deletion syndrome in African-American patients: a diagnostic challenge

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with numerous and variable clinical manifestations including conotruncal heart abnormalities, palatal anomalies, hypoparathyroidism, immune deficiency, and cognitive deficits. The clinical suspicion of this syndrome is often heightened by the presence of characteristic facial features. A previous report highlighted the under‐diagnosis of this condition in African Americans, thought to be related to a paucity of typical facial features. We ascertained the largest cohort (n = 50) of African‐American individuals with 22q11DS reported thus far, across five genetics centers in the United States and report on their facial and other phenotypic features. About of our cohort has at least one dysmorphic facial feature. Auricular abnormalities, especially small ears, are the most common dysmorphic facial feature followed by nasal and ocular abnormalities. Skeletal findings are seen in about 2/3 of our cohort, higher than the typical frequency reported in 22q11DS. Cardiac anomalies, developmental delay, and palatal abnormalities are seen at a lower frequency in our cohort. Thus, it is evident that the features traditionally associated with 22q11DS are difficult to recognize in African‐American individuals with this syndrome, due to both altered frequencies of major anomalies and a non‐classic facial appearance. Therefore, a high index of suspicion is needed to recognize 22q11DS in African‐American individuals. © 2011 Wiley‐Liss, Inc.     

Bernard‐Soulier syndrome associated with 22q11.2 microdeletion

We describe a Japanese girl with Bernard‐Soulier syndrome and 22q11.2 microdeletion. She had viral infections and recurrent thrombocytopenia and hemorrhagic diathesis after cardiac surgery. As congenital heart defects and abnormal immunity are the most common clinical manifestations associated with 22q11.2 deletion, patients with this association may have a greater risk of developing a severe bleeding disorder. © 2001 Wiley‐Liss. Inc.     

Homozygous 22q11.2 distal type II microdeletion is associated with syndromic neurodevelopmental delay

Genomic disorders result from heterozygous copy number variants (CNVs). Homozygous deletions spanning numerous genes are rare, despite the potential contribution of consanguinity to such instances. CNVs in the 22q11.2 region are mediated by nonallelic homologous recombination between pairs of low copy repeats (LCRs), from amongst eight LCRs designated A-H. Heterozygous distal type II deletions (LCR-E to LCR-F) have incomplete penetrance and variable expressivity, and can lead to neurodevelopmental issues, minor craniofacial anomalies, and congenital abnormalities. We report siblings with global developmental delay, hypotonia, minor craniofacial anomalies, ocular abnormalities, and minor skeletal issues, in whom chromosomal microarray identified a homozygous distal type II deletion. The deletion was brought to homozygosity as a result of a consanguineous marriage between two heterozygous carriers of the deletion. The phenotype of the children was strikingly more severe and complex than that of the parents. This report suggests that the distal type II deletion harbors a dosage-sensitive gene or regulatory element, which leads to a more severe phenotype when deleted on both chromosomes.     

Immune status of the murine 22q11.2 deletion syndrome model

Mice modeling the hemizygous deletion of chromosome 22q11.2 (22qMc) have been utilized to address various clinical phenotypes associated with the disease, including cardiac malformations, altered neural circuitry, and behavioral deficits. Yet, the status of the T cell compartment, an important clinical concern among 22q11.2 deletion syndrome (22qDS) patients, has not been addressed. While infancy and early childhood in 22qDS are associated with deficient T cell numbers and thymic hypoplasia, which can be severe in a small subset of patients, studies suggest normalization of the T cell counts by adulthood. We found that adult 22qMc do not exhibit thymic hypoplasia or altered thymic T cell development. Our findings that immune cell counts and inflammatory T cell activation are unaffected in 22qMc lend support to the hypothesis that human 22qDS immunodeficiencies are secondary to thymic hypoplasia, rather than intrinsic effects due to the deletion. Furthermore, the 22q11.2 deletion does not impact the differentiation capacity of T cells, nor their activity and response during inflammatory activation. Thus, 22qMc reflects the T cell compartment in adult 22qDS patients, and our findings suggest that 22qMc may serve as a novel model to address experimental and translational aspects of immunity in 22qDS.     

Anomalies of the genitourinary tract in children with 22q11.2 deletion syndrome

The 22q11.2 deletion syndrome (22q11.2DS) involves multiple organ systems with variable phenotypic expression. Genitourinary tract abnormalities have been noted to be present in up to 30–40% of patients. At our institution, an internationally recognized, comprehensive, and multidisciplinary 22q11.2DS care center has been providing care to these children. We sought to report on the incidence of genitourinary tract anomalies in this large cohort and, therefore, retrospectively reviewed all patients who underwent a complete evaluation from 1992 to March 2017. We identified all children with any genital or urinary tract anomaly. For all children with a diagnosis of hydronephrosis, the underlying etiology was determined, when possible. Overall, 1,073 of 1,267 children with 22q11.2DS underwent renal evaluations at our institution. Hundered Sixty‐Two (15.1%) children had structural abnormalities of their kidneys/urinary tracts. The majority of children with hydronephrosis (63%) had isolated upper tract dilation without any additional diagnoses. Boys were significantly more likely to be diagnosed with a genital abnormality than girls (7.7 vs. 0.5%, p < 0.001). Of the 649 boys in the entire cohort, 24 (3.7%) had cryptorchidism and 24 (3.7%) had hypospadias, which was noted to be mild in all except one boy. Overall, findings of hydronephrosis, unilateral renal agenesis, and multicystic dysplastic kidney occur at higher rates than expected in the general population. Given these findings, in addition to routine physical examination, we believe that all patients with 22q11.2DS warrant screening RBUS at time of diagnosis.     

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.     

Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome

This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.