22q11.2 duplication syndrome: Two new familial cases with some overlapping features with DiGeorge/velocardiofacial syndromes

Abstract

Twenty-one patients, including our two cases, with variable clinical phenotype, ranging from mild learning disability to severe congenital malformations or overlapping features with DiGeorge/velocardiofacial syndromes (DG/VCFS), have been shown to have a chromosome duplication 22q11 of the region that is deleted in patients with DG/VCFS. The reported cases have been identified primarily by interphase FISH and could have escaped identification and been missed by routine cytogenetic analysis. Here we report on two inherited cases, referred to us, to rule out 22q11 microdeletion diagnosis of VCFS. The first patient was a 2-month-old girl, who presented with cleft palate, minor dysmorphic features including short palpebral fissures, widely spaced eyes, long fingers, and hearing loss. Her affected mother had mild mental retardation and learning disabilities. The second patient was a 7(1/2)-year-old boy with velopharyngeal insufficiency and mild developmental delay. He had a left preauricular tag, bifida uvula, bilateral fifth finger clinodactyly, and bilateral cryptorchidism. His facial features appeared mildly dysmorphic with hypertelorism, large nose, and micro/retrognathia. The affected father had mild mental retardation and had similar facial features. FISH analysis of interphase cells showed three TUPLE1-probe signals with two chromosome-specific identification probes in each cell. FISH analysis did not show the duplication on the initial testing of metaphase chromosomes. On review, band q11.2 was brighter on one chromosome 22 in some metaphase spreads. The paucity of reported cases of 22q11.2 microduplication likely reflects a combination of phenotypic diversity and the difficulty of diagnosis by FISH analysis on metaphase spreads. These findings illustrate the importance of scanning interphase nuclei when performing FISH analysis for any of the genomic disorders.

Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes

“…Importantly, in patients for whom parental samples were available we observed a high frequency of familial duplications (two of the five probands with common ϳ3-Mb and proximal "nested" ϳ1.5-Mb duplications, and both of the probands with smaller distal atypical duplications for whom parental samples were available), consistent with what has been observed by others. 9,23,24 These results emphasize the importance of investigating other family members for the microduplication.…”

“…There is some degree of overlap with features seen in VCFS/DGS but to a lesser extent than the first reports of 22q11.2 microduplications indicated, which were limited by ascertainment bias. 9,23,24 Our study avoids this bias to the extent that clinical samples were received for a variety of indications (including developmental delay, dysmorphic features, congenital anomalies, autism, and others), although it is not a truly population-based survey. Four of the five probands with ϳ3-Mb and ϳ1.5-Mb proximal nested microduplications in our cohort were referred for testing because of developmental or speech delay and dysmorphic features.…”

“…This is the only report of ambiguous genitalia in a patient with microduplication of 22q11.2, although other patients have been noted to have a variety of urogenital abnormalities, including urethral stenosis, mild hypospadias, and hydronephrosis 9 and cryptorchidism. 24 Cryptorchidism and hypospadias also occur in patients with chromosome 22q11.2 deletions 54 along with other malformations of the renal system. It is thus plausible that a dosage-sensitive gene within this interval could contribute to developmental disorders of the genitourinary tract, albeit with reduced penetrance because only a subset of patients with copy number abnormalities of chromosome 22q11.2 show evidence of genitourinary malformations.…”

“…3 Additional case reports led to the further characterization of the duplication 22q11.2 syndrome as a new genomic disorder that is complementary to, but distinct from, the 22q11.2 deletion syndrome. 9,[23][24][25] Molecular analyses have revealed that individuals with 22q11.2 microduplication typically carry a ϳ3-Mb duplication that is the reciprocal of the common ϳ3-Mb deletion found in DGS/VCFS, although larger duplications of ϳ4-Mb and ϳ6-Mb that include the DGS/VCFS region were also reported. 9 The phenotypes previously associated with microduplications of 22q11.2 include cardiovascular anomalies, velopharyngeal insufficiency with or without cleft palate, hearing loss, growth and developmental delay, learning disabilities, behavioral problems, and various dysmorphic features.…”

“…9 The phenotypes previously associated with microduplications of 22q11.2 include cardiovascular anomalies, velopharyngeal insufficiency with or without cleft palate, hearing loss, growth and developmental delay, learning disabilities, behavioral problems, and various dysmorphic features. Based on the current literature, the phenotypes in patients with microduplication of 22q11.2 may have partial overlap with DGS/ VCFS 9,23,24 ; however, this degree of overlap is almost certainly the result of ascertainment bias, because the patients thus far reported to harbor 22q11.2 microduplications were generally selected on the basis of clinical features that prompted referral to rule out VCFS/DGS microdeletion. 9,25 Despite the frequency with which 22q11.2 microdeletion occurs, only a small number of patients with microduplication of this region have been described to date; this may be, in part, owing to a highly variable and mild phenotype such that many individuals with microduplications within 22q11.2 may not undergo testing.…”