Atypical Prader-Willi and 15q13.3 Microdeletion Syndromes in a Patient with an Unbalanced Translocation.

Prader-Willi syndrome (PWS) and recurrent 15q13.3 microdeletion syndrome can be caused by genomic rearrangements in the complex 15q11q13 chromosomal region. Here, we describe the first female child with PWS and 15q13.3 microdeletion syndrome resulting from an unusual 10.7-Mb deletion from 15pter to 15q13.3 due to an unbalanced de novo 15;19 translocation. The patient presents with hypotonia, microcephaly, developmental delay with lack of speech, intellectual disability, happy demeanor, clinodactyly of the 4th and 5th fingers, and dysmorphic facial features discordant for PWS and consistent with an atypical phenotype.

Clinical and cytogenomic findings in OAV spectrum.

The oculoauriculovertebral spectrum (OAVS) is characterized by anomalies involving the development of the first and second pharyngeal arches during the embryonic period. The phenotype is highly heterogeneous, involving ears, eyes, face, neck, and other systems and organs. There is no agreement in the literature for the minimum phenotypic inclusion criteria, but the primary phenotype involves hemifacial microsomia with facial asymmetry and microtia. Most cases are sporadic and the etiology of this syndrome is not well known. Environmental factors, family cases that demonstrate Mendelian inheritance, such as preauricular appendages, microtia, mandibular hypoplasia, and facial asymmetry; chromosomal abnormalities and some candidate genes suggest a multifactorial inheritance model. We evaluated clinical, cytogenomic and molecularly 72 patients with OAVS, and compared our findings with patients from the literature. We found 15 CNVs (copy number variations) considered pathogenic or possibly pathogenic in 13 out of 72 patients. Our results did not indicated a single candidate genomic region, but recurrent chromosomal imbalances were observed in chromosome 4 and 22, in regions containing genes relevant to the OAVS phenotype or related to known OMIM diseases suggesting different pathogenic mechanisms involved in this genetically and phenotypic heterogeneous spectrum.

Deletion 21pterq22.11: Report of a Patient with Dysmorphic Features, Hypertonia, and Café-au-Lait Macules and Review of the Literature.

Partial monosomy 21 results in a great variability of clinical features that may be associated with the size and location of the deletion. In this study, we report a 22-month-old girl who showed a 45,XX,add(12)(p13)dn,-21 karyotype. The final cytogenomic result was 45,XX,der(12)t(12;21)(p13;q22.11) dn,-21.arr[hg19] 21q11.2q22.11(14824453_33868129)×1 revealing a deletion from 21pter to 21q22.11. Clinical manifestation of the patient included hypertonia, a long philtrum, epicanthic folds, low-set ears, and café-au-lait macules - a phenotype considered as mild despite the relatively large size of the deletion compared to patients from the literature.

Miller-Dieker Syndrome due to a 5.5-Mb 17p Deletion in a 17;Y Pseudodicentric Chromosome.

Miller-Dieker syndrome (MDS) is a contiguous gene deletion syndrome in which almost all patients present de novo 17p13.3 deletions. We report on a male infant with MDS and an unusual unbalanced translocation involving chromosomes Y and 17 that resulted in a large 5.5-Mb 17pterp13.2 deletion and a karyotype with 45 chromosomes. Apart from the deletion of the MDS critical region, the deletion of additional distal genes seemed to have no major influence on the patient's phenotype, since he did not show any unusual clinical findings that are not commonly described in MDS patients.

Unusual Duplication in the Pericentromeric Region of Chromosome 9 in a Patient with Phenotypic Alterations.

Several alterations involving the pericentromeric region of chromosome 9 are considered as normal population variants. These heterochromatic variants or heteromorphisms can include 9qh+, 9cen+, 9ph+, 9ph-, inv(9)(p11q13), and other patterns which can only be defined by FISH studies. However, some heteromorphisms have been found more frequently in patients with several clinical disorders. Here, we report on a patient with intellectual disability, language and neurodevelopmental delay, as well as facial dysmorphism and an unusual chromosome 9. While the banding karyotype was indicative of a simple pericentric inversion of one chromosome 9 [46,XX,inv(9)(p12q13)], array comparative genomic hybridization showed a 6-Mb duplication, including 22 genes: arr[hg19] 9p13.1p11.2(38,869,901- 44,870,714)×3 dn. Molecular cytogenetics using a panel of probes specific for the pericentromeric region of chromosome 9 showed an unusual, rearranged chromosome 9, der(9)(pter→p11.2::q21.11→q12::p11.2→p13.2::q12→p11.2::q21.11→qter), that has not been described before. The patient's phenotypic alterations are probably due to the de novo 6-Mb 9p duplication, although a review of similar cases showed some reports considering this duplication in the euchromatic region as a benign variant. Interestingly, this is the first report of a possible adverse inversion loop formation due to a known heteromorphic pericentric inversion present in the phenotypically normal father of the patient.

Wolf-Hirschhorn Syndrome with Epibulbar Dermoid: An Unusual Association in a Patient with 4p Deletion and Functional Xp Disomy.

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene and multiple malformation syndrome that results from a deletion in the 4p16.3 region. We describe here a 6-month-old girl that presented with WHS features but also displayed unusual findings, such as epibulbar dermoid in the left eye, ear tags, and left microtia. Although on G-banding her karyotype appeared to be normal, chromosomal microarray analysis revealed an ∼13-Mb 4p16.3p15.33 deletion and an ∼9-Mb Xp22.33p22.31 duplication, resulting from a balanced maternal t(X;4)(p22.31;p15.33) translocation. The patient presented with functional Xp disomy due to an unbalanced X-autosome translocation, a rare cytogenetic finding in females with unbalanced rearrangements. Sequencing of both chromosome breakpoints detected no gene disruption. To the best of our knowledge, this is the first patient described in the literature with WHS and epibulbar dermoid, a typical characteristic of the oculoauriculovertebral spectrum (OAVS). Our data suggest that possible candidate genes for OAVS may have been deleted along with the WHS critical region.

Atypical 581-kb 22q11.21 Deletion in a Patient with Oculo-Auriculo-Vertebral Spectrum Phenotype.

The oculo-auriculo-vertebral spectrum (OAVS) is defined as a group of malformations involving the ears, mouth, mandible, eyes, and cervical spine. Establishing an accurate clinical diagnosis of OAVS is a challenge for clinical geneticists, not only because these patients display heterogeneous phenotypes, but also because its etiology encompasses environmental factors, unknown genetic factors and different chromosome aberrations. To date, several chromosomal abnormalities have been associated with the syndrome, most frequently involving chromosome 22. In the literature, six 22q11.2 microdeletions have been described within the same region, suggesting possible OAVS candidate genes in this segment. Here, we report on a patient with an ∼581-kb 22q11.21 deletion, detected by genomic array and MLPA. This is the 7th case described with OAVS and 22q deletion, suggesting that the 22q11.2 region may be related to the regulation of body symmetry and facial development.