Case Report: Sequential postzygotic HRAS mutation and gains of the paternal chromosome 11 carrying the mutated allele in a patient with epidermal nevus and rhabdomyosarcoma: evidence of a multiple-hit mechanism involving HRAS in oncogenic transformation.

We report a 7-year-old boy born with epidermal nevi (EN) arranged according to Blaschko's lines involving the face and head, right upper limb, chest, and left lower limb, who developed a left paratesticular embryonal rhabdomyosarcoma at 18 months of age. Parallel sequencing identified a gain-of-function variant (c.37G>C, p.Gly13Arg) of HRAS in both epidermal nevus and tumor but not in leukocytes or buccal mucosal epithelial cells, indicating its postzygotic origin. The variant accounted for 33% and 92% of the total reads in the nevus and tumor DNA specimens, respectively, supporting additional somatic hits in the latter. DNA methylation (DNAm) profiling of the tumor documented a signature consistent with embryonal rhabdomyosarcoma and CNV array analysis inferred from the DNAm arrays and subsequent MLPA analysis demonstrated copy number gains of the entire paternal chromosome 11 carrying the mutated HRAS allele, likely as the result of paternal unidisomy followed by subsequent gain(s) of the paternal chromosome in the tumor. Other structural rearrangements were observed in the tumours, while no additional pathogenic variants affecting genes with role in the RAS-MAPK and PI3K-AKT-MTOR pathways were identified. Our findings provide further evidence of the contribution of "gene dosage" to the multistep process driving cell transformation associated with hyperactive HRAS function.

Kagami-Ogata Syndrome: Case Series and Review of Literature.

Kagami-Ogata syndrome (KOS) (OMIM #608149) is a genetic imprinting disorder affecting chromosome 14 that results in a characteristic phenotype consisting of typical facial features, skeletal abnormalities including rib abnormalities described as "coat hanger ribs," respiratory distress, abdominal wall defects, polyhydramnios, and developmental delay. First identified by Wang et al in 1991, over 80 cases of KOS have been reported in the literature. KOS, however, continues to remain a rare and potentially underdiagnosed disorder. In this report, we describe two unrelated male infants with differing initial presentations who were both found to have the characteristic "coat hanger" rib appearance on chest X-ray, raising suspicion for KOS. Molecular testing confirmed KOS in each case. In addition to these new cases, we reviewed the existing cases reported in literature. Presence of polyhydramnios, small thorax, curved ribs, and abdominal wall defects must alert the perinatologist toward the possibility of KOS to facilitate appropriate molecular testing. The overall prognosis of KOS remains poor. Early diagnosis allows for counseling by a multidisciplinary team and enables parents to make informed decisions regarding both pregnancy management and postnatal care.

Biparental/androgenetic mosaicism in a male with features of overgrowth and placental mesenchymal dysplasia.

Biparental/androgenetic mosaicism is a rarely diagnosed condition in humans. It is typically ascertained prenatally on the basis of placental mesenchymal dysplasia. Fetal outcome can range from demise due to intrauterine growth retardation to term delivery. Most of the published cases of liveborns represent females that are either completely normal or have features of Beckwith-Wiedemann syndrome. Only two healthy liveborn males with mosaicism detected in the placenta have been described to date. Here, we report another liveborn male with hepatic mesenchymal hamartoma, soft tissue overgrowth on his right fifth toe, hemangiomas over his chest, right buttock and foot, anemia, thrombocytopenia and congenital hypothyroidism with biparental/androgenetic mosaicism detected in the toe mass in addition to the placenta. This new case adds to the existing literature of individuals with biparental/androgenetic mosaicism and expands the range of clinical presentations that may be seen in male patients with this condition. This study also illustrates the important use of single-nucleotide polymorphism microarray in conjunction with short-tandem repeat analysis on affected tissue to provide a diagnosis for patients with features of overgrowth and prior, non-diagnostic, genetic analyses of their peripheral blood.

Paternal uniparental disomy of chromosome 19 in a pair of monochorionic diamniotic twins with dysmorphic features and developmental delay.

BACKGROUND: We report here clinical, cytogenetic and molecular data for a pair of monochorionic diamniotic twins with paternal isodisomy for chromosome 19. Both twins presented with dysmorphic features and global developmental delay. This represents, to our knowledge, the first individual human case of paternal uniparental disomy for chromosome 19 (UPD19). METHODS: Whole-exome sequencing, together with conventional karyotype and SNP array analysis were performed along with genome-wide DNA methylation array for delineation of the underlying molecular defects. RESULTS: Conventional karyotyping on amniocytes and lymphocytes showed normal karyotypes for both twins. Whole-exome sequencing did not identify any pathogenic sequence variants but >5000 homozygous exonic variants on chromosome 19, suggestive of UPD19. SNP arrays on blood and buccal DNA both showed paternal isodisomy for chromosome 19. Losses of imprinting for known imprinted genes on chromosome 19 were identified, including ZNF331, PEG3, ZIM2 and MIMT1. In addition, imprinting defects were also identified in genes located on other chromosomes, including GPR1-AS, JAKMP1 and NHP2L1. CONCLUSION: Imprinting defects are the most likely cause for the dysmorphism and developmental delay in this first report of monozygotic twins with UPD19. However, epigenotype-phenotype correlation will require identification of additional individuals with UPD19 and further molecular analysis.