Ring Chromosome 15: Expanding the Phenotype

Summary: Ring chromosome 15: expanding the phenotype: Ring chromosome 15 is a rare disorder, with less than 50 cases reported in the literature to date. We report the clinical and cytogenetic evaluation of a patient with ring chromosome 15. Diagnostic tests including echocardiography, abdominal ultrasound, brain computerized tomography (CT), magnetic resonance imaging (MRI) and electroencephalogram (EEG) were done. Clinical examination of the patient revealed the characteristic features of ring chromosome 15, such as growth retardation, hypertelorism, frontal bossing, a highly arched palate, small hands and feet and cafe-au-lait spots. In addition, the patient presented with a mild intellectual disability, a congenital atrial septal heart defect, and abnormal EEG records. We also report 2 novel findings, which to our knowledge; have not been reported before in ring chromosome 15 patients: large areas of hyperpigmentation on the front of both legs and feet and hypogenesis of the corpus callosum. Cytogenetic studies using both conventional G-banding and fluorescence in situ hybridization (FISH) with a Sub Tel 15q probe confirmed the diagnosis of ring chromosome 15.Key-words: Ring chromosome 15 - FISH - Subtelomeric region - Hypogenesis of corpus callosum - Cafe-au-lait pigmentation.___INTRODUCTIONRing chromosomes usually arise from breaks at the ends of both chromosome arms, followed by fusion of the broken ends (25). They may also result from fusion of subtelomeric sequences or telomere-telomere fusion without deletion, leading to incomplete ring chromosome formation (2, 8). Ring chromosomes have been reported in all human chromosomes (24). The clinical phenotype of patients with ring chromosomes may be related to different factors as gene haploinsufficiency, duplications or the instability of the ring. However, the epigenetic factors due to the circular architecture of ring chromosomes should also be considered, since even complete ring chromosomes may result in phenotypic alterations (5).Ring chromosome 15 (r(l 5)} is a rare genetic disorder which was first described by Jacobsen and his colleagues (10). To our knowledge, less than 50 patients with r( 15) have been described in literature with a wide diversity of phenotypic presentation. The most common shared features in patients with ring (15) are: severe intrauterine growth retardation, microcephaly, hypertelorism, ear anomaly, high arched palate, intellec- tuai disability, clinodactyly and brachydactyly of the fifth finger, small hands and feet, and multiple hyperpigmented and/or hypopigmented spots (12). Severe phenotypes were also observed as congenital heart defects and renal anomalies, others presented with hypotonia, hydrocephaly, micrognathia, retinal abnormalities, behavioral disorders and speech delay. Hypogenitalism, cryptorchidism and azospermia were reported in males. On the contrary, female patients had normal sexual development and gonadal function, although uterine hypoplasia has been reported (1,18, 22, 24). A precise genotype-phenotype correlation of ring 15 chromosome is still difficult to be established because of the differences in the breakpoints, level of mosaicism and ring instability that resulted in a variable loss of genetic materials (6).CLINICAL REPORTWe report a 2 years old female patient complaining of failure to thrive and delayed milestones of development who was referred to the Department of Clinical Genetics, National Research Center, Egypt. She was the offspring of a non-consanguineous 24 and 27 years old mother and father, respectively. The pregnancy and delivery histories were unremarkable except for intrauterine growth retardation and low birth weight. On physical examination, the proband was alert, recognized the surrounding and able to follow commands. She had delayed milestones of development, could stand with support and vocalized with single syllable word.Her current weight was 5.8 kg (-4. …