Continuing role for classical cytogenetics: Case report of a boy with ring syndrome caused by complete ring chromosome 4 and review of literature.

Constitutional ring chromosomes can be found for all human chromosomes and are very rare chromosomal abnormalities. A complete ring chromosome without loss of genetic material results from fusion of subtelomeric regions or telomere-telomere fusion. In cases of complete ring chromosome, an increased incidence of severe growth failure with no or only minor anomalies has been observed and attributed to ring syndrome. Ring syndrome is thought to be caused by "dynamic mosaicism" due to ring instability. We report a 6-year-old boy with de novo ring chromosome 4 and typical characteristics of the ring syndrome, namely, proportionate severe growth failure, microcephaly, and minor anomalies. Cytogenetic studies showed complete ring chromosome 4 with mitotic instability. Microarray gave normal results, thus excluding the loss of detectable genetic material. The literature of complete ring chromosome 4 is reviewed. Our case report supports the theory of ring syndrome. No studies about the effects and possible side effects of growth hormone therapy on patients with ring chromosomes have yet been published. We suggest that cytogenetic monitoring of the rate of secondary aberrations in patients with ring chromosome undergoing growth hormone therapy might be feasible. Since the diagnosis would have been missed by molecular karyotyping, our case report underlines the continuing role of classical cytogenetics for the evaluation of structural chromosomal abnormalities in patients with mental and/or physical anomalies. Standard karyotyping is still indispensable and should have an ongoing role as first-tier analysis together with molecular karyotyping. © 2017 Wiley Periodicals, Inc.

Nosological delineation of congenital ocular motor apraxia type Cogan: an observational study.

BACKGROUND: The nosological assignment of congenital ocular motor apraxia type Cogan (COMA) is still controversial. While regarded as a distinct entity by some authorities including the Online Mendelian Inheritance in Man catalog of genetic disorders, others consider COMA merely a clinical symptom. METHODS: We performed a retrospective multicenter data collection study with re-evaluation of clinical and neuroimaging data of 21 previously unreported patients (8 female, 13 male, ages ranging from 2 to 24 years) diagnosed as having COMA. RESULTS: Ocular motor apraxia (OMA) was recognized during the first year of life and confined to horizontal pursuit in all patients. OMA attenuated over the years in most cases, regressed completely in two siblings, and persisted unimproved in one individual. Accompanying clinical features included early onset ataxia in most patients and cognitive impairment with learning disability (n = 6) or intellectual disability (n = 4). Re-evaluation of MRI data sets revealed a hitherto unrecognized molar tooth sign diagnostic for Joubert syndrome in 11 patients, neuroimaging features of Poretti-Boltshauser syndrome in one case and cerebral malformation suspicious of a tubulinopathy in another subject. In the remainder, MRI showed vermian hypo-/dysplasia in 4 and no abnormalities in another 4 patients. There was a strong trend to more severe cognitive impairment in patients with Joubert syndrome compared to those with inconclusive MRI, but otherwise no significant difference in clinical phenotypes between these two groups. CONCLUSIONS: Systematical renewed analysis of neuroimaging data resulted in a diagnostic reappraisal in the majority of patients with early-onset OMA in the cohort reported here. This finding poses a further challenge to the notion of COMA constituting a separate entity and underlines the need for an expert assessment of neuroimaging in children with COMA, especially if they show cognitive impairment.

Microduplication of 3p26.3 in nonsyndromic intellectual disability indicates an important role of CHL1 for normal cognitive function.

Terminal deletions of chromosome 3p26.3 confined to the CHL1 gene have previously been described in children with intellectual disability and epilepsy. Here, we report for the first time, a 3p26.3 duplication including only the CHL1 gene in an intellectually disabled girl with epilepsy. The penetrance of both deletions and duplications in 3p26.3 is reduced because all chromosomal imbalances were inherited from healthy parents. Further studies are needed to specify the pathogenic mechanism of 3p26.3 imbalances and to estimate recurrence risks in genetic counseling. However, the description of both deletions and duplications of chromosome 3p26.3 in nonsyndromic intellectual disability suggests that CHL1 is a dosage-sensitive gene with an important role for normal cognitive development.

A de novo interstitial deletion of 2p23.3-24.3 in a boy presenting with intellectual disability, overgrowth, dysmorphic features, skeletal myopathy, dilated cardiomyopathy.

Interstitial deletions of the distal part of chromosome 2p are rare, with only six reported cases involving regions from 2p23 to 2pter. Most of these were cytogenetic investigations. We describe a 14-year-old boy with an 8.97 Mb deletion of 2p23.3-24.3 detected by array comparative genomic hybridization (array CGH) who had intellectual disability (ID), unusual facial features, cryptorchidism, skeletal myopathy, dilated cardiomyopathy (DCM), and postnatal overgrowth (macrocephaly and tall stature). We compared the clinical features of the present case to previously described patients with an interstitial deletion within this chromosomal region and conclude that our patient exhibits a markedly different phenotype. Additional patients are needed to further delineate phenotype-genotype correlations.