Subtelomeric deletions of chromosome 6p: Molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher?Schinzel (3C) syndrome

Abstract

We have identified six children in three families with subtelomeric deletions of 6p25 and a recognizable phenotype consisting of ptosis, posterior embryotoxon, optic nerve abnormalities, mild glaucoma, Dandy-Walker malformation, hydrocephalus, atrial septal defect, patent ductus arteriosus, and mild mental retardation. There is considerable clinical overlap between these children and individuals with the Ritscher-Schinzel (or cranio-cerebello-cardiac (3C)) syndrome (OMIM #220210). Clinical features of 3C syndrome include craniofacial anomalies (macrocephaly, prominent forehead and occiput, foramina parietalia, hypertelorism, down-slanting palpebral fissures, ocular colobomas, depressed nasal bridge, narrow or cleft palate, and low-set ears), cerebellar malformations (variable manifestations of a Dandy-Walker malformation with moderate mental retardation), and cardiac defects (primarily septal defects). Since the original report, over 25 patients with 3C syndrome have been reported. Recessive inheritance has been postulated based on recurrence in siblings born to unaffected parents and parental consanguinity in two familial cases. Molecular and cytogenetic mapping of the 6p deletions in these three families with subtelomeric deletions of chromosome 6p have defined a 1.3 Mb minimally deleted critical region. To determine if 6p deletions are common in 3C syndrome, we analyzed seven unrelated individuals with 3C syndrome for deletions of this region. Three forkhead genes (FOXF1 and FOXQ1 from within the critical region, and FOXC1 proximal to this region) were evaluated as potential candidate disease genes for this disorder. No deletions or disease-causing mutations were identified.

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

“…45,46 Balanced chromosome rearrangements involving FOXC1 or its surrounding landscape are rare, but a balanced t(6;13) translocation in an ARS patient lead to identification of FOXC1, as a causative gene for this disorder. 11 On the other hand, there are more than 40 deletions, either interstitial or telomeric, involving 6p25 45,47,48 and the patients frequently present with ocular, craniofacial, skeletal, cardiac, and renal malformations, hearing loss, and hydrocephalus. 47 The phenotypic variation seen in these patients are largely because of the size of the deletions and the genes involved.…”

Ritscher–Schinzel cranio-cerebello-cardiac syndrome

“…The subtelomeric deletion 6p25 syndrome is a condition recently separated from 3-C syndrome and characterized by Dandy Walker malformation, Atrial septal defect (ASD) or Ventricular septal defect (VSD), glaucoma, optic nerve abnormality, posterior embryotoxon and ptosis. 12 None of the ocular findings present in this syndrome nor the characteristic chromosomal anomaly were present in our patient. …”

Complex Chromosome Rearrangement of 6p25.3->p23 and 12q24.32->qter in a Child With Moyamoya

“…23,24 Although 6p25.3 deletion is a known clinical entity, our patient does not share characteristic brain or facial features previously reported. 25 The reported phenotype of partial trisomy 6p includes pointed chin, long philtrum, low set ears, hearing loss and developmental delay as in our patient but also typically involves moderate to severe ocular, cardiac and renal disease, and psychomotor delay. 22,26,27 The relative sparing of stigmata in our patient with only mild developmental delay and hearing loss despite the large chromosome rearrangement is likely due to variability of expression frequently seen in chromosome duplication syndromes.…”