Gray Matter Heterotopia, Mental Retardation, Developmental Delay, Microcephaly, and Facial Dysmorphisms in a Boy with Ring Chromosome 6: A 10-Year Follow-Up and Literature Review

Abstract

Ring chromosome 6, r(6), is an extremely rare cytogenetic abnormality with clinical heterogeneity which arises typically de novo. The phenotypes of r(6) can be highly variable, ranging from almost normal to severe malformations and neurological defects. Up to now, only 33 cases have been reported in the literature. In this 10-year follow-up study, we report a case presenting distinctive facial features, severe developmental delay, and gray matter heterotopia with r(6) and terminal deletions of 6p25.3 (115426-384174, 268 kb) and 6q26-27 (168697778-170732033, 2.03 Mb) encompassing 2 and 15 candidate genes, respectively, which were detected using G-banding karyotyping, FISH, and chromosomal microarray analysis. We also analyzed the available information on the clinical features of the reported r(6) cases in order to provide more valuable information on genotype-phenotype correlations. To the best of our knowledge, this is the first report of gray matter heterotopia manifested in a patient with r(6) in China, and the deletions of 6p and 6q in our case are the smallest with the precise size of euchromatic material loss currently known.

Ring chromosome 6 in a child with anterior segment dysgenesis and review of its overlap with other FOXC1 deletion phenotypes

“… and present patient). Contrarily, in patients whose 6p25 deletion does not disrupt FOXC1 , the phenotype is mild or moderate, and does not include ASD . Thus, early reports of patients with a severe r(6) phenotype including clear manifestations of ASD are highly indicative of a FOXC1 deletion, in spite of having an apparently discordant cytogenetic breakpoints on 6p (Table S4).…”

“…3 To date, there are 37 patients with r(6) described worldwide. 4 In a patient with anterior segment dysgenesis (ASD) associated with the deletion of 6p25 due to a r(6), Zhang et al 5 proposed that haploinsufficiency of the FOXC1 gene (OMIM 601090) is the major contributor for the overall phenotype. Furthermore, FOXC1 deletions were found to be associated with Axenfeld-Rieger syndrome type 3 (RIEG3, OMIM 602482), ASD type 3 (ASGD3, OMIM 601631), as well as with most of the features of 6p25 deletion syndrome (OMIM 612582), all which are observed in the r(6) phenotype.…”

“…The severe phenotype may include marked growth retardation and ID, facial dysmorphism, hearing loss, eye anomalies, and cardiac and central nervous system (CNS) malformations . To date, there are 37 patients with r(6) described worldwide …”

The phenotypic spectrum of terminal 6q deletions based on a large cohort derived from social media and literature: a prominent role forDLL1

“…Some clinical characteristics were reported in literature that were not part of the Chromosome 6 Questionnaire. In addition to the brain abnormalities reported above, micrognathia and high arched palate were reported in 13 and 14 individuals in literature, respectively 1,[7][8][9][10]13,19,23,26,28 . These characteristics could also not be related to deletion size.…”

“…For two individuals, their terminal deletion was known to be the result of a ring chromosome 6 23,32 .…”