The 6p25 deletion syndrome: An update on a rare neurocristopathy

Abstract

Anterior segment dysgeneses are developmental anomalies of the anterior eye segment that can occur as isolated defects or as part of various syndromes. A subgroup is caused by abnormal embryonic neural crest development. The Axenfeld-Rieger syndrome is an umbrella term for a continuum of anterior segment dysgeneses of neural crest origin, characterized by the presence of the Axenfeld or Rieger eye malformation predisposing for glaucoma. Additionally, other structures of neural crest origin can be variably affected giving rise to a wide spectrum of associated extra-ocular malformations. Key clinical features comprise facial dysmorphism including mid-face and dental hypoplasia, hearing loss, cardiac anomalies, and involuted periumbilical skin. The Axenfeld-Rieger syndrome is genetically heterogeneous and about 16% of cases are caused by heterozygous mutations in FOXC1 at 6p25.3, a transcription factor gene regulating neural crest cell development. There is considerable clinical overlap between the Axenfeld-Rieger syndrome and the 6p25 deletion syndrome, a microdeletion syndrome characterized by heterozygous loss of FOXC1. In both syndromes, FOXC1 haploinsufficiency seems to be pathogenic. Here, we review the clinical features and pathogenesis of the 6p25 deletion syndrome. ARTICLE HISTORY

A novel unbalanced translocation between the short arms of chromosomes 6 and 16 in a newborn girl: Clinical features and management

“…Other features of this deletion which our patient did not present with include hydrocephalus, dental hypoplasia, hearing loss, renal malformations, involuted periumbilical skin, delayed bone maturation, neuronal defects, learning disabilities, and behavioral problems 1, 6, 7, 8, 9…”

“…In terminal 6p25 deletions, features in common with the patient include developmental delay, facial dysmorphisms such as hypertelorism, high arched palate, oculocraniofacial defects such as cleft lip or palate, anterior segment dysgenesis of the eye such as posterior embryotoxon, single palmar crease, supraventricular tachycardia, cardiac malformations—mainly atrial and ventricular septal defects in combination with a patent ductus arteriosus and patent foramen ovale and skeletal malformations 1, 6, 7, 8, 9. Other features of this deletion which our patient did not present with include hydrocephalus, dental hypoplasia, hearing loss, renal malformations, involuted periumbilical skin, delayed bone maturation, neuronal defects, learning disabilities, and behavioral problems 1, 6, 7, 8, 9…”

Deletion of 6p25.3 Is Associated with Cerebrovascular Dolichoectasia: Report of 2 Cases

“…The FOXC1 gene, included within the deletion discussed here, encodes the FOXC1 transcription factor, which influences neural crest cell development during embryogenesis [4]. This gene is expressed in the brain, eye, heart, and kidney tissues in both embryos and adults, which explains the number of structures affected by its deletion [13].…”

“…This damage to the blood-brain barrier is likely attributed to the involvement of FOXF2 and FOXC1 in the development of pericytes, which surround and support blood vessel walls [6, 8]. FOXF2 forms a gene tandem triplet with FOXC1 and FOXQ1 at 6p25.3 and concurrent deletion of these genes results from 6p25.3 chromosomal deletions [4]. Intracranial dolichoectasia is most commonly expressed in the posterior circulation, predominantly in the vertebrobasilar system [7, 9].…”

“…The FOXC1 gene, which is a transcription factor that contributes to the development and migration of neural crest cells and vascular development during embryogenesis, is often included in this deletion and has been cited as a driver of the phenotypic characteristics of these patients [4, 5]. Because of its neural crest cell disruption, this syndrome is associated with a myriad of symptoms ranging from dysmorphic facial features to congenital heart disease.…”