Chromosome 6pter-P24 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome.

See also Axenfeld-Rieger syndrome type 3 (RIEG3; 602482), which shows phenotypic overlap with chromosome 6pter-p24 deletion syndrome, and branchiooculofacial syndrome (BOFS; 113620), caused by mutation or deletion of the TFAP2A gene (107580) on chromosome 6p24.3, centromeric to the deletion interval.

Clinical Features

Davies et al. (1999) reported 6 patients with interstitial or terminal 6pter-p24 deletions. All patients had developmental delay and hypotonia, and most had an abnormal skull shape, such as brachycephaly, dolichocephaly, or frontal bossing. Variable features included downslanting palpebral fissures, midface hypoplasia, anterior eye chamber abnormalities (see RIEG3, 602482), ear anomalies, hearing loss, heart defects, and a short neck.

Mirza et al. (2004) reported 6 additional patients with developmental delay and hypotonia associated with deletions involving chromosome 6pter-p24 region. Common clinical features included hypertelorism, structural eye defects, anterior eye chamber abnormalities, palatal and dental abnormalities, hearing loss, congenital heart defects, neuronal defects, and anomalies of the extremities. Less common features included structural ear and nose anomalies, and kidney defects. Mirza et al. (2004) suggested that the FOXC1 (601090) was likely involved in the eye anomalies.

Lin et al. (2005) reported 4 patients with a distinct recognizable pattern of malformations including hypertelorism, downslanting palpebral fissures, flat nasal bridge, tented mouth, Dandy-Walker malformation/variant (see 220210), congenital heart defects, anterior eye-chamber abnormalities, hearing loss, hypotonia, and developmental delay. All were found to have terminal deletions involving the chromosome 6pter-p24 and -p25 chromosomal segment.

DeScipio et al. (2005) reported 6 children from 3 families with subtelomeric deletions of chromosome 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 was considerable phenotypic overlap with 3C syndrome (220210).

Maclean et al. (2005) stated that 12 cases had been reported of a distinctive clinical phenotype associated with deletion of distal chromosome 6p, the features of which included Axenfeld-Rieger malformation, hearing loss, congenital heart disease, dental anomalies, developmental delay, and a characteristic facial appearance. They reported the case of a child in whom recognition of the specific ocular and facial phenotype led to identification of a 6p microdeletion arising from a de novo 6;18 translocation. Detailed analysis confirmed deletion of the FOXC1, FOXF2 (603250), and FOXQ1 (612788) forkhead gene cluster at chromosome 6p25. CNS anomalies included hydrocephalus and hypoplasia of the cerebellum, brainstem, and corpus callosum with mild to moderate developmental delays. Unlike previous reports, hearing was normal.

Martinet et al. (2008) reported 2 unrelated patients with de novo subtelomeric terminal deletion of chromosome 6p. An 8-month-old girl had dysmorphic facial features, including broad forehead, hypertelorism, downslanting palpebral fissures, midface hypoplasia, dysplastic ears and short neck, with severe developmental delay, profound bilateral neurosensory deafness, poor visual contact, and hypsarrhythmia since the age of 6 months. A 5-year-old male born with unilateral hip dysplasia had the characteristic facial phenotype, high-arched palate with abnormal tooth position, bilateral posterior embryotoxon, atrial septal defect, and moderate mental retardation. High-resolution array comparative genomic hybridization (CGH) showed that the girl had an 8.1-Mb deletion of chromosome 6pter-p24.3 associated with a contiguous 5.8-Mb duplication of chromosome 6p24.3-p24.1. The boy had a 5.7-Mb deletion of 6pter-p25.1 partially overlapping that of the first patient.

Cytogenetics

By molecular and cytogenetic mapping of the 6p deletions in 3 families, DeScipio et al. (2005) delineated a 1.3-Mb minimally deleted common critical region. Molecular analysis excluded mutations in the FOXC1, FOXF2, and FOXQ1 genes. Of note, DeScipio et al. (2005) did not identify deletions of 6p in 7 additional unrelated patients with 3C syndrome.

Molecular Genetics

Aldinger et al. (2009) analyzed brain imaging studies in 18 individuals with chromosome 6p25 copy number variation involving the FOXC1 gene and 3 patients with intragenic mutations of FOXC1, all of whom had previously been reported by Pearce et al. (1982, 1983); Gould et al. (1997); Mears et al. (1998); Nishimura et al. (1998); Lehmann et al. (2000); DeScipio et al. (2005); Lin et al. (2005); Maclean et al. (2005); Chanda et al. (2008), with phenotypes of anterior segment dysgenesis (ASGD3; 601631), Axenfeld-Rieger syndrome type 3 (RIEG3; 602482), cardiac malformations, and/or brain anomalies, particularly Dandy-Walker malformation. All of the patients had abnormalities on MRI, showing classic or mild Dandy-Walker malformation (DWM), mega cisterna magna (MCM), or cerebellar vermis hypoplasia (CVH). The combined genotype and phenotype data showed consistently more severe phenotypes among individuals with large compared to small deletions, suggesting contributions from more than 1 causative gene in the region; in addition, all 12 deletions involved the FOXC1 gene plus at least 2 exons of the GMDS gene (602884), implicating 1 or both of these genes as having a previously unrecognized role in cerebellar development. In 3 patients from 2 families with missense mutations in FOXC1 resulting in Axenfeld anomaly (601090.0003) and Axenfeld-Rieger syndrome type 3 (601090.0008), respectively, Aldinger et al. (2009) observed mild CVH and an abnormal white matter signal corresponding to prominent perivascular spaces; the authors concluded that alteration of FOXC1 function alone can cause CVH and contributes to MCM and DWM.