Pre‐ and postnatal phenotype of 6p25 deletions involving the FOXC1 gene

Abstract

FOXC1 deletion, duplication, and mutations are associated with Axenfeld-Rieger anomaly, and Dandy-Walker malformation spectrum. We describe the clinical history, physical findings, and available brain imaging studies in three fetuses, two children, and one adult with 6p25 deletions encompassing FOXC1. Various combinations of ocular and cerebellar malformations were found. In all three fetuses, necropsy including detailed microscopic assessments of the eyes and brains showed ocular anterior segment dysgenesis suggestive of Axenfeld-Rieger anomaly. Five 6p25 deletions were terminal, including two derived from inherited reciprocal translocations; the remaining 6p25 deletion was interstitial. The size and breakpoints of these deletions were characterized using comparative genomic hybridization arrays. All six deletions included FOXC1. Our data confirm that FOXC1 haploinsufficiency plays a major role in the phenotype of patients with 6p25 deletions. Histopathological features of Axenfeld-Rieger anomaly were clearly identifiable before the beginning of the third-trimester of gestation.

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…”

A Case of Dandy-Walker Malformation Complicated by Axenfeld-Rieger Syndrome

“…Both the patient and her father had a mutation of FOXC1, although her father had ARS without DWM. FOXC1 deletion, duplication, and mutations are reportedly associated with Axenfeld-Rieger anomaly and with DWM [8,11]. Various combinations of ocular and cerebellar malformations have been found in three fetuses with 6p25 deletions encompassing FOXC1 [11].…”

“…Previously, there have been a few reports regarding patients with a combination of DWM and Axenfeld-Rieger anomaly or glaucoma (but not ARS) [11,12]. In this report, we present a rare case of a patient with ARS complicated with DWM, whose father was also diagnosed with ARS.…”

“…DWM has a frequency of approximately 1 per 25,000-35,000 live births and affects more females than males. Although there are some reports that DWM is caused by heterozygous loss of zinc finger genes (ZIC1 and ZIC4) or mutations affecting FOXC1 and FGF17 [6][7][8][9][10][11], the etiology is still unclear.…”