Case report: Extending the spectrum of clinical and molecular findings in FOXC1 haploinsufficiency syndrome

Front Genet. 2023 Jun 23:14:1174046. doi: 10.3389/fgene.2023.1174046. eCollection 2023.

Abstract

FOXC1 is a ubiquitously expressed forkhead transcription factor that plays a critical role during early development. Germline pathogenic variants in FOXC1 are associated with anterior segment dysgenesis and Axenfeld-Rieger syndrome (ARS, #602482), an autosomal dominant condition with ophthalmologic anterior segment abnormalities, high risk for glaucoma and extraocular findings including distinctive facial features, as well as dental, skeletal, audiologic, and cardiac anomalies. De Hauwere syndrome is an ultrarare condition previously associated with 6p microdeletions and characterized by anterior segment dysgenesis, joint instability, short stature, hydrocephalus, and skeletal abnormalities. Here, we report clinical findings of two unrelated adult females with FOXC1 haploinsufficiency who have ARS and skeletal abnormalities. Final molecular diagnoses of both patients were achieved using genome sequencing. Patient 1 had a complex rearrangement involving a 4.9 kB deletion including FOXC1 coding region (Hg19; chr6:1,609,721-1,614,709), as well as a 7 MB inversion (Hg19; chr6:1,614,710-8,676,899) and a second deletion of 7.1 kb (Hg19; chr6:8,676,900-8,684,071). Patient 2 had a heterozygous single nucleotide deletion, resulting in a frameshift and a premature stop codon in FOXC1 (NM_001453.3): c.467del, p.(Pro156Argfs*25). Both individuals had moderate short stature, skeletal abnormalities, anterior segment dysgenesis, glaucoma, joint laxity, pes planovalgus, dental anomalies, hydrocephalus, distinctive facial features, and normal intelligence. Skeletal surveys revealed dolichospondyly, epiphyseal hypoplasia of femoral and humeral heads, dolichocephaly with frontal bossin gand gracile long bones. We conclude that haploinsufficiency of FOXC1 causes ARS and a broad spectrum of symptoms with variable expressivity that at its most severe end also includes a phenotype overlapping with De Hauwere syndrome.

Keywords: Axenfeld-Rieger Syndrome; De Hauwere Syndrome; FOXC1; case report; genome sequencing; skeletal anomalies.

Publication types

  • Case Reports

Grants and funding

Financial support was provided by grants from Sällsyntafonden (GG), Stiftelsen Sällskapet Barnavård (AH), Stiftelsen Promobilia (GG), Stiftelsen Frimurare (GG), Swedish Research Council and the Region Stockholm (GG), grants from Karolinska Institutet (AH and GG). All data analyzed at the Karolinska University laboratory cannot be shared as a whole data set according to European law (https://eur-lex.europa.eu/eli/reg/2016/679/oj). However, subsets of variants of interest can be shared upon request. All variants identified in this study are submitted to ClinVar (SUB1291463 and SUB12914356). Primer positions for breakpoint sequencing as well as for the confirmation of the single nucleotide deletion are available on request.