AUTHOR=Garza Flores Alexandra , Nordgren Ida , Pettersson Maria , Dias-Santagata Dora , Nilsson Daniel , Hammarsjö Anna , Lindstrand Anna , Batkovskyte Dominyka , Wiggs Janey , Walton David S. , Goldenberg Paula , Eisfeldt Jesper , Lin Angela E. , Lachman Ralph S. , Nishimura Gen , Grigelioniene Giedre 

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

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1174046

DOI=10.3389/fgene.2023.1174046

ISSN=1664-8021

ABSTRACT=<p><italic>FOXC1</italic> is a ubiquitously expressed forkhead transcription factor that plays a critical role during early development. Germline pathogenic variants in <italic>FOXC1</italic> 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 <italic>FOXC1</italic> 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 <italic>FOXC1</italic> 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 <italic>FOXC1</italic> (NM_001453.3): c.467del, p.(Pro156Arg<italic>fs</italic>*25). Both individuals had moderate short stature, skeletal abnormalities, anterior segment dysgenesis, glaucoma, joint laxity, <italic>pes planovalgus</italic>, 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 <italic>FOXC1</italic> 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.</p>