What happens when losing one copy of a developmental gene produces not just eye disease, but a much broader skeletal and neurologic picture? This case report shows how genome sequencing exposed that expanded spectrum. FOXC1 is a ubiquitously expressed forkhead transcription factor that plays a critical role during early development.

Pathogenic variants are associated with anterior segment dysgenesis and Axenfeld-Rieger syndrome, or ARS, which includes eye abnormalities, glaucoma risk, distinctive facial features, and dental, skeletal, audiologic, and cardiac anomalies. The report focuses on two unrelated adult females with FOXC1 haploinsufficiency who had ARS and skeletal abnormalities, with both diagnoses established using genome sequencing.

Figure one follows two patients across childhood and adulthood, pairing facial photographs with skull, chest, spine, limb, and hip imaging. The authors highlight recurring features such as prominent foreheads, hypertelorism, dolichospondyly, narrow thoraces, gracile bones, and abnormal hip development; patient two also shows spinal stenosis and advanced hip degeneration.

This matters because the visual connects recognizable facial findings with progressive, multisystem skeletal abnormalities. Patient one had early multisystem findings, including tracheomalacia at two months, relative macrocephaly, frontal bossing, hypertelorism, short limbs, increased joint laxity, and mild hypotonia.

Infancy and early childhood also included poor growth, conductive hearing loss from congenitally fused ossicles, recurrent otitis media, a bicuspid aortic valve, and a persistent superior vena cava to the coronary sinus. The clinical picture resembled De Hauwere syndrome, or DHS.

Genome sequencing found a complex rearrangement involving deletion of FOXC1 in one patient, while the other had a single-nucleotide deletion leading to a frameshift and stop codon. The study places DHS at the most severe end of FOXC1-related disorders.

For patient one, genome sequencing used the human genome Hg19 assembly as the reference and showed a four-point-nine kilobase deletion including the FOXC1 coding region, followed by a seven-point-zero megabase inversion and a seven-point-one kilobase deletion. The FOXC1 breakpoint was analyzed using IGV and confirmed with Sanger sequencing, while genome sequencing focused on five hundred twenty-eight known skeletal dysplasia genes was normal.

Figure two shows two molecular routes disrupting FOXC1. In patient one, the schematic and Sanger traces confirm a complex rearrangement: a four-point-nine kilobase deletion including FOXC1, an approximately seven-megabase inversion, and a seven-point-one-kilobase deletion, with the breakpoint pattern differing from a normal control.

In patient two, genome data and Sanger sequencing identify a single-base deletion, c.467del, predicted to cause the frameshift p.(Pro156Argfs*25). Together, the figure supports FOXC1 haploinsufficiency through distinct genetic mechanisms.

The two individuals shared overlapping clinical features caused by FOXC1 haploinsufficiency. One had a complex rearrangement in the FOXC1 locus, and the other had a nonsense variant in the same gene. In addition to ARS, both individuals showed significant skeletal abnormalities that required orthopedic surgeries.

Complex structural rearrangements can cause developmental anomalies, but before genome sequencing they often escaped detection in routine genetic investigations. The more severe phenotype in patient one may be related to the seven-megabase inversion, which involves several developmentally important genes.

FOXC1 haploinsufficiency may produce a spectrum ranging from isolated anterior segment dysgenesis, through ARS, to a phenotype overlapping with DHS. The recommended care is multisystem, including comprehensive ophthalmologic, neurologic, otologic, audiologic, cardiac, dental, and orthopedic evaluations, with a low threshold for brain imaging.

The skeletal manifestations may be under-ascertained and may become more apparent as patients age, so all patients with relevant FOXC1-related diagnoses should be screened for skeletal problems. FOXC1 haploinsufficiency can range from isolated eye abnormalities to a phenotype overlapping De Hauwere syndrome, so care should extend across ophthalmologic, neurologic, skeletal, cardiac, dental, and hearing systems.