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

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.

FIGURE 1

Clinical and radiographic findings at different ages (A–C): Facial features of patient 1 at 4.5 and 30 years. Note broad and prominent forehead, sparse anterior hairline and medial eyebrows, prominent eyes, epicanthal folds, hypertelorism, telecanthus, depressed nasal root, bulbous nasal tip, prognathism, malar flattening, thin upper lip vermilion and mildly posteriorly rotated ears. (D–I): Radiographic examination of patient 1 showed mild dolichocephaly with frontal bossing, dolichospondyly, a mildly narrow thorax, gracile long bones, and flat capital femoral epiphyses. The elbow joint was dislocated. (J–L): Facial features of patient 2 at 7 and 49 years. Note hypertelorism with telecanthus, down slanting palpebral fissures, depressed nasal bridge, maxillary hypoplasia, broad and prominent forehead, mildly posteriorly rotated ears and short neck. The photographs are published with informed signed consents from both patients. (M–Q): Radiographic examination of patient 2 showed dolichocephaly with frontal bossing, dolichospondyly, a narrow thorax with glenoid dysplasia, gracile ulna and radius and hip dysplasia. The computer tomography of the lumbar spine radiograms showed spondylosis and spinal canal stenosis with posterior scalloping of the vertebral bodies. The radiograms of the hip joints showed advanced degenerative joint disease along with subluxation of the left. The femoral heads were small, and the femoral necks were short.

FIGURE 2

Molecular findings: (A) Schematic representation of the complex rearrangement and confirmation of the 5´breakpoint (BP1) using Sanger sequencing in patient 1 and in a normal control DNA sample. Complex genomic rearrangement includes: 4.9 kb deletion including FOXC1 followed by an inversion of approximately 7 MB and a 7.1 kB deletion. Primer pairs used for amplification and sequencing of the breakpoints 1 (BP1) were P1F and P1R. For amplification of the normal control sequence corresponding to the position of BP1 we used primer pairs P1F and P3R. (B) Genome and Sanger sequencing of DNA sample from patient 2 showing stop-gain variant in FOXC1 (NM_001453.3):c.467del, p.(Pro156Argfs*25).