You might know this gene for causing eye defects, but what if it also breaks your bones? This case study reveals a hidden skeletal crisis hiding behind a common genetic diagnosis. The authors introduce FOXC1 as a critical transcription factor where germline variants usually cause Axenfeld-Rieger syndrome with eye and facial issues.

They note that De Hauwere syndrome was previously linked to large deletions and includes joint instability and hydrocephalus alongside eye problems. This paper reports two adult females with FOXC1 haploinsufficiency who display both Axenfeld-Rieger syndrome and significant skeletal abnormalities.

The study confirms that one patient has a complex rearrangement deleting FOXC1 while the other has a single nucleotide deletion causing a frameshift. These findings solidify the conclusion that De Hauwere syndrome represents the most severe end of the FOXC1-related disorder spectrum.

Patient one was born at term with a normal karyotype but presented early with a hoarse cry, clubfoot, and right scapular hemangioma. By age three and a half, her growth had dropped significantly with a height z-score of negative three point two and she developed radial head subluxation.

Her eye exam showed infantile glaucoma, iris hypoplasia, and abnormal angulation requiring multiple surgeries including trabeculectomy. Before surgery, her intraocular pressure measured thirty millimeters of mercury bilaterally with corneal thicknesses over six hundred micrometers.

At age thirty, the patient stood only one hundred forty-three centimeters tall with a height z-score of negative four point eighteen. She suffered from chronic joint pain, had undergone vertebral fusion, and had all teeth extracted due to enamel hypoplasia.

A DEXA scan revealed osteoporosis in her femoral necks with a T-score of negative three point zero. Radiological surveys showed dolichospondyly, gracile long bones, and epiphyseal dysplasia of the proximal humeri and femora. Dislocations of the elbow and patellofemoral joints were noted alongside pes planovalgus.

Patient two is the first of four children whose mother suffered from glaucoma, blindness, and fragile teeth before dying of cervical cancer. Her affected sister was born with anterior segment dysgenesis and atrial septal defect and later became blind from undiagnosed childhood glaucoma.

Patient two presented with precocious puberty at age seven and was diagnosed with hydrocephalus and a large suprasellar arachnoid cyst. A shunt was placed when she was nine, yet she continues to suffer from frequent headaches independent of shunt function. At age forty-nine, she weighed eighty-one kilograms with a BMI of thirty-nine and had redundant umbilical skin.

text Her skeleton showed severe coxarthrosis, dolichospondyly, and dysplastic proximal femoral epiphyses with short femoral necks. Lumbar spine imaging revealed spondylosis and spinal canal stenosis with posterior scalloping of the vertebral bodies.

Figure 1 documents the clinical and radiographic progression of two patients, illustrating how their distinct craniofacial features and skeletal abnormalities persist from childhood into adulthood. The authors highlight consistent phenotypes such as frontal bossing, hypertelorism, and gracile long bones across both individuals.

Furthermore, the radiographic panels reveal severe structural complications, including spinal stenosis with posterior scalloping of vertebral bodies and advanced degenerative joint disease in the hips. Genome sequencing of patient one revealed a complex rearrangement starting with a four point nine kilobase deletion including the FOXC1 coding region.

This was followed by a seven megabase inversion and a second deletion of seven point one kilobases. Analysis showed the inversion disrupts multiple topologically associating domains across several tissues. Patient two had a heterozygous single nucleotide deletion in FOXC1 resulting in a frameshift and premature stop codon.

This variant was confirmed using Sanger sequencing and submitted to ClinVar. Figure 2 details the molecular findings for two patients, revealing distinct genetic mechanisms causing FOXC1 haploinsufficiency. Panel A illustrates a complex rearrangement in patient one, characterized by a four point nine kilobase deletion encompassing the gene, followed by an inversion of approximately seven megabases and a second seven point one kilobase deletion.

In contrast, panel B displays a simpler stop-gain variant in patient two, specifically a single nucleotide deletion at position c dot four six seven that results in a frameshift mutation. Previous studies found that twenty-three of sixty-nine individuals with FOXC1 variants had short stature, hip abnormalities, or joint hypermobility.

The authors speculate that phenotype variability may occur due to incomplete penetrance and variable expressivity. Mouse models show that Foxc1 is essential for endochondral ossification via interaction with Gli2 in the Indian hedgehog signaling pathway.

Homozygous loss-of-function mice exhibited delayed ossification, short limbs, and low bone mineralization. The authors conclude that patients with FOXC1 haploinsufficiency require a multisystem approach including orthopedic and brain imaging evaluations.

They caution that skeletal manifestations are likely under-ascertained and recommend screening all patients with apparent isolated anterior segment dysgenesis. FOXC1 mutations cause a severe spectrum from eye issues to full-body skeletal collapse, proving that De Hauwere syndrome is just the extreme end of this single-gene disorder.