Geleophysic dysplasia (GD) is caused by recessive mutations in ADAMTSL2 (GD1, ∼50% of cases), or dominant mutations in FBN1 (GD2, ∼50% of cases) or LTBP3 (GD3, <1% of cases). GD is characterized by severe short stature and other skeletal abnormalities, characteristic facial features, thick skin, and hypermuscular build. Life-threatening complications can arise from progressive heart valve disease and narrowing of the large airways, resulting in ∼33% mortality before the age of five. Despite high childhood mortality and significant morbidity, no disease-modifying treatments exist for GD. To model disease progression and enable efficacy testing of mechanism-based therapeutic approaches, a mouse model for severe GD1 was generated by introducing the patient-specific ADAMTSL2 c.499G>A (p.D167N) mutation into the mouse Adamtsl2 locus. Homozygous Adamtsl2D167N/D167N (D167N) mice had reduced postnatal survival and developed short stature. Like GD1 patients, radiographs demonstrated significantly shortened hind- and forelimb bones with delayed mineralization and abnormally shaped (ovoid) vertebrae. Histological investigation revealed a shortened growth plate, suggesting abnormalities in chondrogenesis. Cardiac histomorphometry revealed dysplastic aortic heart valves, consistent with progressive heart valve disease observed in GD1 patients. In the lungs, bronchial obstruction by vesicular structures was observed, as previously reported for global Adamtsl2 knockout mice, likely resulting in occlusion of the affected airways. Thus, the ADAMTSL2 D167N mouse model recapitulates key clinical manifestations of GD1 patients.

Geleophysic dysplasia represents an exceedingly uncommon autosomal recessive skeletal disorder marked by profound growth restriction, contractures affecting multiple joints, and cardiac valve abnormalities. The molecular foundation involves ADAMTSL2 gene mutations disrupting extracellular matrix architecture. We document a 29-year-old Taiwanese woman followed longitudinally for 25 years, presenting with severe short stature measuring 141.2 cm, widespread joint contractures, thoracolumbar scoliosis, and distinctive gait abnormalities. Whole-exome sequencing identified compound heterozygous ADAMTSL2 mutations: c.286C>T resulting in p. Arg96Trp and c.454_459del causing p. Cys152_Thr153del deletion. The clinical course revealed musculoskeletal deterioration alongside mild mitral valve involvement and os odontoideum. Bilateral glaucoma, consistent with previously reported ocular manifestations in geleophysic dysplasia, was diagnosed at age 26. Notably, recent ophthalmologic evaluation revealed keratoconus-like corneal ectasia with paradoxically increased central corneal thickness measuring 690-693 μm bilaterally, substantially exceeding normal values of 520-560 μm. This paradoxical corneal thickening, contrasting with the stromal thinning characteristic of classical keratoconus, represents a novel ADAMTSL2-related corneal phenotype. The patient maintained normal intellectual capacity despite physical limitations, contrasting with published early mortality rates approaching 33%. This extended clinical documentation establishes keratoconus-like corneal ectasia with paradoxical corneal thickening as a novel ophthalmologic manifestation in geleophysic dysplasia, while adding to prior reports of glaucoma in this condition. These findings emphasize the necessity for comprehensive ophthalmologic monitoring in ADAMTSL2-related disorders and supporting multidisciplinary management strategies.

Geleophysic dysplasia (GD) is a rare genetic skeletal disorder belonging to the acromelic group, characterized by short stature, distinctive facial features, thickened skin, and progressive cardiac involvement. We report a case of a 3-year-old boy with GD caused by a heterozygous c.5198G>A variant in the FBN1 gene, presenting with ocular abnormalities. The patient demonstrated coarse facial features, short hands and feet, and a history of mitral valve stenosis requiring mechanical valve replacement. He was referred to the ophthalmology department for evaluation of left eye strabismus and elevated intraocular pressure. Fundus examination revealed a pink optic disc with blurred margins, slightly elevated above the retinal plane, absent foveal reflex, and tortuous vessels, consistent with optic disc drusen on ocular ultrasonography. Photopic negative response (PhNR) testing showed markedly reduced amplitudes in both eyes, indicating retinal ganglion cell dysfunction. Pattern VEP revealed normal P100 latencies in both eyes, with a 30% reduction in amplitude in the left eye, likely related to poorer fixation. This case highlights optic disc drusen and retinal ganglion cell dysfunction as potential ocular manifestations of geleophysic dysplasia, emphasizing the need for comprehensive ophthalmologic evaluation in affected patients.

FBN1 gene mutation-associated geleophysic dysplasia (GD) leads to the formation of complex and refractory pulmonary hypertension (PH) through a multifactorial combination of precapillary factors, postcapillary factors, and respiratory pathology. However, clinical experience regarding the diagnosis and management of these patients remains limited. The patient was admitted to the hospital with severe PH symptom. He exhibited typical facial features, severe disproportionate short stature, and was diagnosed with GD following the identification of a heterozygous mutation in exon 42 of the FBN1 gene via whole-exome sequencing. Pulmonary artery pressure was reduced after admission and treatment with treprostinil, but mitral stenosis progressively worsened. The patient was then treated with mitral valvuloplasty + atrial septal windowing at an outside hospital, the procedure was successful, but the patient could not be weaned from ECMO after the procedure. This case expands our understanding of therapeutic strategies for PH associated with FBN1 mutation-related GD. Treprostinil may be effective in the treatment of these patients. Given the risk of progressive pulmonary disease, early surgical intervention for mitral valve pathology may be crucial for improving prognosis.