Clinical characteristics: Geleophysic dysplasia, a progressive condition resembling a lysosomal storage disorder, is characterized by short stature, short hands and feet, progressive joint limitation and contractures, distinctive facial features, progressive cardiac valvular disease, and thickened skin. Intellect is normal. The characteristic clinical findings are likely to be present in the first year of life. Cardiac, airway, and pulmonary involvement result in death before age five years in approximately 33% of individuals.

Diagnosis/testing: The clinical diagnosis of geleophysic dysplasia can be established in a proband with characteristic clinical and radiographic findings; the molecular diagnosis of geleophysic dysplasia is established in a proband with characteristic clinical and radiographic findings and one of the following on molecular genetic testing: biallelic pathogenic variants in ADAMTSL2 or a heterozygous pathogenic variant in either FBN1 or LTBP3.

Management: Treatment of manifestations: Ongoing physiotherapy to prevent joint limitation; treatment of hip dysplasia, osteochondritis, and carpal tunnel syndrome per orthopedist; cardiac valve replacement in those with severe stenosis or insufficiency; management of cardiac septal defect per cardiologist and cardiac surgeon; tracheostomy as needed for severe tracheal stenosis; treatment of restrictive lung disease, obstructive sleep apnea, and/or asthma per pulmonologist; standard treatments for hearing loss and recurrent otitis media; treatment of ophthalmologic manifestations per ophthalmologist.

Surveillance: Frequent assessments in infancy and early childhood of growth, motor and speech development, frequency of ear infections, respiratory compromise, cardiac and pulmonary examination, and liver size; annual clinical assessments after age three years. Intermittent evaluation with clinical genetics and genetic counseling. Annual orthopedic evaluation until age 18 years, then every two years. EMG for carpal tunnel syndrome every two years beginning at age 11 years. Evaluation with cardiologist (including EKG and echocardiogram), pulmonologist, ENT specialist, and audiologist annually from birth until age three years, then at specific intervals. Thoracic CT examination at age six years; polysomnography as needed. Ophthalmology and funduscopic examination at specific intervals.

Genetic counseling: Geleophysic dysplasia caused by biallelic pathogenic variants in ADAMTSL2 is inherited in an autosomal recessive manner. Geleophysic dysplasia caused by a heterozygous pathogenic variant in either FBN1 or LTBP3 is inherited in an autosomal dominant manner.

Autosomal recessive inheritance: If both parents are known to be heterozygous for an ADAMTSL2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives requires prior identification of the ADAMTSL2 pathogenic variants in the family.

Autosomal dominant inheritance: All probands reported to date with FBN1- or LTBP3-related geleophysic dysplasia whose parents have undergone molecular genetic testing have had the disorder as the result of a de novo pathogenic variant. If a molecular diagnosis has been established in the proband and the pathogenic variant identified in the proband is not identified in either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism.

Once the geleophysic dysplasia-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.