Geleophysic Dysplasia

Excerpt

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. Major findings are likely to be present in the first year of life. Cardiac, respiratory, and lung involvement result in death before age five years in approximately 33% of individuals with ADAMTSL2-related geleophysic dysplasia.

Diagnosis/testing: The clinical diagnosis of geleophysic dysplasia is based on clinical and radiographic findings. The molecular diagnosis is established in a proband who also has 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: Regular physiotherapy to prevent joint limitation; cardiac valve replacement as needed; tracheostomy as required.

Surveillance: Annual multidisciplinary examination to access height and range of motion of the joints; echocardiography for evidence of valvular stenosis and/or arterial narrowing; clinical assessment for evidence of tracheal stenosis and respiratory compromise; clinical assessment and ultrasound examination, if needed, to assess liver size.

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.

1. Autosomal recessive inheritance. At conception, each sib of an affected individual has 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.

2. Autosomal dominant inheritance. To date, all individuals diagnosed with FBN1- or LTBP3-related geleophysic dysplasia have had a de novo pathogenic variant. If the FBN1 or LTBP3 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism.

Once the pathogenic variant(s) in a family are known, the following are possible: carrier testing for relatives at increased risk for autosomal recessive geleophysic dysplasia, preimplantation genetic testing, and prenatal testing for pregnancies at increased risk for either autosomal recessive or autosomal dominant geleophysic dysplasia.