PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome

Clinical characteristics: PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive generalized connective tissue disorder characterized by hypotonia, early-onset kyphoscoliosis, and generalized joint hypermobility in association with skin fragility and ocular abnormality. Intelligence is normal. Life span may be normal, but affected individuals are at risk for rupture of medium-sized arteries. Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure.

Diagnosis/testing: The diagnosis of PLOD1-related kEDS is established in a proband with typical clinical findings and biallelic pathogenic (or likely pathogenic) variants in PLOD1 identified by molecular genetic testing. If only one or no pathogenic variant is identified, testing for a markedly increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by high-performance liquid chromatography (HPLC) (a highly sensitive, specific, and inexpensive test) may be necessary for confirmation of the diagnosis.

Management: Treatment of manifestations: Management of kyphoscoliosis by an orthopedic surgeon, including surgery as needed; physical therapy to strengthen large muscle groups; bracing to support unstable joints; protective pads and helmets during active sports; control of blood pressure to reduce the risk for arterial rupture; treatment with beta-blockers as needed to prevent aortic dilatation.

Prevention of secondary complications: Standard American Heart Association guidelines for antimicrobial prophylaxis for mitral valve prolapse.

Surveillance: Regular follow up by an orthopedic surgeon for management of kyphoscoliosis; routine examination for inguinal hernia; routine ophthalmologic examination for management of myopia and early detection of glaucoma or retinal detachment; echocardiogram at five-year intervals even if the initial echocardiogram is normal.

Agents/circumstances to avoid: Sports that stress the joints, such as gymnastics or long-distance running; high-impact sports for eye injury concerns.

Pregnancy management: Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries.

Genetic counseling: PLOD1-related kEDS is inherited in an autosomal recessive manner. At conception, each sib of a proband with EDS, kyphoscoliotic form 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. Once the PLOD1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.