PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome

Clinical characteristics: PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS) is characterized by hypotonia, generalized joint hypermobility, early-onset kyphoscoliosis, skin fragility, and ocular abnormality. Intelligence is normal. Life span may be normal, but affected individuals are at risk of life-threatening arterial ruptures and spontaneous dissections 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-kEDS is established in a proband with characteristic clinical features and biallelic pathogenic variants in PLOD1 identified by molecular genetic testing. If only one pathogenic variant and/or variants of uncertain significance are identified, testing for a markedly increased ratio of deoxypyridinoline to pyridinoline cross-links in urine measured by high-performance liquid chromatography (a highly sensitive, specific, and inexpensive test) may be necessary for confirmation of the diagnosis.

Management: Treatment of manifestations: Physical therapy to strengthen large muscle groups; swimming; management of kyphoscoliosis by an orthopedic surgeon, including surgery as needed; bracing to support unstable joints; protective pads and helmets during active sports; dermal wounds should be closed without tension, preferably in two layers; deep stitches should be applied generously; cutaneous stitches should be left in place twice as long as usual, and additional fixation of adjacent skin with adhesive tape can help prevent stretching of the scar; treatment of cardiovascular manifestations per a cardiologist; control of blood pressure to reduce the risk of arterial rupture; treatment with beta-blockers as needed to prevent aortic dilatation; standard American Heart Association guidelines for antimicrobial prophylaxis for mitral valve prolapse; corrective lenses for myopia and/or astigmatism; laser treatment of the retina for those with imminent detachment; careful stitching for hernia repair.

Surveillance: Annual physical therapy assessment for weakness and motor issues and orthopedic assessment for management of kyphoscoliosis and recurrent dislocations; assessment for osteopenia as needed beginning at age ten to 12 years; assessment for respiratory complications as needed; echocardiogram at five-year intervals beginning at age five years; consider intermittent surveillance of the entire aorta with CT or MRA beginning in young adulthood and at least annually in anyone with aortic or arterial dilatation; annual ophthalmology examination; annual examination for inguinal hernia.

Agents/circumstances to avoid: Sports that stress the joints, such as gymnastics or long-distance running; high-impact sports (collision sports); heavy lifting and weight training with extreme lifting; arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury.

Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Pregnancy management: Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries. Monitoring aortic root measurement during pregnancy by echocardiogram is recommended. Delivery should be performed in a medical center with a high-risk perinatologist in attendance.

Genetic counseling: PLOD1-kEDS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PLOD1 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. If both PLOD1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.