TNXB-Related Classical-Like Ehlers-Danlos Syndrome

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.


Clinical characteristics: The clinical features of TNXB-related classical-like Ehlers-Danlos syndrome (clEDS) strongly resemble those seen in classic EDS (cEDS). Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising, but do not have atrophic scarring, as is seen in cEDS. There are also several other distinguishing clinical findings including anomalies of feet and hands, edema in the legs in the absence of cardiac failure, mild proximal and distal muscle weakness, and axonal polyneuropathy. Vaginal, uterine, and/or rectal prolapse can also occur. Tissue fragility with resulting rupture of the trachea, esophagus, and small and large bowel has been reported. Vascular fragility causing a major event occurs in a minority of individuals. Significant variability in the severity of musculoskeletal symptoms and their effect on day-to-day function between unrelated affected individuals as well as among affected individuals in the same family has been reported. Fatigue has been reported in more than half of affected individuals. The severity of symptoms in middle-aged individuals can range from joint hypermobility without complications to being wheelchair-bound as a result of severe and painful foot deformities and fatigue.

Diagnosis/testing: The diagnosis of TNXB-related clEDS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in TNXB identified by molecular genetic testing.

Management: Treatment of manifestations: Non-weight-bearing exercise, physical therapy, and careful selection of analgesic medication to address joint pain; if pain is severe or debilitating, consider referral to a pain management specialist or clinic. The use of opioid medication should be avoided for chronic pain, as this does not lead to long-term pain relief and has the potential for addiction issues. Long-term chronic pain may result in the need for mental health services. Prompt assessment and management in a tertiary center is required for bowel rupture, arterial rupture, or organ rupture. Ascorbic acid (vitamin C) may reduce easy bruising but has no effect on the key characteristics of skin hyperextensibility and joint hypermobility. DDAVP® (deamino-delta-D-arginine vasopressin) may also be useful to normalize bleeding time in those with easy bruising. Standard treatment is applicable for joint dislocations, subjective muscle weakness, and cardiac abnormalities.

Prevention of primary manifestations: Maintenance of a health body weight; low threshold for referral to gastroenterologist for evaluation of gastrointestinal symptoms; special attention during general anesthesia in order to provide adequate positioning and support as well as being aware of tissue fragility, which has been reported after intubation. Avoid invasive procedures unless absolutely medically necessary; consider carrying medical information or wearing jewelry denoting an increased risk of tissue fragility.

Surveillance: Routine follow up ideally with rheumatologist, pain management clinic, and/or specialized EDS services, if available.

Agents/circumstances to avoid: Sports with heavy joint strain, as well as contact sports; invasive procedures unless they are absolutely medically necessary; acetylsalicylate (aspirin) and long-term use of NSAIDS; use of opioid medication for chronic pain.

Pregnancy management: It is important that the obstetrician and midwives are made aware of the diagnosis of clEDS during a pregnancy. Reported pregnancy and postpartum issues in affected women include miscarriage, premature rupture of membranes, post- or peripartum hemorrhage, and prolapse of the rectum, vagina, and/or uterus. Specialist delivery is strongly advised in view of reported trachea rupture during intubation and esophagus rupture after insertion of a transesophageal ultrasound probe.

Genetic counseling: TNXB-related clED is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TNXB pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the TNXB pathogenic variants have been identified in an affected family member, carrier testing and prenatal/preimplantation genetic testing are theoretically possible.

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