Clinical characteristics: Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Diagnosis/testing: The diagnosis of LDS is established in individuals based on characteristic clinical findings in the proband and family members and/or by the identification of a heterozygous pathogenic variant in SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, or TGFBR2.
Management: Treatment of manifestations: Important considerations when managing cardiovascular features of LDS: aortic dissection can occur at smaller aortic diameters and at younger ages than observed in Marfan syndrome; vascular disease is not limited to the aortic root; angiotensin receptor blockers, beta-adrenergic receptor blockers, or other medications are used to reduce hemodynamic stress; and aneurysms are amenable to early and aggressive surgical intervention. Surgical fixation of cervical spine instability may be necessary to prevent spinal cord damage. Treatment is standard for clubfeet and severe pes planus. Management by a craniofacial team is preferred for treatment of cleft palate and craniosynostosis. Standard treatment for allergic complications with consideration of referral to an allergy/immunology specialist in severe cases. Careful and aggressive refraction and visual correction is mandatory in young children at risk for amblyopia. Hernias tend to recur after surgical intervention. A supporting mesh can be used during surgical repair to minimize recurrence risk. Optimal management of pneumothorax to prevent recurrence may require chemical or surgical pleurodesis or surgical removal of pulmonary blebs.
Prevention of secondary complications: Consider subacute bacterial endocarditis (SBE) prophylaxis in those undergoing dental work or other procedures expected to contaminate the bloodstream with bacteria. Because of high risk for cervical spine instability, a flexion/extension x-ray of the cervical spine should be performed prior to intubation or any other procedure involving manipulation of the neck.
Surveillance: All individuals with LDS require echocardiography at frequent intervals to monitor the status of the ascending aorta; the frequency of magnetic resonance angiography (MRA) or computerized tomography angiography (CTA) evaluation to image the entire arterial tree depends on clinical findings. Individuals with cervical spine instability and severe or progressive scoliosis should be followed by an orthopedist.
Agents/circumstances to avoid: Contact sports, competitive sports, and isometric exercise; agents that stimulate the cardiovascular system including routine use of decongestants or triptan medications for the management of migraine headache; activities that cause joint injury or pain; for individuals at risk for recurrent pneumothorax, breathing against a resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., SCUBA diving).
Evaluation of relatives at risk: If the pathogenic variant in the proband is known, molecular genetic testing can be used to clarify genetic status of at-risk family members; if the pathogenic variant is not known, relatives at risk should be evaluated for signs of LDS, including echocardiography and extensive vascular imaging if findings suggest LDS or if findings were subtle in the index case.
Pregnancy management: Pregnancy and the postpartum period can be dangerous for women with LDS because of increased risk of aortic dissection/rupture and uterine rupture. Increased frequency of aortic imaging is recommended, both during pregnancy and in the weeks following delivery.
Therapies under investigation: The safety and efficacy of angiotensin II receptor type 1 blockers (ARBs) has not been addressed for persons with LDS in a clinical trial setting, but ARBs have proven safe and comparable or superior to beta blockers in treating other vascular connective tissue disorders, such as Marfan syndrome.
Genetic counseling: LDS is inherited in an autosomal dominant manner. Approximately 25% of individuals diagnosed with LDS have an affected parent; approximately 75% of probands have LDS as the result of a de novo pathogenic variant. Each child of an individual with LDS has a 50% chance of inheriting the pathogenic variant and the disorder. Prenatal testing for a pregnancy at increased risk for LDS is possible if the pathogenic variant in the family is known.
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