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, and cervical spine malformation and/or instability), craniofacial features (hypertelorism, 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 (1) a proband with characteristic clinical findings or (2) by the identification of a heterozygous pathogenic variant in SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, or TGFBR2 or biallelic pathogenic variants in IPO8 in a proband with aortic root enlargement, type A dissection, other characteristic clinical features of LDS, or a family history of an established diagnosis of LDS.
Management: Treatment of manifestations: Important considerations when managing cardiovascular features of LDS include the following: 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. Consider subacute bacterial endocarditis prophylaxis in those undergoing dental work or other procedures expected to contaminate the bloodstream with bacteria. Management of orthopedic manifestations per orthopedist. Surgical fixation of cervical spine instability may be necessary to prevent spinal cord damage. Management by a craniofacial team is preferred for treatment of cleft palate and craniosynostosis. Hernias tend to recur after surgical intervention; a supporting mesh can be used during surgical repair to minimize recurrence risk. Standard treatment for allergic complications with consideration of referral to an allergy/immunology specialist in those with severe disease. Careful and aggressive refraction and visual correction is mandatory in young children at risk for amblyopia. Optimal management of pneumothorax to prevent recurrence may require chemical or surgical pleurodesis or surgical removal of pulmonary blebs. Counseling regarding risk and clinical manifestations of organ rupture.
Surveillance: Echocardiography to monitor the status of the aortic root and ascending aorta (at least annually) and magnetic resonance angiography or computerized tomography angiography to assess the entire arterial tree (at least every other year); more frequent imaging may be indicated based on genotype, family history, absolute vessel size or growth rate, or vascular pathology. Assess for skeletal deformity, joint manifestations, pes planus, hernia, and allergic and inflammatory manifestations at each visit or as needed. Individuals with cervical spine instability and severe or progressive scoliosis should be followed by an orthopedist. Eye examination per ophthalmologist.
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: Clarify the genetic status of at-risk relatives of any age either by molecular genetic testing (if the LDS-related pathogenic variant[s] in the family are known) or by clinical examination including echocardiography and extensive vascular imaging if findings suggest LDS or if findings were subtle in the index case (if the pathogenic variant[s] in the family are not known) so that affected individuals can undergo regular cardiovascular screening to detect aortic aneurysms and initiate appropriate medical or surgical intervention.
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.
Genetic counseling: LDS caused by a pathogenic variant in SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, or TGFBR2 is inherited in an autosomal dominant manner. IPO8-related LDS is inherited in an autosomal recessive manner.
Autosomal dominant inheritance: Approximately 75% of probands diagnosed with LDS have the disorder as the result of a de novo pathogenic variant; approximately 25% of individuals diagnosed with LDS have an affected parent. Each child of an individual with LDS has a 50% chance of inheriting the pathogenic variant and the disorder.
Autosomal recessive inheritance: The parents of a child with IPO8-related LDS are presumed to be heterozygous for an IPO8 pathogenic variant. If both parents are known to be heterozygous for an IPO8 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. Carrier testing for at-risk relatives requires prior identification of the IPO8 pathogenic variants in the family.
If the LDS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
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