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.

Suggestive Findings

Loeys-Dietz syndrome (LDS) should be suspected in individuals with the following vascular, skeletal, craniofacial, cutaneous, allergic/inflammatory, and ocular findings [Loeys et al 2005].

Vascular

• Dilatation or dissection of the aorta and other arteries. Aortic root dilatation is seen in more than 95% of probands; the aortic root is the most common site for a dissection to occur. In rare circumstances, aneurysms or dissections can be seen in other arteries in the head, chest, abdomen, or extremities in the absence of aortic involvement.
• Other arterial aneurysms and tortuosity
  • Evaluation is best done with magnetic resonance angiography (MRA) or CT angiogram (CTA) with 3D reconstruction from head to pelvis to identify arterial aneurysms or dissections and arterial tortuosity throughout the arterial tree.
  • Tortuosity is often most prominent in head and neck vessels.
  • Approximately 50% of individuals with LDS studied had an aneurysm distant from the aortic root that would not have been detected by echocardiography.

Skeletal

• Pectus excavatum or pectus carinatum
• Scoliosis
• Joint laxity or contracture (typically involving the fingers)
• Arachnodactyly
• Talipes equinovarus
• Cervical spine malformation and/or instability
• Osteoarthritis

Craniofacial

• Widely spaced eyes
• Bifid uvula / cleft palate
• Craniosynostosis, in which any sutures can be involved

Cutaneous

• Soft and velvety skin
• Translucent skin with easily visible underlying veins
• Easy bruising
• Dystrophic scars
• Milia, prominently on the face

Allergic/inflammatory disease

• Food allergies
• Seasonal allergies
• Asthma / chronic sinusitis
• Eczema
• Eosinophilic esophagitis/gastritis
• Inflammatory bowel disease

Ocular. Blue or dusky sclerae

Establishing the Diagnosis

The diagnosis of Loeys-Dietz syndrome is established in a proband (by definition a person without a known family history of LDS) who has a heterozygous pathogenic (or likely pathogenic) variant in SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, or TGFBR2 (see Table 1) and EITHER of the following [MacCarrick et al 2014]:

• Aortic root enlargement (defined as an aortic root z-score ≥2.0) or type A dissection
• Compatible systemic features including characteristic craniofacial, skeletal, cutaneous, and/or vascular manifestations found in combination. Special emphasis is given to arterial tortuosity, prominently including the head and neck vessels, and to aneurysms or dissections involving medium-to-large muscular arteries throughout the arterial tree.

Note: (1) In the presence of a family history of documented LDS, the diagnosis can be made in at-risk relatives on the basis of molecular genetic testing even if vascular involvement or other features are not yet apparent (see Evaluation of Relatives at Risk). (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (3) Identification of a heterozygous variant of uncertain significance in one of the genes included in Table 1 does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (serial single-gene testing or a multigene panel) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because of clinical overlap, it is difficult to predict which of the known LDS-related genes will be causative in any given affected individual. Although individuals with the distinctive findings of LDS described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), those who do not have sufficiently discriminating features to consider the diagnosis of LDS are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Loeys-Dietz syndrome represents a wide phenotypic spectrum in which affected individuals may have various combinations of clinical features ranging from a severe syndromic presentation with significant extravascular systemic findings in young children to predominantly thoracic aortic aneurysm/dissection occurring in adults. Clinical variability is also observed among individuals in the same family who have the same pathogenic variant. The most common findings involve the vascular, skeletal, craniofacial, cutaneous, allergic/inflammatory, and ocular systems [Loeys et al 2005, Loeys et al 2006].

Phenotype Correlations by Gene

Various clinical presentations have in the past been labeled as LDS type I (craniofacial features present), LDS type II (minimal to absent craniofacial features), LDS type III (presence of osteoarthritis), and so on. These subtype designations provide a general indication of the spectrum of disease severity, from most to least severe: LDS1=LDS2>LDS3>LDS4>LDS5. Note: There is not yet enough information on the spectrum of features of LDS caused by heterozygous pathogenic variants in SMAD2 to place this gene on the continuum or in Table 2.

Genotype-Phenotype Correlations

While the implicated gene can correlate broadly with disease severity (see Phenotype Correlations by Gene), there are few specific genotype-phenotype correlations in LDS. Wide intrafamilial phenotypic variability has been documented. The identical pathogenic variant has also been described in unrelated affected individuals with phenotypes ranging from predominantly thoracic aortic disease to classic and severe LDS. These data suggest the strong influence of genetic modifiers of disease that are independent of the pathogenic variant itself.

Penetrance

Intrafamilial clinical variability has been described and rare examples of non-penetrance in LDS have been documented. In one case, this was related to somatic mosaicism; in another, no evidence for mosaicism was observed.

Intrafamilial variability likely relates to genetic modification; genes encoding factors that regulate TGFβ signaling are excellent candidates for sites of modifying variation.

Nomenclature

Marfan syndrome type 2 was a designation initially applied by Mizuguchi et al [2004] to describe individuals with "classic" Marfan syndrome caused by a heterozygous pathogenic variant in TGFBR2. At the time of the report other discriminating features of LDS had not yet been described. There has not been documentation of individuals with a heterozygous pathogenic variant inTGFBR1 or TGFBR2 that satisfied diagnostic criteria for Marfan syndrome including the stipulation requiring absence of discriminating features of LDS [Loeys et al 2006, Van Hemelrijk et al 2010]. The term Marfan syndrome type 2 should not be used to refer to LDS.

Prevalence

The prevalence of LDS is unknown.

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with pathogenic variants in SMAD3, TGFB2, or TGFB3. While pathogenic variants in TGFB3 have been associated with Rienhof syndrome, this phenotype is clinically related to Loeys-Dietz syndrome.

SMAD2. Two pathogenic variants in SMAD2 have been reported in a series of 362 individuals with severe congenital heart disease [Zaidi et al 2013]. These two individuals presented with dextrocardia associated with multiple other congenital heart defects.

TGFBR1 and TGFBR2. A number of disorders have been thought to be caused by a heterozygous pathogenic variant in TGFBR1 or TGFBR2 (see Differential Diagnosis).

The only disorder not clinically related to Loeys-Dietz syndrome that is caused by a heterozygous loss-of-function variant in TGFBR1 is multiple self-healing squamous epithelioma, also known as Ferguson-Smith disease [Goudie et al 2011].

Syndromic Forms of Thoracic Aortic Aneurysms

Marfan syndrome is a systemic disorder with a high degree of clinical variability. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems [Judge & Dietz 2005]. Cardiovascular manifestations include dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Marfan syndrome is caused by mutation of FBN1 and inherited in an autosomal dominant manner.

Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis, distinctive craniofacial features, skeletal changes, neurologic abnormalities, mild-to-moderate intellectual disability, and brain anomalies. Cardiovascular anomalies (mitral valve prolapse, mitral regurgitation, and aortic regurgitation) may occur, but aortic root dilatation is less commonly observed than in LDS, and can be mild. An important feature distinguishing SGS from LDS is the near-uniform incidence of developmental delay in SGS.

Molecular analysis of a series of individuals with typical SGS did not reveal pathogenic variants in TGFBR1 or TGFBR2 [Loeys et al 2005]. Affected individuals are usually simplex cases (i.e., no family history of SGS), although rare instances of apparent autosomal dominant inheritance have been described. Most individuals with SGS have a heterozygous de novo pathogenic missense variant in SKI [Carmignac et al 2012, Doyle et al 2012]. The SKI protein is a known repressor of TGFβ signaling, functionally linking SGS to LDS. Note: An individual reported with SGS by Kosaki et al [2006] was felt to have LDS based on the presence of arterial tortuosity and a bifid uvula [Robinson et al 2006].

BGN-associated aortic aneurysm syndrome is an X-linked condition caused by a hemizygous pathogenic variant in BGN, coding for biglycan [Meester et al 2017a]. Clinical features significantly overlap with both Marfan syndrome and Loeys-Dietz syndrome, including early-onset aortic root dilatation and dissection, widely spaced eyes, joint hypermobility, contractures, bifid uvula, and pectus deformities. In some families, heterozygous females are also affected. The type of pathogenic variants in BGN suggest loss of function as the mechanism of disease.

MASS phenotype (OMIM 604308) is characterized by mitral valve prolapse, myopia, borderline and non-progressive aortic enlargement, and nonspecific skin and skeletal findings that overlap with those seen in Marfan syndrome. One is most confident in this diagnosis when concordant manifestations are seen in multiple generations in a given family. However, some individuals in such a family could be predisposed to more severe vascular involvement, and thus a regimen of intermittent cardiovascular imaging should be maintained. It is difficult to distinguish MASS phenotype from "emerging" Marfan syndrome when assessing a simplex case (i.e., single occurrence in a family), especially during childhood. Heterozygous variants in FBN1 can be causative. Inheritance is autosomal dominant.

The Ehlers-Danlos syndromes

Congenital contractural arachnodactyly (CCA) is characterized by a Marfan-like appearance (tall, slender habitus in which arm span exceeds height) and long, slender fingers and toes (arachnodactyly). Progressive enlargement of the ascending aorta at the sinuses of Valsalva has been reported, but there is no evidence that the aortic dilatation progresses to dissection or rupture [Gupta et al 2002]. Infants have been observed with a severe/lethal form characterized by multiple cardiovascular and gastrointestinal anomalies in addition to the typical skeletal findings. CCA is caused by mutation of FBN2 and is inherited in an autosomal dominant manner.

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disorder, mainly characterized by severe tortuosity, stenosis, and aneurysms of the aorta and middle-sized arteries [Wessels et al 2004]. Skeletal and skin involvement is also common. The underlying genetic defect is homozygosity for loss-of-function variants in SLC2A10, the gene encoding solute carrier family 2, facilitated glucose transporter member 10. Although a glucose transporter defect would not be expected to cause abnormal arterial patterning, additional studies indicated upregulation of the TGFβ signaling pathway [Coucke et al 2006], consistent with the pathophysiology in LDS and Marfan syndrome.

Other Syndromes Associated with Ascending Aortic Aneurysms

Turner syndrome, one of the most common sex chromosome aneuploidy syndromes, is caused by the loss of one of the X chromosomes (45,X). The most important phenotypic features are short stature, gonadal dysgenesis, neck webbing, and an increased incidence of renal and cardiovascular abnormalities. The latter include bicuspid aortic valve (BAV), coarctation of the aorta, and thoracic aortic aneurysms. Aortic root dilatation is observed in up to 40% of women with Turner syndrome, but the frequency with which it leads to aortic dissection is unknown. Current health surveillance recommendations for Turner syndrome include echocardiography or MRI for evaluation of the diameter of the aortic root and ascending aorta at least every five years.

Noonan syndrome is characterized by short stature, congenital heart defect, and developmental delay of variable degree. Congenital heart disease occurs in 50%-80% of affected individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of affected individuals. Hypertrophic cardiomyopathy, found in 20%-30% of affected individuals, may be present at birth or appear in infancy or childhood. Other structural defects frequently observed include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Rarely, aortic aneurysms have been described. Noonan syndrome is caused by mutation of BRAF, KRAS, MAP2K1, NRAS, PTPN11, SOS1, RAF1, or RIT1. Inheritance is autosomal dominant.

Cutis laxa. Autosomal dominant cutis laxa (ADCL) was historically considered a strictly cutaneous disorder without systemic involvement, in contrast to autosomal recessive cutis laxa (ARCL), which is associated with high morbidity and mortality resulting from pulmonary emphysema and aortic aneurysms.

Nonsyndromic Familial Thoracic Aortic Aneurysms and Dissections

Bicuspid aortic valve with thoracic aortic aneurysm (BAV/TAA). Many cases of a dilated ascending aorta are associated with an underlying BAV. A bicuspid aortic valve is present in 1%-2% of the general population. Among persons with aortic dissection detected at postmortem examination, 8% have BAVs. Histologic studies show elastin degradation and cystic medial necrosis in the aorta above the valve. For a long time, it was believed that the aneurysms were caused by "post-stenotic dilatation" of the ascending aorta. However, echocardiography of young persons with normally functioning BAVs shows that aortic root dilatation is common (52%) [Nistri et al 1999]. Importantly, the aortic dilatation often occurs above the sinuses of Valsalva.

BAVs cluster in families and are found in 9% of first-degree relatives of affected individuals. Family members of probands with BAV and aneurysm can show aneurysm and dissection in the absence of the accompanying valve abnormality, suggesting that both BAV and aneurysm represent primary manifestations of the underlying gene defect [Loscalzo et al 2007]. In family studies, reduced penetrance is common.

Thus far, pathogenic variants have been identified in NOTCH1 (OMIM 190198) and SMAD6 (OMIM 602931) in rare individuals with additional congenital cardiac malformations. NOTCH1 pathogenic variants appear specific to individuals and families with significant valve calcification and stenosis, findings not observed in most families with BAV/TAA. Linkage analysis suggests genetic heterogeneity with loci identified on chromosomes 18q, 5q, and 13q [Martin et al 2007]. SMAD6 loss-of-function variants account for about 2% of all cases of BAV/TAA [Gillis et al 2017].

Persistent patent ductus arteriosus with thoracic aortic aneurysm (PDA/TAA). A report describing a single large family with 179 members who have a high incidence of thoracic aortic aneurysm and dissection (TAAD) in conjunction with PDA suggests that a novel genetic defect underlies both vascular conditions in this family. Linkage analysis excluded all known genes or loci implicated in familial TAAD or autosomal recessive PDA. The disease was mapped to chromosome 16p12 [Khau Van Kien et al 2005]. Mutation of MYH11 (encoding myosin-11, a specific contractile protein of smooth muscle cells) is causative. The structural defect leads to lower aortic compliance, smooth muscle cell loss, and elastolysis, but the precise pathophysiology remains unclear [Zhu et al 2006].

Fibromuscular dysplasia (FMD) (OMIM 135580) is a nonatherosclerotic, noninflammatory vascular disease that can affect almost every artery, but most frequently affects the renal and internal carotid arteries. Most commonly, medial hyperplasia leads to a classic "strings of beads" stenotic arterial appearance. Macro-aneurysms and dissections are complications. It is possible that genetic factors play a role in the pathogenesis: the disease is observed among the first-degree relatives of persons with fibromuscular dysplasia of the renal arteries. The underlying genetic cause for nonsyndromic FMD has not been identified, although PHACTR1 has been reported as a genetic susceptibility locus for FMD [Kiando et al 2016].

Familial thoracic aortic aneurysm and dissection (FTAAD). Cardiovascular manifestations of FTAAD include the following:

• Dilatation of the aorta at the level of either the ascending aorta or the sinuses of Valsalva
• Aneurysms and dissections of the thoracic aorta involving either the ascending or descending aorta

TAAD is diagnosed based on the presence of dilatation and/or dissection of the thoracic aorta, absence of Marfan syndrome and other connective tissue abnormalities, and presence of a positive family history.

Cardiovascular manifestations are usually the only findings. Affected individuals typically have progressive enlargement of the ascending aorta leading to either aortic dissection involving the ascending aorta (type A dissection) or consequent tear or rupture. The onset and rate of progression of aortic dilatation is highly variable; however, persons with familial TAAD present with aortic disease at a mean age of 56.8 years, which is younger than that for sporadic TAAD (64.3 years) but significantly older than that for Marfan syndrome (24.8 years) [Coady et al 1999].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Loeys-Dietz syndrome (LDS), the following evaluations are recommended if they were not completed as part of the evaluation that led to the diagnosis:

• Echocardiography. Aortic root measurements must be interpreted based on consideration of normal values for age and body size [Roman et al 1989]. Select findings (e.g., severe aortic dilatation) may require the immediate attention of a cardiologist or cardiothoracic surgeon.
• MRA or CT scan with 3D reconstruction from head to pelvis to identify arterial aneurysms and arterial tortuosity throughout the arterial tree
  Note: Approximately half of the individuals with LDS studied had an aneurysm distant from the aortic root that would not have been detected by echocardiography.
• Radiographs (including flexion and extension views of the cervical spine) to detect skeletal manifestations that may require attention by an orthopedist (e.g., severe scoliosis, cervical spine instability)
• Craniofacial examination for evidence of cleft palate and craniosynostosis
• Eye examination by an ophthalmologist with expertise in connective tissue disorders, including: slit-lamp examination through a maximally dilated pupil for exclusion of lens (sub)luxation; careful refraction and visual correction, especially in young children at risk for amblyopia; specific assessment for retinal detachment
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management of LDS is most effective through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon. An extensive review of management guidelines has been published [MacCarrick et al 2014] (full text).

Prevention of Secondary Complications

Use of subacute bacterial endocarditis prophylaxis should be considered for individuals with connective tissue disorders and documented evidence of mitral and/or aortic regurgitation who are undergoing dental work or other procedures expected to contaminate the bloodstream with bacteria.

Because of a high risk of cervical spine instability, a flexion and 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 MRA or CTA evaluations should be tailored to clinical findings.

Individuals with cervical spine instability and severe or progressive scoliosis should be followed by an orthopedist.

Agents/Circumstances to Avoid

The following should be avoided:

• Contact sports, competitive sports, and isometric exercise
  Note: Individuals can and should remain active with aerobic activities performed in moderation.
• Agents that stimulate the cardiovascular system including routine use of decongestants or triptans for migraine headache management
• 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

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those individuals who need regular cardiovascular screening to detect aortic aneurysms and initiate appropriate medical or surgical intervention. Evaluations can include the following:

• Molecular genetic testing if the pathogenic variant in the family is known
• Signs of the disorder if the pathogenic variant in the family is not known. Echocardiography and extensive vascular imaging of relatives is indicated upon appreciation of any suspicious signs of LDS, and even in apparently unaffected individuals if findings are subtle in the index case.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy can be dangerous for women with LDS. Complications include aortic dissection/rupture or uterine rupture during pregnancy or delivery, or aortic dissection/rupture in the immediate postpartum period. Increased frequency of aortic imaging is recommended, both during pregnancy and in the weeks following delivery. However, with appropriate supervision and high-risk obstetric management, women with Loeys-Dietz syndrome can tolerate pregnancy and delivery [Gutman et al 2009, Frise et al 2017].

Therapies Under Investigation

Experimental evidence suggests that many manifestations of LDS relate to excess activation of and signaling by the growth factor TGFβ.

Animal trials have shown that TGFβ antagonizing agents, such as angiotensin II receptor type 1 blockers (ARBs), can slow or prevent vascular manifestations of LDS [Gallo et al 2014]. ARBs also attenuate the biochemical abnormalities in the aortic wall of mouse models of LDS. The safety and efficacy of such interventions 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.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Loeys-Dietz syndrome (LDS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 25% of individuals diagnosed with LDS have an affected parent.
• Approximately 75% of probands with LDS have the disorder as the result of a de novo pathogenic variant.
• If the SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, or TGFBR2 pathogenic variant in a proband is known, molecular genetic testing of both parents is indicated. If the pathogenic variant is unknown, it is appropriate to evaluate both parents for manifestations of LDS, including a comprehensive clinical examination.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (both parental somatic and germline mosaicism have been reported in rare cases).
• The family history of some individuals diagnosed with LDS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• The sibs of a proband with clinically unaffected parents are still at increased risk for LDS because of the possibility of reduced penetrance in a parent.
• If the SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, or TGFBR2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

• Each child of an individual with LDS has a 50% chance of inheriting the pathogenic variant.
• The penetrance of SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, and TGFBR2 pathogenic variants is reported to be near 100%; thus, offspring who inherit a pathogenic variant from a parent will have LDS, although the severity cannot be predicted.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with LDS has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. If the SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, or TGFBR2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Ultrasound examination in the first two trimesters is insensitive in detecting manifestations of LDS, but prenatal occurrence of aortic dilatation has been described.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

In the initial description of TGFBR2 pathogenic variants causing a phenotype similar to Marfan syndrome [Mizuguchi et al 2004] it was observed that recombinantly expressed mutated receptors in cells that were naïve for TGFβ receptors could not support TGFβ signaling. Furthermore, there was no apparent dominant-negative interference on the function of coexpressed wild type receptor. These data were interpreted to indicate haploinsufficiency and consequent reduced TGFβ signaling as the relevant pathogenic mechanisms.

In keeping with this hypothesis, one of the original individuals with a Marfan syndrome-like phenotype was shown to harbor a translocation breakpoint within TGFBR2. Complicating this hypothesis, however, is the observation of a distinct paucity of pathogenic nonsense or frameshift variants in either of the TGFβ receptor genes in persons with LDS or related phenotypes. The mutated receptor subunits may not traffic to the cell surface or may not cycle, resulting in "functional haploinsufficiency." The only reported nonsense variant occurs at the very distal margin of the penultimate exon. As opposed to more proximal pathogenic nonsense variants, this context is not predicted to induce nonsense-mediated mRNA decay and clearance of the mutated transcripts. As a result, most (if not all) pathogenic variants in the TGFβ receptor genes associated with vascular phenotypes are predicted to give rise to a mutated receptor protein that has the ability to traffic to the cell surface and bind extracellular ligand, but that specifically lacks the ability to propagate the intracellular TGFβ signal. This hypothesis is also consistent with the finding that pathogenic variants cluster in the intracellular part of both TGFBR1 and TGFBR2 (serine-threonine kinase domains), with few pathogenic variants described in the extracellular domain. However, a model that singularly invokes decreased TGFβ signaling would be difficult to reconcile with the substantial evidence that many aspects of Marfan syndrome, including those that overlap with LDS, are caused by too much TGFβ signaling and can be attenuated or prevented by TGFβ antagonism in animal models.

Experiments exploring TGFβ signaling in cells that only express mutated receptors may not be informative for the situation in vivo when affected individuals are heterozygous for these pathogenic variants. Diminished but not absent function of TGFβ receptors may initiate chronic and dysregulated compensatory mechanisms that result in too much TGFβ signaling. Indeed, the study of fibroblasts derived from heterozygous individuals with LDS failed to reveal any defect in the acute phase response to administered ligand and showed an apparent increase in TGFβ signaling after 24 hours of ligand deprivation and a slower decline in the TGFβ signal after restoration of ligand. An even more informative result was the observation of increased nuclear accumulation of pSmad2 in the aortic wall of persons with either Marfan syndrome or LDS, and increased expression of TGFβ-dependent gene products such as collagen and CTGF. Taken together, these data demonstrate increased TGFβ signaling in the vasculature of persons with LDS and in a context that is directly relevant to tissue development and homeostasis in vivo. Although the basis for this observation remains incompletely understood, it also seems possible that dysregulation of signaling requires the cell surface expression of receptors that can bind TGFβ ligands, but that cannot propagate signal because of a deficiency in kinase function. In support of this hypothesis, it was shown that transgenic expression of a mutated, kinase domain-deleted form of TβRII leads to increased TGFβ signaling, including stimulation of the intracellular signaling cascade and increased output of TGFβ-responsive genes, clearly suggesting a gain-of-function mechanism for mutated TGFβ receptors in LDS.

Revision History

• 1 March 2018 (ma) Comprehensive update posted live
• 11 July 2013 (me) Comprehensive update posted live
• 29 April 2008 (cd) Revision: deletion/duplication testing for TGFBR1 available clinically
• 28 February 2008 (me) Review posted live
• 2 July 2007 (bl) Original submission

Published Guidelines / Consensus Statements

• MacCarrick G, Black JH 3rd, Bowdin S, El-Hamamsy I, Frischmeyer-Guerrerio PA, Guerrerio AL, Sponseller PD, Loeys B, Dietz HC 3rd. Loeys-Dietz syndrome: a primer for diagnosis and management. Available online. 2014. Accessed 9-26-22.

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