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.

Suggestive Findings

LDS should be suspected in individuals with the following vascular, skeletal, craniofacial, cutaneous, allergic/inflammatory, ocular, and family history 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

• Hypertelorism
• 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, predominantly 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

Family history is most often consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations), except in those with IPO8-related LDS (LDS7), which is inherited in an autosomal recessive manner. Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Clinical diagnosis. The clinical diagnosis of LDS can be established in a proband with suggestive findings. Note: No consensus clinical diagnostic criteria are published.

Molecular diagnosis. The molecular diagnosis of LDS can be established in a proband who has a heterozygous pathogenic (or likely pathogenic) variant in SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, or TGFBR2 or biallelic pathogenic (or likely pathogenic) variants in IPO8 (see Table 1) AND any of the following [MacCarrick et al 2014]:

• Aortic root enlargement (defined as an aortic root z score ≥2 standard deviations above the mean) or type A dissection
• Other characteristic clinical features of LDS: craniofacial, skeletal, cutaneous, and/or vascular manifestations (especially arterial tortuosity, prominently including the head and neck vessels, and aneurysms or dissections involving medium-to-large muscular arteries throughout the arterial tree)
• Family history of established diagnosis of LDS

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Loeys-Dietz syndrome (LDS) 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

Genes are listed in Table 2 in order of phenotypic severity (from those genes associated with the most severe phenotype to the least severe phenotype).

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 and interfamilial phenotypic variability has been reported. 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.

Penetrance

Rare examples of non-penetrance in LDS have been documented. In some instances, non-penetrance is explained by mosaicism [Baban et al 2018].

Nomenclature

While various clinical presentations have in the past been labeled as LDS type I (craniofacial features present), LDS type II (minimal to absent craniofacial features), and LDS type III (presence of osteoarthritis), it is now recognized that LDS caused by a heterozygous pathogenic variant in any of the seven known genes (see Table 1) is a continuum in which affected individuals may have various combinations of clinical features.

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.

TGFB3-related LDS may also be referred to as Rienhoff syndrome.

Prevalence

The exact prevalence of LDS is unknown but estimated to be 1:50,000. More than 1,000 families with LDS have been described in the literature.

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with germline pathogenic variants in IPO8.

Other phenotypes associated with germline pathogenic variants in SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, and TGFBR2 are summarized in Table 3.

Marfan Syndrome and Shprintzen-Goldberg Syndrome

FBN1-related Marfan syndrome is a systemic disorder with a high degree of clinical variability. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. 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 pathogenic variants in 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 Loeys-Dietz syndrome (LDS) and can be mild. An important feature distinguishing SGS from LDS is the near-uniform incidence of developmental delay in individuals with SGS. SGS is caused by heterozygous pathogenic variants in SKI and most individuals have a de novo pathogenic variant. The protein encoded by SKI, ski oncogene, is a known repressor of transforming growth factor beta signaling.

Genes of Interest in the Differential Diagnosis of Loeys-Dietz Syndrome

Other Considerations

Bicuspid aortic valve (BAV) with thoracic aortic aneurysm. A dilated ascending aorta may be associated with an underlying BAV (a BAV 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. 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. MIB1, NOTCH1, ROBO4, and SMAD6 pathogenic variants have been identified in rare (<1%) individuals with a BAV with or without ascending aortic aneurysm [Gould et al 2019, Luyckx et al 2019, Tessler et al 2023].

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 30% 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.

Fibromuscular dysplasia (FMD) (OMIM 135580) is a non-atherosclerotic, non-inflammatory 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. Macroaneurysms 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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with LDS, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management of LDS is most effective through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, cardiothoracic surgeon, orthopedist, and ophthalmologist (see Table 7).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 8 are recommended.

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 triptan medications 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 recommended that the genetic status of relatives of any age at risk for LDS be clarified either by molecular genetic testing or by clinical examination so that affected individuals can undergo regular cardiovascular screening to detect aortic aneurysms and initiate appropriate medical or surgical intervention (see Surveillance). Approaches include the following:

• Molecular genetic testing if the LDS-related pathogenic variant(s) in the family is known
• Examination for manifestations of LDS if the pathogenic variant(s) in the family is not known. Echocardiography and extensive vascular imaging of relatives is indicated upon identification of any suggestive findings 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 LDS can tolerate pregnancy and delivery [Gutman et al 2009, Frise et al 2017].

Therapies Under Investigation

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) 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 – Risk to Family Members

Parents of a proband

• Approximately 75% of individuals 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. Familial recurrence is more common in less severe presentations of LDS.
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for both parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for surveillance. If a molecular diagnosis has not been established in the proband, it is appropriate to evaluate both parents for manifestations of LDS, including a comprehensive clinical examination.
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism * (parental somatic and gonadal mosaicism have been reported in rare families [Baban et al 2018]). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * 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.
• A proband may appear to be the only family member with LDS 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, de novo occurrence of an LDS-related pathogenic variant in the proband cannot be confirmed unless appropriate clinical evaluation of the parents and/or molecular genetic testing has demonstrated that neither parent has the pathogenic variant.

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

• If a parent of the proband is affected and/or is known to have the LDS-related pathogenic variant identified in the proband, the risk to the sibs is 50%.
• Clinical variability may be observed among individuals in the same family who have the same pathogenic variant.
• If the proband has a known LDS-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [Baban et al 2018]).
• If both parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but still increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal 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. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or is known to have the pathogenic variant identified in the proband, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an IPO8 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an IPO8 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with IPO8-related LDS are obligate heterozygotes (carriers) for a pathogenic variant in IPO8.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an IPO8 pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the IPO8 pathogenic variants in the family.

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.

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.
• Pregnancy can be dangerous for women with LDS; appropriate supervision and high-risk obstetric management is recommended (see Pregnancy Management).

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 LDS-related pathogenic variant(s) have been identified in an affected family member, prenatal 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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic 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, it was observed that recombinantly expressed mutated receptors in cells that were naïve for transforming growth factor beta (TGF-β) receptors could not support TGF-β signaling [Mizuguchi et al 2004]. 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 TGF-β 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 contain 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 TGF-β receptor genes in persons with Loeys-Dietz syndrome (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 TGF-β 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 ligands, but that specifically lacks the ability to propagate the intracellular TGF-β 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 TGF-β 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 TGF-β signaling and can be attenuated or prevented by TGF-β antagonism in animal models.

Experiments exploring TGF-β 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 TGF-β receptors may initiate chronic and dysregulated compensatory mechanisms that result in too much TGF-β 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 TGF-β signaling after 24 hours of ligand deprivation and a slower decline in the TGF-β signal after restoration of ligand. An even more informative result was the observation of increased nuclear accumulation of phosphorylated mothers against decapentaplegic homolog 2 (the protein encoded by SMAD2) in the aortic wall of persons with either Marfan syndrome or LDS, and increased expression of TGF-β-dependent gene products such as collagen and CCN family member 2 (also called connective tissue growth factor, or CTGF; encoded by CTGF). Taken together, these data demonstrate increased TGF-β 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 TGF-β 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 transforming growth factor beta receptor type-2 (TGFR-2) leads to increased TGF-β signaling, including stimulation of the intracellular signaling cascade and increased output of TGF-β-responsive genes. Recent work in animal models of LDS has shown that adjacent cell types in the arterial wall have different susceptibility to the influence of heterozygous loss-of-function variants in genes that encode positive effectors of TGF-β signaling. Attempts at compensation in more vulnerable cell types can include greatly enhanced secretion of TGF-β ligands, which can overdrive TGF-β signaling in less vulnerable adjacent cells. Notably, aortic aneurysm and dissection can be prevented in LDS mice through genetic manipulations that specifically attenuate TGF-β signaling in hyperresponsive vascular smooth muscle cells (i.e., those derived from the cardiac neural crest).

Mechanism of disease causation. Loss of function of the individual components of the TGF-β signaling pathway but overall a paradoxical gain of function of TGF-β-related signaling pathways

Author Notes

Gretchen Oswald (ude.imhj@1dlawsog) is actively involved in clinical research regarding individuals with Loeys-Dietz syndrome (LDS). They would be happy to communicate with persons who have any questions regarding diagnosis of LDS or other considerations.

Prof Harry C Dietz (ude.imhj@zteidh) and Prof Bart L Loeys (eb.prewtnau@syeol.trab) are also interested in hearing from clinicians treating families affected by LDS in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in LDS.

Contact Prof Dietz and Prof Loeys to inquire about review of variants of uncertain significance in genes associated with LDS.

Acknowledgments

HD would like to acknowledge funding support from the Howard Hughes Medical Institute, the National Institutes of Health, the Bloomberg Fund of the Marfan Foundation, the Smilow Center for Marfan Syndrome Research, the Loeys-Dietz Syndrome Foundation, the Feather Foundation, the DEFY Foundation, the Ehlers-Danlos Syndrome Foundation, and the Kasper, Aldredge, Coles and Daskal Family Foundations for generous research support. BL would like to acknowledge funding support from the European Research Council (ERC), Research Foundation Flanders (FWO), the F101G Foundation, and the Methusalem fund from the University of Antwerp. Both HD and BL thank their colleagues, trainees, and patients for essential contributions, inspiration, and insights.

Revision History

• 12 September 2024 (sw) Comprehensive update posted live
• 1 March 2018 (ma) Comprehensive update posted live
• 11 July 2013 (me) Comprehensive update posted live
• 28 February 2008 (me) Review posted live
• 2 July 2007 (bl) Original submission

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