Loeys-Dietz Syndrome
Summary
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 diagnosis for pregnancies at increased risk for LDS is possible if the pathogenic variant in the family is known.
Diagnosis
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) (see Phenotype Correlations by Gene), it is now recognized that LDS caused by a heterozygous pathogenic variant in any of the six known genes (see Table 1) is a continuum in which affected individuals may have various combinations of clinical features.
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 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: 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).
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).
Option 1
When the clinical findings suggest the diagnosis of LDS, molecular genetic testing approaches can include serial single-gene testing or use of a multigene panel.
Serial single-gene testing. Sequence analysis of the genes listed in Table 1 can be performed first, typically in order of descending frequency (i.e., TGFBR2, TGFBR1, SMAD3, TGFB2, SMAD2, and TGFB3). Gene targeted deletion/duplication analysis for SMAD3, TGFB2, and TGFB3 should be considered upon strong clinical suspicion and normal sequence analysis.
- Sequencing of SMAD3 could be considered first if early osteoarthritis is evident in the proband or family.
- TGFB2 or TGFB3 can be analyzed first in individuals with milder phenotypes.
A multigene Marfan syndrome / Loeys-Dietz syndrome / familial thoracic aortic aneurysms and dissections panel that includes SMAD2, SMAD3, TGFB2, TGFB3,TGFBR1, and TGFBR2 as well as a number of other genes associated with disorders that include aortic aneurysms and dissections (see Differential Diagnosis) may be offered by clinical laboratories. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For LDS a multigene panel that also includes deletion/duplication analysis may be considered (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from other inherited disorders with features observed in LDS syndrome, molecular genetic testing approaches can include comprehensive genomic testing (exome sequencing and genome sequencing).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Loeys-Dietz Syndrome
| Gene 1 | Proportion of LDS Attributed to Pathogenic Variants in Gene 2 | Proportion of Pathogenic Variants 3 Detected by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| SMAD2 | ~1%-5% | 90%-95% | Unknown 6 |
| SMAD3 | ~5%-10% | 90%-95% | Rare 7 |
| TGFB2 | ~5%-10% | 90%-95% | Rare 8 |
| TGFB3 | ~1%-5% | 90%-95% | Rare 9 |
| TGFBR1 | ~20%-25% | ~100% | See footnote 10. |
| TGFBR2 | ~55%-60% | ~100% | See footnote 10. |
| Unknown 11 | NA | ||
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
Meester et al [2017b]
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
No data on gene-targeted del/dup analysis are available.
- 7.
Hilhorst-Hofstee et al [2013]
- 8.
Lindsay et al [2012], Gaspar et al [2017]
- 9.
Deletion of TGFB3 has been observed [Author, personal communication].
- 10.
Whole-gene deletion of TGFBR2 [Campbell et al 2011] or TGFBR1 [Redon et al 2006] and duplication of a 14.6-Mb region surrounding TGFBR1 [Breckpot et al 2010] have been reported; however, these individuals lacked aortic involvement. Several other persons with deletions of TGFBR1 or TGFBR2 have not developed aortic aneurysms to date, suggesting that at least some mutated protein needs to be present [Lindsay & Dietz 2011]. As such, whole deletion/duplication of TGFBR1 or TGFBR2 do not present with clear features of Loeys-Dietz syndrome. Smaller deletions/duplications that lead to in frame events are likely to cause an LDS phenotype, whereas events leading to out of frame are not.
- 11.
Based on rare individuals with discriminating features of LDS who show no pathogenic variants in the known genes, additional LDS-associated genes remain to be identified [Authors, personal observation].
Clinical Characteristics
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].
Cardiovascular
The major sources of morbidity and early mortality in LDS are dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic dissection and rupture, mitral valve prolapse (MVP) with or without regurgitation, and enlargement of the proximal pulmonary artery.
Individuals with LDS have a more aggressive vascular course (with routine involvement of vascular segments distant from the aortic root) than that observed in Marfan syndrome. Mean age at death is 26 years [Loeys et al 2006]. Attias et al [2009] reported that the proportion of individuals with aortic dilatation, the age at dissection, and the need for surgery were similar in those with a heterozygous TGFBR2 pathogenic variant and those with a heterozygous FBN1 pathogenic variant causative of Marfan syndrome; however, the rate of death was greater in families with a heterozygous TGFBR2 pathogenic variant. Similarly, a study of 228 families with a heterozygous pathogenic variant in either TGFBR1 or TGFBR2 demonstrated similar aortic risk (dissection or aortic surgery) in both groups [Jondeau et al 2016].
Arterial aneurysms have been observed in almost all side branches of the aorta including (but not limited to) the subclavian, renal, superior mesenteric, hepatic, and coronary arteries.
Aortic dissection has been observed in early childhood (age ≥6 months) and/or at aortic dimensions that do not confer risk in other connective tissue disorders such as Marfan syndrome.
Arterial tortuosity can be generalized but most commonly involves the head and neck vessels:
- The arterial involvement is widespread, and arterial tortuosity is present in a majority of affected individuals.
- Most affected individuals have multiple arterial anomalies.
- Vertebral and carotid artery dissection and cerebral bleeding have been described; however, isolated carotid artery dissection in the absence of aortic root involvement has not been observed.
MVP with mitral regurgitation has been observed in individuals with LDS, although less frequently than in Marfan syndrome.
Other recurrent cardiovascular findings include patent ductus arteriosus, atrial septal defects, and bicuspid aortic valve. Although all of these findings are common in individuals who do not have LDS, the incidence in LDS exceeds by at least five times that seen in the general population.
Aortic histopathology. Histologic examination of aortic tissue reveals fragmentation of elastic fibers, loss of elastin content, and accumulation of amorphous matrix components in the aortic media. Structural analysis shows loss of the intimate spatial association between elastin deposits and vascular smooth muscle cells and a marked excess of aortic wall collagen. These characteristics are observed in young children and in the absence of inflammation, suggesting a severe defect in elastogenesis rather than secondary elastic fiber destruction.
Aortic samples from individuals with LDS had significantly more diffuse medial degeneration than did samples from individuals with Marfan syndrome or control individuals. The changes are not entirely specific for LDS, but in the appropriate clinico-pathologic setting help differentiate it from other vascular diseases [Maleszewski et al 2009].
Skeletal
The skeletal findings are characterized by Marfan syndrome-like skeletal features and joint laxity or contractures [Erkula et al 2010]:
Skeletal overgrowth in LDS is less pronounced than in Marfan syndrome and usually affects the digits more prominently than the long bones.
Arachnodactyly is present in some, but true dolichostenomelia (leading to an increase in the arm span-to-height ratio and a decrease in the upper-to-lower segment ratio) is less common in LDS than in Marfan syndrome.
Combined thumb and wrist signs were present in one third of individuals with LDS.
Note: (1) The Walker-Murdoch wrist sign is the overlapping of the complete distal phalanx of the thumb and fifth finger when wrapped around the opposite wrist. (2) The "thumb sign" (Steinberg) is an extension of the entire distal phalanx of the thumb beyond the ulnar border of the hand when apposed across the palm.
Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum).
Joint hypermobility is common and can include congenital hip dislocation and recurrent joint subluxations. Paradoxically, some individuals can show reduced joint mobility, especially of the hands (camptodactyly) and feet (clubfeet).
Spine anomalies, including congenital malformations of the cervical vertebrae and cervical spine instability, are common, especially in individuals with more severe craniofacial features.
Preliminary data suggest that approximately one third (or more) of affected individuals have structural cervical spine anomalies and at least 50% have cervical spine instability.
Other skeletal findings
- Spondylolisthesis and scoliosis can be mild or severe and progressive.
- Acetabular protrusion, present in one third of individuals, is usually mild but can be associated with pain or functional limitations.
- Pes planus, often associated with inward rotation at the ankle, contributes to difficulty with ambulation, leg fatigue, and muscle cramps.
- Preliminary evidence suggests that individuals with LDS have an increased incidence of osteoporosis with increased fracture incidence and delayed bone healing [Kirmani et al 2010].
Note: Musculoskeletal findings, including hypotonia, have been observed in neonates with LDS [Yetman et al 2007].
Craniofacial
In their most severe presentation, craniofacial anomalies in individuals with LDS are characterized by widely spaced eyes and craniosynostosis. Craniosynostosis most commonly involves premature fusion of the sagittal suture (resulting in dolichocephaly). Coronal suture synostosis (resulting in brachycephaly) and metopic suture synostosis (resulting in trigonocephaly) have also been described.
- Bifid uvula is considered the mildest expression of a cleft palate. Sometimes the uvula has an unusual broad appearance with or without a midline raphe.
- Other craniofacial characteristics include malar flattening and retrognathia.
Cutaneous
The skin findings, similar to those seen in vascular Ehlers-Danlos syndrome (see Differential Diagnosis), include velvety, thin, translucent skin with visible veins on the chest wall, easy bruising (other than on the lower legs), and slower scar formation and dystrophic scarring.
Allergy and Gastrointestinal Disease
Individuals with LDS are predisposed to developing allergic disease including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. Some affected individuals have exhibited elevated immunoglobulin E levels, eosinophil counts, and T helper 2 (TH2) cytokines in plasma [Frischmeyer-Guerrerio et al 2013, Felgentreff et al 2014].
Ocular
Myopia is less frequent and less severe than that seen in Marfan syndrome. Significant refractive errors can lead to amblyopia. Other common ocular features include strabismus and blue sclerae. Retinal detachment has been reported in rare cases. Ectopia lentis is not observed.
Other
Life-threatening manifestations include spontaneous rupture of the spleen and bowel, and uterine rupture during pregnancy.
The two most common neuroradiologic findings are dural ectasia (the precise incidence of which is unknown, as only a minority of affected individuals have undergone appropriate examination) and Arnold-Chiari type I malformation, which may be relatively rare.
A minority of affected individuals have developmental delay. When present, developmental delay is most often associated with craniosynostosis and/or hydrocephalus, suggesting that learning disability is an extremely rare primary manifestation of LDS.
Less common associated findings requiring further exploration include submandibular branchial cysts and defective tooth enamel.
Pregnancy. Pregnancy can be dangerous for women with LDS; see Pregnancy Management.
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.
Table 2.
Loeys-Dietz Syndrome (LDS): Associated Genes and Subtypes
| Gene | Subtype of LDS 1 | Comment | Reference |
|---|---|---|---|
| TGFBR1 | LDS1 2 | Loeys et al [2005], Loeys et al [2006] | |
| TGFBR2 | LDS2 2 | ||
| SMAD3 | LDS3 3 | Strong predisposition for osteoarthritis 4 | van de Laar et al [2011] |
| TGFB2 | LDS4 | Systemic findings possibly less severe & more like Marfan syndrome 5 | Lindsay et al [2012], Bertoli-Avella et al [2015] |
| TGFB3 | LDS5 |
- 1.
Ordered from most to least severe
- 2.
No differences in phenotype are observed between individuals with a heterozygous pathogenic variant in TGFBR1 and those with a heterozygous pathogenic variant in TGFBR2.
- 3.
The severity of aortic disease in individuals with a heterozygous pathogenic variant in SMAD3 is similar to that associated with a heterozygous pathogenic variant in TGFBR1 or TGFBR2.
- 4.
Several individuals with a heterozygous pathogenic variant in SMAD3 who do not have osteoarthritis have been reported [Wischmeijer et al 2013].
- 5.
Boileau et al [2012]
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.
Neither apparent enrichment in any ethnic or racial group nor gender preference has been reported.
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].
Differential Diagnosis
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].
Table 3.
Clinical Features of Loeys-Dietz Syndrome by Associated Gene Compared to the Clinical Features of Marfan Syndrome and Shprintzen-Goldberg Syndrome
| Clinical Feature | Marfan Syndrome | Loeys-Dietz Syndrome | Shprintzen -Goldberg Syndrome | ||||
|---|---|---|---|---|---|---|---|
| FBN1 | TGFBR1/ TGFBR2 | SMAD3 | TGFB2 | TGFB3 | SMAD2 | SKI | |
| Developmental delay | − | − | − | − | − | − | ++ |
| Ectopia lentis | +++ | − | − | − | − | − | − |
| Cleft palate / bifid uvula | − | ||||||