Inherited Connective Tissue Disorders

Marfan Syndrome

MFS is a well-described heritable connective tissue disorder with a broad phenotypic spectrum. Its prevalence is 1 case in 3000 to 5000 individuals, irrespective of gender or ethnicity. Mutations in the FBN1 gene (locus 15q21.1), which encodes the extracellular matrix protein fibrillin-1, cause the disease. Major clinical manifestations are seen in the cardiovascular, ocular, and skeletal systems.

The diagnosis is based on the Ghent nosology, which was revised by an international expert panel in 2010 ( Tables 33.2 and 33.3 ). The revised criteria place increased importance on the cardinal clinical features of aortic root dilation/dissection and ectopia lentis and on genetic test findings in the absence of a family history.

MFS is inherited in an autosomal dominant manner; 25% of patients have sporadic, new mutations without a family history. After an individual is diagnosed with MFS, first-degree relatives should be screened for the condition by physical examination, accompanied by ophthalmologic assessment and echocardiography if clinically appropriate. With advances in molecular genetic testing, a causative mutation in the FBN1 gene can be found in more than 90% of individuals fulfilling the clinical diagnostic criteria for MFS.

Over the past 25 years, more than 3000 FBN1 mutations have been described. Despite a considerable effort to identify genotype-phenotype correlations for MFS, few definitive correlations have emerged, and so far none have been specific enough to define clinical management. Of the identified associations, patients with the most severe phenotype (also called the infantile Marfan syndrome ) harbor FBN1 mutations in the central portion of the gene , between exons 24 and 32. In contrast, mutations in FBN1 that produce milder disease forms have included mutations in the C-terminus region, which result in only the skeletal manifestations of MFS. Mutations in exons 59 to 65 and in exons 1 to 10 have been associated with phenotypes lacking significant aortic involvement or with only late-onset and relatively mild cardiovascular features. Researchers have also determined that the mutation type—one causing haploinsufficiency (resulting in less fibrillin protein) versus one with a dominant-negative effect (incorporating normal and mutated forms of fibrillin-1 in the extracellular matrix)—may affect clinical outcomes. Patients with haploinsufficiency have larger baseline aortic diameters, more rapid aortic growth, and higher risk of death and dissection.

Approximately 60% to 80% of adult patients with MFS develop aortic root dilation, with a higher prevalence among males. The mean rate of growth in the ascending aorta or root is 0.26 cm ± 0.05 cm/year, with annual rates up to 0.46 cm in individuals with an aneurysm larger than 6.0 cm. One study followed individuals with initial normal aortic dimensions in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC registry). Bicuspid aortic valve (BAV) (39%) and MFS (22%) were the leading diagnoses among participants. Over a 3-year period, the aortic dissection rate was 1.6%; 61% of the dissections occurred in individuals with MFS. The cumulative incidence of aortic dissection was sixfold higher among patients with MFS (4.5%) compared with other conditions. including BAV, for which the incidence was only 0.3%.

Outcomes in patients with MFS have improved over the past decade, coinciding with surgical advancements. Since the emergence of composite graft aortic root surgery in the mid-1970s, life expectancy has almost doubled. The mainstay of treatment is careful surveillance with echocardiography and other imaging modalities and elective aortic repair.

Other Fibrillinopathies

FBN1 mutations have been reported in distinct phenotypes that overlap with MFS but do not confer the high risk of aortic complications. They include mitral valve prolapse (MVP) syndrome, the MASS phenotype ( M VP, borderline a ortic enlargement, nonspecific s kin and s keletal signs, and myopia), isolated ectopia lentis, and stiff skin syndrome. Together, MFS and the Marfan-related phenotypes have been called type 1 fibrillinopathies .

Congenital contractural arachnodactyly (CCA, also known as Beals syndrome), another connective tissue disorder similar to MFS, is caused by fibrillin-2 gene ( FBN2 ) mutations. It can be difficult to differentiate between these two syndromes because of the similar skeletal complications, including arachnodactyly, pectus deformities, and scoliosis. CCA usually manifests with multiple joint contractures and crumpled ear helices.

Loeys-Dietz Syndrome

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disease associated with arterial aneurysms and dissections and with other systemic involvements. ^, LDS is characterized by the clinical triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Aneurysms occur in the aortic root, but unlike in MFS, they are also commonly found in other arteries. The arterial tortuosity most commonly affects the head and neck vessels. Aortic dissection can occur at diameters smaller than those observed in MFS.

LDS is associated with deregulation in transforming growth factor-β (TGF-β) signaling; it is divided into six subtypes based on the pathologic gene variant ( Table 33.4 ), all of which encode proteins involved in the TGF-β signaling pathway. There is considerable overlap among the subtypes, and they are considered part of the same clinical continuum.

Specific diagnostic criteria for LDS have not been established. Typically, the diagnosis is rendered when a patient has findings for some of the commonly affected organ systems in addition to identification of a disease-causing mutation on genetic testing. The five main groups of clinical findings are vascular, skeletal, craniofacial, ocular, and cutaneous ( Table 33.5 ). An important distinguishing feature between LDS and MFS is the lack of ectopia lentis in LDS.

We recommend genetic testing for LDS-associated gene mutations in patients with aortic root dilation and any suggestive clinical features, in patients who have had aortic dissection at diameters less than 5 cm without another identified causative condition, and in families in which multiple members have aortic or other arterial dilation. Some patients with aortic dilation and dissection have mutations in TGF-β pathway genes without physical features of LDS. These patients fall in the category of thoracic aortic aneurysms and dissections (discussed later).

The most important complication in LDS is aortic root dilation and dissection. The mean age at death in original case series was 26 years. Almost all patients had aortic root aneurysms that led to dissection. Dissection can occur at aortic dimensions that are not considered high risk in MFS (<5.0 cm); dissections have been reported in infancy and early childhood. Approximately one half of patients with LDS have dilation or tortuosity in the arterial tree away from the aortic root, and these vascular features differentiate the vascular disease in LDS from that of MFS. These distal lesions are not detected by echocardiography. Additional cardiac malformations include patent ductus arteriosus, atrial septal defects, MVP, and BAV.

Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of hereditary connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. It is marked by pathologic variants encoding collagen or collagen-modifying genes. Initially, EDS was categorized in six subtypes, but in 2017, classification of EDS was expanded to 13 subtypes based on clinical findings, inheritance patterns, and molecular defects. The estimated prevalence of EDS is 1 case in 5000 to 25,000 persons. The classic and hypermobile forms account for more than 90% of EDS cases (involving hyperextensibility, fragile “cigarette paper” skin, scoliosis, and hernias). Between one fourth and one third of individuals with classic and hypermobile types of EDS have aortic dilation, but usually only to a mild degree. Aortic dissection is rare in the absence of significant preexisting dilation.

Vascular EDS, which is considered the most malignant form of EDS given the increased susceptibility to spontaneous vascular dissection, represents less than 5% of cases. Inheritance is autosomal dominant and involves the type III collagen gene (COL3A1) . The median age at death is 51 years. Large vessel dissections can involve the aorta, but the cerebral and abdominal large arteries are also at risk.

The sites of arterial rupture are the thorax and abdomen (50%), head and neck (25%), and extremities (25%). Uncommonly, the vascular type of EDS is a cause of stroke in young adults. The mean age at intracranial aneurysmal rupture, spontaneous carotid-cavernous sinus fistula, or cervical artery aneurysm is 28 years. Hyperelastic tissues and hyperextensible joints are less common manifestations, but easy bruising, poor wound healing, and rupture of the gastrointestinal tract are commonly seen.

There is no consensus regarding appropriate cardiovascular screening for patients with EDS. It is reasonable to obtain surveillance aortic imaging at least every 3 to 5 years for patients with vascular EDS and more frequently if there is evidence of aortic dilation. Mitral valve disease and aortic insufficiency may also exist. However, the fragile nature of the large vessels in the vascular form of EDS increases surgical morbidity and mortality rates. It is unclear whether early prophylactic repair of unruptured aneurysms in vascular EDS should be pursued.

Familial Thoracic Aortic Aneurysm And Dissection

Nonsyndromic familial thoracic aortic aneurysm and dissection (familial TAAD) is characterized by defects of the aorta without associated outward physical manifestations. The diagnosis of familial TAAD is based on progressive enlargement of the ascending aorta, positive family history of TAAD, and exclusion of syndromic causes of TAAD such as MFS, LDS, and EDS. Only 30% of patients with nonsyndromic TAAD have an identified gene mutation, but new gene associations are discovered regularly. Most of the identified pathogenic mutations involve genes in the TGF-β pathway (i.e., TGFBR1 , TGFBR2 , TGFB2 ligand , TGFB3 ligand, SMAD3 , and SMAD6 ) or genes involved in smooth muscle cell function: smooth muscle cell–specific myosin heavy chain 11 ( MYH11) , smooth muscle–specific alpha actin ( ACTA2), myosin light chain kinase ( MYLK ), and cyclic guanosine monophosphate (cGMP)–dependent protein kinase 1 ( PRKG1 ).

Patients with familial TAAD typically come to medical attention earlier than patients with spontaneous dissections or dilation but later than those with MFS or LDS. As in LDS, dissections have been reported at smaller aortic dimensions than is typical for MFS.

Bicuspid Aortic Valve

BAV is the most common congenital heart disorder, affecting approximately 1% to 2% of the population with a 2:1 to 3:1 male to female ratio. BAV is a heritable trait. Family studies report the prevalence of BAV in first-degree relatives of an individual with BAV to be 9% to 10%. ^, The inheritance of BAV is consistent with an autosomal dominant pattern with reduced penetrance. Monozygotic twins do not necessarily both have BAV, highlighting the incomplete penetrance of this disorder.

The genetic causes of BAV remain elusive. Mutations in NOTCH1 are associated with BAV and may result in aortic aneurysms and early aortic calcification. Mutations in other single genes, such as ACTA2 , TGFB2 , GATA5 , NKX2-5 , and SMAD6 , have been associated with BAV. In most patients, no specific genetic variant is discovered. BAV is also prevalent among genetic conditions such as DiGeorge syndrome, LDS, Anderson syndrome ( KCNJ2 mutation), Turner syndrome, and complex congenital heart disease such as the Shone complex and hypoplastic left heart syndrome. ^,

Patients with a BAV are at increased risk for aortic aneurysm ( Fig. 33.1 ). More than one half of those with BAV will have aortic enlargement greater than 2 standard deviations above the norm by 30 years of age. Compared with controls, patients who have a BAV have larger aortic annulus, sinus, and ascending aortic dimensions, even after adjusting for age, valvular lesions, and hypertension ( Fig. 33.2 ).

Histologic examination shows pathologic changes in the aortic wall, including decreased fibrillin-1, loss of elastic fibers, increased apoptosis, and altered smooth muscle cell alignment. There is uncertainty regarding the cause of BAV aortopathy, but genetic and hemodynamic contributions have been implicated. Aortic dilation is greater in patients with aortic regurgitation than in those with stenotic or functionally normal BAVs. ^, However, dilation of the aorta (which can involve the root to the arch) frequently accompanies BAV even in the absence of aortic stenosis or aortic regurgitation. First-degree relatives of BAV patients who have a tricuspid aortic valve tend to have larger aortas than the control population, suggesting an inherited phenotype. However, cardiac MRI flow patterns have revealed distinct aortic dilation patterns based on the variation in laminar blood flow and increased wall stress, underscoring the importance of flow hemodynamics.

The rate of aortic growth among patients with BAV ranges from 0.2 to 2.3 mm/year and varies based on age, underlying valve disease (aortic regurgitation versus stenosis), location of the dilation, baseline aortic diameter, family history, and leaflet morphology. The risk of aortic dissection in BAV populations is unclear. In historic necropsy studies, dissections were found in 6% to 15% of subjects with BAV. Studies have shown that the absolute lifetime risk of aortic dissection for a BAV patient followed with routine surveillance imaging is quite low, with an incidence of 3.1 per 10,000 patient-years, and it depends most significantly on the size of the aorta and the patient’s age. Dissection rates are similar or only slightly higher than those for patients with a tricuspid valve but comparably sized aneurysms. ^, Some studies have reported that individuals with BAV experience dissection at larger dimensions than their counterparts with tricuspid aortic valve (62 vs. 53 mm). The increased risk of aortic dissection in patients with a BAV seems limited to a small subset of the overall BAV population. We speculate that for this subsegment of the population, the concomitant finding of a BAV and aortic aneurysm and dissection indicates genetic underpinnings and is a manifestation of a systemic connective tissue disorder.

Turner Syndrome

Patients with Turner syndrome are at high risk for left heart pathology, particularly BAV and coarctation of the aorta. Those with Turner syndrome have a higher incidence of systemic hypertension (even in the absence of anatomic cardiac pathology). Generalized vasculopathy in those with Turner syndrome is well described and is characterized by aortic wall stiffness, arterial dilation, vessel wall thickening, and abnormal pulse wave propagation. Aortic dissection occurs in approximately 1.4% of patients with Turner syndrome, and dissection often occurs at a young age (mean, 30 years). Between 80% and 90% of those with aortic dissection have systemic hypertension or a BAV.

Criteria with which to assign risk have been difficult to ascertain, particularly because most criteria are based on somatic growth (i.e., height, weight, and body surface area). Patients with Turner syndrome have short stature, and the relationship between somatic growth and expected aortic dimension remains problematic. For this reason, the definition of normal aortic size, especially in light of the potentially confounding factors (i.e., hypertension, BAV, and coarctation of the aorta), is unclear. The American and European guidelines recommend indexing aortic dimensions to body surface area. Whether the general adult guidelines for the prediction of heightened risk for aortic dissection can translate to adults with Turner syndrome remains undetermined. The relative aortic dimensions guiding when aggressive pharmacologic and/or surgical intervention should be instituted are unclear.

Study results on aortic size and growth rates in Turner syndrome have varied over the years. A cross-sectional study of girls younger than 18 years of age revealed that even in the absence of a BAV, Turner syndrome patients had a larger aorta at the levels of the aortic root, sinotubular junction, and ascending aorta, suggesting that Turner syndrome alone predicts aortic dilation. The effect of a BAV added incrementally to this independent effect. However, a prospective cardiac MRI study showed no differences in absolute or indexed aortic growth rates between patients with Turner syndrome and age-matched heathy female controls at the aortic root and proximal aorta. There was larger variation in the Turner population, and the finding of BAV and coarctation was associated with accelerated growth rates.

Nevertheless, aortic complications are more numerous in the Turner population. In a study that followed 198 Turner syndrome patients over a 23-year period, 9 suffered aortic dissection, a 12-fold increase compared with the general female population. Dissection risk was associated with aortic dilation, diagnosis of hypertension, BAV, and coarctation.

Questions regarding aortic dilation and dissection risk in the setting of Turner syndrome remain. Better understanding of the relationship between dilation and dissection in this population will enable development of better treatment protocols.