Cardiac Valvular Dysplasia, X-Linked

A number sign (#) is used with this entry because of evidence that X-linked cardiac valvular dysplasia is caused by mutation in the FLNA gene (300017) on chromosome Xq28.

Description

X-linked cardiac valvular dysplasia is a rare form of heart disease characterized by multivalvular dysplasia and regurgitation, which can lead to lethal heart failure in some patients. Heterozygous females are more mildly affected than hemizygous males. Some patients also exhibit features of Ehler-Danlos syndrome (EDS; see 130000), with hyperextensible skin and joint hypermobility, whereas others have stiffening of joints from early childhood (Kyndt et al., 2007; Ritelli et al., 2017; Mercer et al., 2017).

Clinical Features

Monteleone and Fagan (1969) described 6 definite and 1 probable case of congenital heart disease in males in 4 sibships of 3 generations of a black kindred in a pattern suggesting X-linked recessive inheritance. Four had mitral and aortic regurgitation, of whom 2 also had tricuspid regurgitation. The fifth definite case had only mitral regurgitation. Histologically, changes in the mitral valve of 1 case resembled those seen in the 'floppy valve syndrome' (Read et al., 1965) or in Marfan syndrome (which was suggested by no other feature of the cases).

Di Ferrante et al. (1975) reported 2 Italian maternal cousins with congenital heart disease, 'floppy valve syndrome,' hernias, short stature, stretchable skin, and moderate joint hypermobility, which the authors considered to represent an X-linked form of Ehlers-Danlos syndrome (EDS5; see HISTORY). The proband's cousin had an affected younger brother who had died from severe congestive heart failure. Analysis of the proband's fibroblasts showed deficient activity of lysyl oxidase, the enzyme responsible for oxidative deamination of lysine and hydroxylysine in collagen as a first step in cross-linking of collagen. Addition of catechin, a flavonoid, to the proband's cultured fibroblasts decreased the solubility of collagen they produced.

Balaji et al. (1991) reported a 3-generation family in which 6 members had Ebstein anomaly (EA) of the tricuspid valve. The index patient presented at age 5 years with an asymptomatic heart murmur that was clinically diagnosed as EA, which was confirmed on cardiac catheterization 3 years later. At age 30 years, she remained asymptomatic, although echocardiography showed a large right atrium, small right ventricle, and moderate tricuspid regurgitation. She had an asymptomatic 7-year-old daughter with mild EA on echocardiography, and a 3-year-old son with severe EA, who experienced cyanosis and heart failure as a neonate, with moderate tricuspid stenosis and regurgitation as well as a dysplastic stenotic mitral valve on echocardiography. The proband's unaffected sister had 3 affected children, including a 5-year-old asymptomatic girl, a male infant who died at 1 day of life with severe EA, and a 1-month old boy who was born with cyanosis and signs of heart failure who had mild EA by echocardiography. The sisters' 67-year-old father had a history of a 'weak heart' and underwent aortic valve replacement at age 62 years for aortic stenosis; preoperative cardiac catheterization did not show any right heart abnormalities. All of the family members had mild skeletal anomalies, including joint contractures and/or proximally placed and externally rotated fifth toes. The authors stated that it was not clear whether the skeletal findings were coincidental in this family or part of an inherited syndrome with EA.

Newbury-Ecob et al. (1993) described a British family in which 2 brothers and the son of a daughter of one of them had valvular dysplasia. The grandson died in severe heart failure in the first day of life. All 4 heart valves were abnormal. The tricuspid and mitral valves had edematous and irregular cusps with short and irregular chordae. The aortic and pulmonary valves were bicuspid but also showed thickening and edema of the cusps. The aortic ring was stenotic. The maternal grandfather was asymptomatic until the age of 25 years when he developed progressive breathlessness; at the age of 41 years, he underwent surgical replacement of the aortic mitral and tricuspid valves, which were the site of myxomatous degeneration with secondary calcification and regurgitation. His brother had severe mitral valve prolapse.

Kyndt et al. (2007) studied a large French pedigree segregating X-linked cardiac valvular disease, originally reported by Benichou et al. (1997) and Kyndt et al. (1998), and identified a new branch of the family with a common ancestor born in the eighteenth century. The extended family included 14 affected males, all of whom had mitral valve disease and all but 1 of whom also had aortic valve regurgitation. Twelve male patients had progressive mitral valve prolapse, found on the anterior valve in 4 and on both valves in 8. Five male patients underwent valve surgery, 3 for replacement of the aortic valve, 1 for both aortic and mitral valve replacement, and 1 for mitral valvuloplasty. Mild to moderate tricuspid valve regurgitation was found in 11 affected males, and mild pulmonary regurgitation in 4, but none had surgery of the tricuspid or pulmonary valves. In all but 1 of the affected males, valvular disease was associated with mild hemophilia A (306700), with factor VIII (300841) activity between 15% and 50%. Haplotype analysis in the patient with normal coagulation factor activity demonstrated that valvulopathy and hemophilia were transmitted as independent traits (see MAPPING). There were 30 carrier females in the family, all of whom were asymptomatic; upon examination, however, 14 of the carrier females were considered affected, 12 had minor valve disease and were designated 'undetermined,' and only 4 were considered unaffected. Among carrier females, 4 had mitral valve prolapse, involving the anterior valve in 3 cases and the posterior valve in 1 case; mitral valve regurgitation was mild in 19 and moderate in 4; aortic valve regurgitation was mild in 8, moderate in 3, and severe in 1; tricuspid valve regurgitation was mild in 9 and moderate in 1; and pulmonary valve regurgitation was mild in 2 and moderate in 1. None of the carrier females had undergone valvular surgery.

Ritelli et al. (2017) restudied the Italian family with multivalvular disease and features consistent with Ehlers-Danlos syndrome that was originally reported by Di Ferrante et al. (1975), and identified 4 more affected individuals over 3 generations, for a total of 1 female and 5 male patients, who had all died of congestive heart failure. Both male cousins exhibited dysmorphic facial features, including bilateral ptosis, hypertelorism, prominent columella, long philtrum, and thick lower lip. Additional findings included joint hypermobility, mild scoliosis, genua valga, flexible flat feet, and soft, doughy, and hyperextensible skin. The index patient (III.1) experienced progressive heart failure due to an intrinsic defect of all valves, and died awaiting transplantation.

Mercer et al. (2017) reexamined 6 affected individuals, 2 brother/sister pairs and their respective mothers, from the family with Ebstein anomaly originally reported by Balaji et al. (1991). The 2 male patients were the most severely affected; in addition to EA, both exhibited mitral valve dysplasia with stenosis and regurgitation as well as pulmonary regurgitation, and 1 also had bicuspid aortic valve with regurgitation. Other cardiac abnormalities in the 4 female patients included patent foramen ovale in 1 and pulmonary regurgitation in another. The men also showed facial dysmorphism, including prominent supraorbital ridges, hypertelorism, and proptosis. All 6 patients had joint stiffness that began in childhood and was most severe in the men, who had fixed flexion of the knees and ankles; both men and 2 women also had limited supination of the elbows. In addition, both men and 1 woman had reduced limb musculature. All 6 patients exhibited proximally placed and externally rotated fifth toes, and keloid scarring was noted in all.

Mapping

Benichou et al. (1997) did linkage studies of a large 5-generation French pedigree in which males were severely affected and carrier females were also affected but to a milder extent, consistent with X-linked inheritance. Using dinucleotide repeat markers, they assigned the gene for CVD to an 8-cM region of Xq28. A 5.91 lod score was obtained for 2 distal markers, including an intronic microsatellite of the factor VIII gene. In the full report of this study, Kyndt et al. (1998) reported a maximum lod score of 6.54 at theta = 0.0 for 2 polymorphic microsatellite markers, INT3 and DXS1008, the first being intronic to the factor VIII gene. Kyndt et al. (1998) referred to X-linked CVD as X-linked myxomatous valvular dystrophy (XMVD). Haplotype analysis of this chromosomal region allowed definition of an 8-cM minimal interval containing the gene for XMVD, between DXS8011 and Xqter. Kyndt et al. (2007) performed additional linkage analysis in the large French pedigree with valvular dysplasia, including a new branch of the family with a common ancestor born in the eighteenth century, and refined the critical region to a 2.5-Mb interval between DXS10049 and the GAB3 gene (300482) that excluded the factor VIII gene (300841).

Molecular Genetics

Kyndt et al. (2007) analyzed candidate genes in the large French pedigree with X-linked cardiac valvular disease and identified a hemizygous mutation in the FLNA gene (P637Q; 300017.0030) that segregated with disease. In the British family originally studied by Newbury-Ecob et al. (1993) and in 2 additional families with cardiac valvular disease, Kyndt et al. (2007) identified respective mutations in the FLNA gene (300017.0031-300017.0033). The mutations segregated with disease in the families and were not found in control chromosomes. All 4 families presented no clinically apparent extracardiac abnormalities, no dysmorphic features, and no epileptic seizures.

Using DNA from 2 affected male cousins from a 3-generation Italian family originally reported by Di Ferrante et al. (1975), in which 5 affected males and 1 female had died of congestive heart failure due to multivalvular disease, Ritelli et al. (2017) performed exome sequencing and identified hemizygosity for a splicing mutation in the FLNA gene (300017.0037). No other family members were available for segregation analysis.

In a 3-generation family with multivalvular dysplasia, originally reported by Balaji et al. (1991) and negative for mutation in the MYH7 (160760) and NKX2-5 (600584) genes, Mercer et al. (2017) analyzed exome data and identified a missense mutation in the FLNA gene (G1554R; 300017.0038) that segregated with the disease.

History

Beighton (1968) described 2 families in which X-linked inheritance of Ehlers-Danlos syndrome, designated EDS5, was probable. The clinical features included hyperextensible skin and bruising tendency. Fragility of skin was unimpressive. In contrast to the findings of Di Ferrante et al. (1975), a study of material from Beighton's original cases by Siegel et al. (1979) demonstrated no deficiency of lysyl oxidase, and Byers (1980) suggested that such a deficiency was unlikely in this condition. Beighton and Curtis (1985) provided follow-up on the 2 families studied by Beighton (1968). In family 1, a sister of 3 affected males had produced an affected son. The authors noted that all affected individuals from both families had red hair. Steinmann et al. (2002) questioned the existence of EDS V as a distinct entity. They considered the phenotype too ill defined, and thought it more likely that the patients originally reported by Di Ferrante et al. (1975) as having EDS5 had cardiac valvular dysplasia. Malfait et al. (2017) stated that the condition designated EDS5 is no longer included in the EDS spectrum.