SNOMEDCT: 720858001; ORPHA: 230851; DO: 0080730;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q21.3 | Ehlers-Danlos syndrome, cardiac valvular type | 225320 | Autosomal recessive | 3 | COL1A2 | 120160 |
A number sign (#) is used with this entry because of evidence that the cardiac valvular type of Ehlers-Danlos syndrome (EDSCV) is caused by homozygous or compound heterozygous mutation in the COL1A2 gene (120160) on chromosome 7q21.
For discussion of genetic heterogeneity of Ehlers-Danlos syndrome, see 130000.
The hallmark of the cardiac valvular type of Ehlers-Danlos syndrome (EDSCV) is the severe cardiac-valvular disease, necessitating valve replacement surgery at adult age, in conjunction with variable skin hyperextensibility, atrophic scarring, and joint hypermobility (summary by Brady et al., 2017).
Shohet et al. (1987) reported 2 unrelated patients, aged 10 and 11 years, who had minor signs of Ehlers-Danlos syndrome but severe changes in the aorta requiring surgical repair with fatal complications in 1 patient. One of the patients had a similarly affected sister and brother who died at age 4 and 7.5 years, respectively.
Schwarze et al. (2004) described 3 unrelated patients with a rare, recessively inherited form of Ehlers-Danlos syndrome characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects. The first patient was a 45-year-old man who had received the diagnosis of EDS type II (see 130010) because of recurrent shoulder dislocations since childhood, small joint hypermobility, pectus excavatum, muscle and tendon tears, bilateral inguinal hernias, small scars under the chin and on the forehead, atrophic scars over the knees and shins, easy bruisability, and generally hyperextensible and thin skin. He was myopic and had bilateral astigmatism. The patient had severe mitral regurgitation and moderate aortic regurgitation with borderline dilatation of the aortic root (McKusick, 2002). Schwarze et al. (2004) reported that, following episodes of arrhythmias and atrial fibrillation, the patient underwent mitral and aortic valve replacement surgery. Although the procedure itself was uneventful, once the prosthetic valves were placed, first the mitral annulus (not the prosthetic valve) dehisced from the ventricle, then the aortic valve separated from the atrioventricular groove, and finally there was massive leakage through the left ventricular myocardium with disintegration of the entire left ventricle, from the which the patient died. The second patient, who had been described by Hata et al. (1988) and Kojima et al. (1988), had also been diagnosed with EDS type II. At age 38 years, she sought evaluation because of palpitations, pansystolic murmur, dyspnea, and fatigue, which led to the diagnosis of mitral valve insufficiency. Mitral valve replacement surgery was successfully performed; at the time of the report of Schwarze et al. (2004) the patient was 65 years old. The third patient was a 30-year-old man, the child of phenotypically normal second-cousin parents. He was born with bilateral inguinal hernias and, as a teenager, underwent surgical repair of pes planus and calcaneovalgus. He had always had significant large- and small-joint hypermobility, with bilateral genu recurvatum. His skin was soft and hyperextensible, with striae at the lateral aspect of the abdomen. He bruised easily, and his wound healing was delayed. He had a large secundum-type atrial septal defect, mitral valve prolapse with significant mitral regurgitation, and severe aortic valve regurgitation. His aortic root diameter at age 29 years was 36 mm, at the upper limit of normal. He developed marked left ventricular enlargement and had his aortic and mitral valves replaced with prosthetic valves, with no surgical complications. Perforation of the femoral artery and vein occurred in the course of preoperative diagnostic cardiac catheterization, and the cardiac surgeon described the tissues as extremely soft. A younger brother had hyperextensible small joints and soft but not significantly hyperextensible skin, and required aortic valve replacement at age 25 years because of aortic insufficiency.
Guarnieri et al. (2019) reported a 24-year-old woman and her 12-year-old sister, born to apparently unrelated parents in a small town in southern Italy, with EDSCV. The sisters had generalized joint hypermobility that was more severe in the extremities, severe flatfeet, minor skin changes, lower eyelid ectropion/ptosis, and hypoplastic distal interphalangeal creases. Cardiac involvement was progressive from mild to moderate-severe mitral valve insufficiency at ages 16 and 24 years, respectively, in the older sister and mild in the younger sister. The aortic valve was normal in both. A review of their patients and the 5 previously reported patients indicated that the core phenotype consists of joint hypermobility limited or marked at the hands and feet (100%); skin hyperextensibility (100%); mitral valve insufficiency (83%); genu recurvatum (66%); bilateral pes planus (66%); soft, doughy, and thin skin (66%); variable atrophic scarring (50%); easy bruising (50%); and bilateral inguinal hernia (50%). None of the patients reported recurrent fractures, dark blue sclerae, or bone deformities. The authors noted that some minor features (e.g., lower eyelid ectropion and hypoplastic distal interphalangeal creases) could be possible clues to the phenotype.
The transmission pattern of EDSCV in the patients reported by Schwarze et al. (2004) was consistent with autosomal recessive inheritance.
In 2 of the patients with EDS studied by Schwarze et al. (2004), COL1A2 mRNA instability resulted from compound heterozygosity for splice site mutations in the COL1A2 gene (120160.0045-120160.0046 and 120160.0047-120160.0048, respectively). In the third patient, Schwarze et al. (2004) identified homozygosity for a nonsense mutation (E1201X; 120160.0051), which also resulted in COL1A2 mRNA instability.
Malfait et al. (2006) reported the clinical features of a 6-year-old boy in whom complete lack of alpha-2 chains of type I collagen (120160.0052) was associated with a phenotype reminiscent of mild hypermobility EDS (225320). Careful cardiac follow-up with ultrasonography was highly recommended because of the risk for cardiac valvular problems developing in adulthood. The 6-year-old patient reported by Malfait et al. (2006) already showed abnormal mitral valve bulging. Malfait et al. (2006) suggested a possible mechanism for the variable phenotype in patients with complete deficiency of the alpha-2 chain. In most cases, the underlying COL1A2 mutations result in nonsense-mediated RNA decay (NMD) and a loss-of-function effect. The phenotypic consequences are those of a form of EDS with hypermobility in childhood, complicated by cardiac valve disease in adulthood.
By screening the coding regions of 20 genes involved with EDS, Guarnieri et al. (2019) identified a homozygous nonsense mutation in the COL1A2 gene (120160.0051) in 2 sisters, born to apparently unrelated parents in a small town in southern Italy, with EDSCV. The parents were heterozygous for the mutation, which was not found in large population databases. The same mutation had been identified in a patient with EDSCV by Schwarze et al. (2004).
Brady, A. F., Demirdas, S., Fournel-Gigleux, S., Ghali, N., Giunta, C., Kapferer-Seebacher, I., Kosho, T., Mendoza-Londono, R., Pope, M. F., Rohrbach, M., Van Damme, T., Vandersteen, A., van Mourik, C., Voermans, N., Zschocke, J., Malfait, F. The Ehlers-Danlos syndromes, rare types. Am. J. Med. Genet. 175C: 70-115, 2017. [PubMed: 28306225] [Full Text: https://doi.org/10.1002/ajmg.c.31550]
Guarnieri, V., Morlino, S., Di Stolfo, G., Mastroianno, S., Mazza, T., Castori, M. Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2. Am. J. Med. Genet. 179A: 846-851, 2019. [PubMed: 30821104] [Full Text: https://doi.org/10.1002/ajmg.a.61100]
Hata, R., Kurata, S., Shinkai, H. Existence of malfunctioning pro-alpha-2(I) collagen genes in a patient with a pro-alpha-2(I)-chain-defective variant of Ehlers-Danlos syndrome. Europ. J. Biochem. 174: 231-237, 1988. [PubMed: 3383844] [Full Text: https://doi.org/10.1111/j.1432-1033.1988.tb14087.x]
Kojima, T., Shinkai, H., Fujita, M., Morita, E., Okamoto, S. Case report and study of collagen metabolism in Ehlers-Danlos syndrome type II. J. Derm. 15: 155-160, 1988. [PubMed: 3049731] [Full Text: https://doi.org/10.1111/j.1346-8138.1988.tb03668.x]
Malfait, F., Symoens, S., Coucke, P., Nunes, L., De Almeida, S., De Paepe, A. Total absence of the alpha-2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems. J. Med. Genet. 43: e36, 2006. Note: Electronic Article. [PubMed: 16816023] [Full Text: https://doi.org/10.1136/jmg.2005.038224]
McKusick, V. A. Personal Communication. Baltimore, Md. 5/3/2002.
Schwarze, U., Hata, R.-I., McKusick, V. A., Shinkai, H., Hoyme, H. E., Pyeritz, R. E., Byers, P. H. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am. J. Hum. Genet. 74: 917-930, 2004. [PubMed: 15077201] [Full Text: https://doi.org/10.1086/420794]
Shohet, I., Rosenbaum, I., Frand, M., Duksin, D., Engelberg, S., Goodman, R. M. Cardiovascular complications in the Ehlers-Danlos syndrome with minimal external findings. Clin. Genet. 31: 148-152, 1987. [PubMed: 2952379] [Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb02786.x]