Ehlers-Danlos Syndrome, Musculocontractural Type, 1

A number sign (#) is used with this entry because of evidence that Ehlers-Danlos syndrome musculocontractural type 1 (EDSMC1) is caused by homozygous or compound heterozygous mutation in the CHST14 gene (608429) on chromosome 15q14.

Description

The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility (Beighton et al., 1998).

The major characteristics of the musculocontractural form of EDS include distinctive craniofacial dysmorphism, congenital contractures of thumbs and fingers, clubfeet, severe kyphoscoliosis, muscular hypotonia, hyperextensible thin skin with easy bruisability and atrophic scarring, wrinkled palms, joint hypermobility, and ocular involvement (summary by Malfait et al., 2010).

Janecke et al. (2015) reviewed the clinical findings in 34 reported EDSMC patients, 31 with CHST14 mutations and 3 with DSE (605942) mutations (see 615539), and stated that the disorder can be recognized based on the presence of distal arthrogryposis, including adducted thumbs or clenched fists and talipes equinovarus, as well as hands with atypically shallow palmar creases and tapering fingers, and neonatal muscular hypotonia. Characteristic craniofacial features include brachycephaly, large fontanel, hypertelorism, downslanting palpebral fissures, microcorneae, strabismus, prominent nasolabial folds, short philtrum, thin upper lip, small mouth, high palate, microretrognathia, and prominent and often low-set and posteriorly rotated ears. In addition, EDSMC patients show muscular hypoplasia and weakness, which has been confirmed by ultrasound and electromyography, and intellectual development appears to be normal.

Genetic Heterogeneity of Musculocontractural Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome musculocontractural type 2 (EDSMC2; 615539) is caused by mutation in the DSE gene (605942) on chromosome 6q22.

Nomenclature

The kyphoscoliotic type of Ehlers-Danlos syndrome (see 225400) was at one time separated into EDS VIA (with lysyl hydroxylase deficiency) and EDS VIB (with normal lysyl hydroxylase activity). What was designated EDS VIB is now known to represent 2 distinct entities: the brittle cornea syndrome (229200), caused by mutation in the ZNF469 gene (612078), and musculocontractural EDS-1.

Clinical Features

Steinmann et al. (1975) described 2 severely affected Pakistani sibs who had marked muscle weakness at birth as well as clubfeet and fragile skin, with delayed motor development but normal intellectual development. Examination at ages 18 and 20 years, respectively, showed mild scoliosis, muscular hypotonia, velvety and hyperelastic skin with hyperalgesia to pressure, hyperflexibility of joints, high narrow palate, and microcornea. Steinmann et al. (1975) reported markedly decreased lysyl hydroxylase activity in cultured skin fibroblasts from these patients, but subsequent analysis of cultured fibroblasts, both in the original laboratory and in 2 independent laboratories, showed normal levels of lysyl hydroxylase activity (Royce et al., 1989), suggesting EDS VIB. Electron microscopy of the reticular layer of the dermis revealed that a great proportion of collagen fibrils were not integrated into fibers and fiber bundles; consequently, fiber bundles were poorly delineated, and nonintegrated fibrils formed an irregular texture. Janecke et al. (2015) provided follow-up on these sibs. The brother, who had mitral valve prolapse with moderate insufficiency, died at age 28 years from fulminant endocarditis despite prophylaxis. The sister acquired large cutaneous and subcutaneous hematomas after minor trauma, and had a prolonged bleeding time with normal clotting factors. She experienced bilateral retinal detachments at age 45, and died at age 59 from intracerebral hemorrhage after a fall.

In male and female first cousins, each the offspring of consanguineous Turkish parents, Dundar et al. (1997) found severe psychomotor developmental delay, ocular anterior chamber abnormality, facial dysmorphism (broad, bossed forehead, late-closing fontanel, telecanthus, downslanting palpebral fissures, posteriorly rotated ears, and downturned angle of mouth), arachnodactyly, and distal arthrogryposis with severely adducted thumbs and clubfeet. The patients were aged 18 months and 3.5 years. The authors noted that the phenotype had some similarities to the multiple pterygium syndrome, or Escobar syndrome (265000), but concluded that it is probably distinct and suggested the designation 'adducted thumb-clubfoot syndrome.'

Sonoda and Kouno (2000) reported 2 Japanese brothers with distal arthrogryposis involving phalangeal, hand, foot, and hip joints; abnormal facial appearance, including blepharophimosis, hypertelorism, and depressed nasal bridge, cleft palate, short stature, hydronephrosis, and undescended testes. Intelligence was normal. The parents were first cousins once removed and were phenotypically normal.

Janecke et al. (2001) described 2 male sibs, born to fourth-cousin Austrian parents, with dysmorphic facies including broad bossed forehead, telecanthus, downward slanting palpebral fissures, and abnormally placed ears. They also had widely patent anterior fontanel, low anterior hairline, brachycephaly, short neck, arachnodactyly, adducted thumbs, and bilateral talipes equinovarus. Mild ventricular enlargement with ventricular asymmetry was present, as was absent septum pellucidum in one case. One child had an atrial septal defect, mild coarctation of the aorta, and a horseshoe kidney. This child died shortly after birth from respiratory failure; the other child was reported to have decreased muscle tone but normal psychomotor development at 12 months of age. Janecke et al. (2001) pointed out the similarities between the patients they described and those described by Dundar et al. (1997) and Sonoda and Kouno (2000), and suggested that all these children had the same condition.

Dundar et al. (2001) described another case of this syndrome in the offspring of first-cousin Turkish parents. In addition to adducted thumbs and clubfeet, the clinical features included distal arthrogryposis and dysmorphic facies. The parents had 3 similarly affected children who died of unknown causes. The patient had bilateral nephrolithiasis, unilateral inguinal hernia, and bilateral cryptorchidism.

Kosho et al. (2005) reported 2 unrelated Japanese girls with an Ehlers-Danlos VIB-like phenotype who had additional clinical manifestations, including a characteristic facies with thick eyebrows, hypertelorism, blue sclerae, strabismus, hypoplastic columella, thin upper lip, high-arched palate, and low-set and slanted ears. Features present in childhood that faded with age included downslanting palpebral fissures, drooping lower eyelids, short nose, small mouth, and long philtrum. Both patients had cylindrical fingers; tubular stenosis of the phalanges, metacarpals, and metatarsals; abnormal palmar creases; absent or decreased physiologic curvature of the spine with tall vertebrae; congenital joint contractures including talipes equinovarus; and progressive talipes valgus. Both also had hearing impairment of high-pitched sounds, recurrent urinary tract infections with an enlarged or atonic bladder, and constipation. Kosho et al. (2005) noted similarities to the Pakistani brother and sister reported by Steinmann et al. (1975).

Dundar et al. (2009) provided follow-up clinical information on 7 patients with adducted thumbs and clubfeet from 4 families previously reported by Dundar et al. (1997), Sonoda and Kouno (2000), Janecke et al. (2001), and Dundar et al. (2001), respectively. Dundar et al. (2009) noted that the patients could be recognized by a pattern of features comprising a severely wasted build with dry and translucent skin, brachycephaly, and facial characteristics that included broad and flat forehead, hypertelorism, downslanting palpebral fissures, malar flatness, retrognathia, and prominent ears. The anterior fontanel was large at birth, with closure delayed until 2 years of age. The congenital contractures of the thumbs improved spontaneously within weeks, whereas the clubfeet required surgical correction. Marked arachnodactyly and tapering of the fingers, as well as hypermobility of the joints were present, and patients had delayed wound healing, ecchymoses, and hematoma formation. Coagulation studies in an 8-year-old boy previously reported by Janecke et al. (2001) revealed a prolonged bleeding time. Mild osteopenia was apparent in childhood. Minor degrees of cranial ventricular enlargement were present in all 5 patients examined, and bluish sclerae and intermittent exotropia were observed in 4 patients. Although the disorder was initially categorized as a new form of arthrogryposis, Dundar et al. (2009) concluded that it represented a recognizable generalized connective tissue disorder with normal cognitive development.

Kosho et al. (2010) described 6 Japanese patients, including the 2 unrelated female patients previously reported by Kosho et al. (2005) and a man previously studied by Yasui et al. (2003), who had distinct craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and progressive multisystem fragility-related manifestations, including recurrent large subcutaneous hematomas and other cardiac, respiratory, gastrointestinal, and ophthalmologic complications. Craniofacial features noted in infancy included large fontanel, hypertelorism, short and downslanting palpebral fissures, blue sclerae, short nose with hypoplastic columella, low-set and rotated ears, high palate, long philtrum, thin vermilion of the upper lip, small mouth, and microretrognathia; in adolescence, patients developed a slender and asymmetric face with a protruding jaw. There was gross motor developmental delay noted in 5 of the 6 patients. Skeletal anomalies included flexion-adduction contractures of the bilateral thumbs in all patients as well as congenital contractures of the fingers, wrists, and hips, and talipes equinovarus with anomalous insertions of flexor muscles; progressive joint laxity with recurrent dislocations; slender and/or cylindrical fingers with progressive talipes valgus and cavum or planus, with diaphyseal narrowing of phalanges, metacarpals, and metatarsals; pectus deformities; and scoliosis or kyphoscoliosis with decreased physiologic curvature of thoracic spine and tall vertebrae. Cutaneous manifestations included progressive hyperextensibility, bruisability, and fragility of skin with atrophic scars, and fine palmar creases in childhood that appeared as prominent acrogeria-like wrinkles in adulthood. The patients all developed large recurrent subcutaneous hematomas in childhood, and had recurrent subcutaneous infections with fistula formation. Cardiac valve abnormalities, constipation, gastrointestinal diverticula with perforation, hemopneumothorax, strabismus, glaucoma, refractive errors, and hearing impairment were also observed. Kosho et al. (2010) noted similarities to the kyphoscoliosis type of Ehlers-Danlos syndrome (225400), but lysyl hydroxylase deficiency was not present in these probands. In addition, the vascular type of EDS (130050) was excluded because the patients had normal production of procollagen types I (see 120150) and III (see 120180); and they were also negative for mutation in the TGFBR1 (190181) and TGFBR2 (190182) genes, thus excluding the diagnosis of Loeys-Dietz syndrome (see LDS1, 609192).

Miyake et al. (2010) examined skin biopsies from 2 of the patients previously studied by Kosho et al. (2010) (patients 5 and 6). Light microscopy showed that fine collagen fibers were predominant in the reticular to papillary dermis and normally thick collagen bundles were markedly reduced. Electron microscopy revealed collagen fibrils that were dispersed in the reticular dermis, in contrast to the regularly and tightly assembled fibrils in a control; however, the patients' collagen fibrils were smooth and round, not varying in size or shape, similar to those of the control.

Malfait et al. (2010) reported 2 Turkish sisters and a girl of Indian origin from consanguineous families who were born with clubfeet and flexion contractures of the thumbs and developed kyphoscoliosis and joint laxity with dislocations; they also had blue sclerae and fragile, hyperextensible skin. Additional features included facial dysmorphism and ocular involvement, with early-onset high myopia, glaucoma, and retinal detachment in the Turkish sisters, and microcornea, bulging eyes, and myopia in the Indian girl. The older Turkish sister had umbilical and hiatal hernias, her younger sister had spontaneous rupture of the abdominal muscles and diastasis recti, and the Indian girl had duodenal obstruction due to malrotation requiring surgical correction. Malfait et al. (2010) stated that these patients closely resembled the Pakistani sibs described by Steinmann et al. (1975).

Uehara et al. (2018) reported the results of comprehensive investigations of spinal lesions in 12 patients from 11 families with EDSMC1. Mean age at the first visit was 13.4 years, with a range of 4 to 28 years. Scoliosis was seen in 8 patients (66.7%), with severe scoliosis in 1. Kyphosis at the thoracolumbar junction was seen in 5 (41.7%) patients. Three (25%) of the 5 had severe thoracolumbar kyphosis, 2 of whom underwent surgical correction, which was complicated by fistula formation in one and a successful 2-stage operation in the other. Cervical kyphosis was seen in 6 (50%) patients (50%), all but one of whom also had kyphosis at the thoracolumbar level. Atlantoaxial subluxation was seen in 2 patients (16.7%), and cervical vertebral malformations were seen in 10 (83.3%). Bone mineral density was measured in 6 patients, only 1 of whom had a bone mineral density lower than that of age- and sex-matched controls. Uehara et al. (2018) recommended regular surveillance including total spine radiology for patients with EDSMC1 and also recommended 2-stage surgery for patients with severe progressive thoracolumbar kyphosis. The authors noted that these findings support a critical role of dermatan sulfate in development and maintenance of the spine.

Mapping

Dundar et al. (2009) performed a genomewide linkage scan in 4 affected and 11 unaffected individuals from an Austrian family and 2 Turkish families with adducted thumb, clubfoot, and progressive joint laxity syndrome, previously described by Janecke et al. (2001) and Dundar et al. (1997, 2001), respectively. A multipoint lod score of 5.91 (theta = 0.0) was obtained at several SNPs within a 3.76-Mb interval bounded by rs10520118 and rs10518779 on chromosome 15q15, a region containing 73 genes.

Miyake et al. (2010) performed whole genome homozygosity mapping of 2 unrelated probands with bilateral thumb adduction, clubfeet, and progressive joint and skin laxity, and 6 unaffected relatives from 2 consanguineous Japanese families, respectively, 1 originally reported by Kosho et al. (2005) and the other previously studied by Kosho et al. (2010). Miyake et al. (2010) identified an 8.15-Mb homozygous region at chromosome 15q14-q15.3, obtaining a maximum lod score of 2.885; analysis of additional satellite markers narrowed the critical interval to a 7.3-Mb region containing 109 known genes.

Molecular Genetics

In 3 families with adducted thumbs, clubfeet, and progressive joint and skin laxity mapping to chromosome 15q15, Dundar et al. (2009) sequenced 2 candidate genes and identified homozygous mutations in the CHST14 gene in each family, including a 1-bp deletion (608429.0001) in the Turkish family originally reported by Dundar et al. (1997), a missense mutation (608429.0002) in the Austrian family originally reported by Janecke et al. (2001), and a complex mutation (608429.0003) in the Turkish family originally reported by Dundar et al. (2001). Subsequent analysis of the CHST14 gene in the Japanese family previously reported by Sonoda and Kouno (2000) revealed a homozygous mutation (Y293C; 608429.0004) in the 2 affected brothers. The mutations segregated with disease in each family and were not found in controls.

In 2 unrelated Japanese probands with bilateral thumb adduction, clubfeet, and progressive joint and skin laxity, 1 of whom was a female patient originally reported by Kosho et al. (2005) and the other a male patient previously studied by Kosho et al. (2010), Miyake et al. (2010) identified homozygosity for the same P281L mutation (608429.0005) in both patients. Genetic analysis of 4 more unrelated Japanese probands with similar features identified compound heterozygosity for P281L and another missense mutation (608429.0007) in a female patient originally reported by Kosho et al. (2005), compound heterozygosity for P281L and a nonsense mutation (608429.0006) in a male patient previously studied by Yasui et al. (2003), and compound heterozygosity for P281L and the Y293C mutation in 2 probands. The mutations were not identified in 376 Japanese control individuals. The 2 probands carried the same Y293C mutation as the Japanese brothers originally reported by Sonoda and Kouno (2000).

In 2 Turkish sisters and an Indian girl with a form of Ehlers-Danlos syndrome involving congenital flexion contractures of the thumbs, clubfeet, and progressive kyphoscoliosis and skin and joint laxity, Malfait et al. (2010) identified homozygosity for a 1-bp deletion (608429.0001) and a 20-bp duplication (608429.0008) in the CHST14 gene, respectively. Malfait et al. (2010) proposed that this CHST14-related disorder should be designated 'musculocontractural Ehlers-Danlos syndrome.'

Janecke et al. (2011) proposed the term 'dermatan sulfate-deficient adducted thumb-clubfoot syndrome' for this disorder, indicating that it represents another congenital disorder of glycosylation (see 212065).

In 2 unrelated Japanese boys with the musculocontractural type of Ehlers-Danlos syndrome, Shimizu et al. (2011) identified compound heterozygosity for 3 different missense mutations in the CHST14 gene (608429.0004, 608429.0005, and 608429.0008). The authors stated that phenotypic features in the 2 boys, aged 2 and 6 years, bore a striking resemblance to the features seen in infancy to early childhood in previously reported patients with the musculocontractural type of EDS. Shimizu et al. (2011) also provided a comprehensive review of 20 reported patients with CHST14 deficiency. They noted that the disorder satisfies all the hallmarks of EDS, including skin hyperextensibility, joint hypermobility, and tissue fragility affecting the skin, ligaments, joints, blood vessels, and internal organs, and that lifelong management of these patients should reflect the presence of generalized connective tissue fragility.

In a consanguineous Afghan family in which 2 sisters had the musculocontractural type of Ehlers-Danlos syndrome, Mendoza-Londono et al. (2012) identified a homozygous missense mutation in the CHST14 gene (R274P; 608429.0009) that segregated with disease. The authors stated that this was the first report of this phenotype in an Afghan family. Mendoza-Londono et al. (2012) suggested that the condition should be considered when clenched fists and amniochorion separation are seen prenatally, as was the case with the younger affected sister.

In 5 patients with the clinical hallmarks of EDSMC from 4 families with different ethnic origins, including 2 Asian families, 1 of Moroccan origin, and 1 from Curacao, Syx et al. (2015) sequenced the CHST14 gene and identified homozygous mutations in all affected individuals. Reviewing the features of the 26 previously reported EDSMC patients from 17 unrelated families with mutations in CHST14, the authors concluded that EDSMC1 is a clinically homogeneous, severe, and progressive disorder, characterized by a typical mix of symptoms that result from generalized connective tissue fragility and/or from disturbances in signaling pathways during development.

In 7 patients with EDSMC from 4 families, including the Pakistani sibs originally reported by Steinmann et al. (1975), Janecke et al. (2015) identified homozygosity or compound heterozygosity for mutations in the CHST14 gene (see, e.g., 608429.0002 and 608429.0010).