Clinical characteristics.

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is characterized by multiple congenital contractures, progressive foot and ankle deformities, hypermobility of the small joints, recurrent dislocations, spinal deformities, characteristic craniofacial features (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia), skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars), large subcutaneous hematoma, and ocular abnormalities (strabismus, refractive errors, and glaucoma). Additional organ systems can be involved including genitourinary, cardiovascular, neurologic, and gastrointestinal.

Diagnosis/testing.

The diagnosis of mcEDS is established in a proband with suggestive findings and biallelic pathogenic variants in CHST14 or DSE identified by molecular genetic testing.

Management.

Treatment of manifestations: Braces for joint and spine deformities with surgical correction as needed per orthopedist; standard treatment for osteoporosis and constipation; surgical sutures as needed for skin lacerations; hygiene and topical or oral antibiotics as needed for skin fistula; corrective lenses for refractive errors and strabismus; surgical correction as needed for strabismus; treatment of glaucoma and retinal detachment per ocular specialist; surgical fixation of cryptorchidism; prophylactic antibiotics for recurrent urinary tract infection and surgical correction of urologic abnormalities if necessary; treatment of nephrolithiasis and urolithiasis per nephrologist and/or urologist; compression, icing, surgical drainage, and administration of desmopressin if necessary for large subcutaneous hematomas; treatment of cardiac valve abnormalities and congenital heart defects per cardiologist and cardiac surgeon; physical therapy for hypotonia and motor delay; surgical treatment as needed for hernia; treatment of diverticula per gastroenterologist; hearing aids as needed; treatment of pneumothorax per intensivists and thoracic surgeon; dental correction as needed; surgical closure for cleft palate and speech therapy as needed; psychosocial counseling.

Surveillance: Orthopedic evaluation of foot deformities every three months in infancy, every six months in childhood, and annually in adolescence and adulthood; orthopedic evaluations of spine deformities and digit contractures every six to 12 months beginning in infancy; bone density scan annually beginning in adulthood; orthodontic evaluation annually beginning in childhood; ophthalmologic evaluation, urologic evaluation including ultrasound, cardiac evaluation, and otologic evaluation annually beginning in infancy; assessment of gross motor skills every three months beginning in infancy and every six months throughout childhood.

Agents/circumstances to avoid: Contact or competitive sports; upper arm sphygmomanometer and use of a tight tourniquet during blood collection in individuals with hyperalgesia to pressure.

Pregnancy management: Pregnancy and delivery in women with mcEDS should be managed in a perinatal center; planned cesarean section would be a reasonable approach due to risk of premature rupture of membranes, birth canal laceration, and excessive bleeding with vaginal delivery.

Genetic counseling.

Musculocontractural EDS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CHST14 or DSE pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the mcEDS-related pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Musculocontractural EDS should be suspected in probands with two major criteria; the presence of any additional minor criteria supports the diagnosis [Malfait et al 2017].

Major criteria

• Multiple congenital contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot)
• Characteristic craniofacial features, which are evident at birth or in early infancy (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia)
• Characteristic cutaneous features (including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling)

Minor criteria

• Recurrent/chronic joint dislocations
• Pectus excavatum or flat sternum with loss of normal thoracic curve
• Spinal deformities (scoliosis, kyphoscoliosis)
• Characteristic finger morphology (tapered, slender, cylindrical)
• Progressive foot and ankle deformities (valgus deformity of the ankle, pes planus, pes cavus)
• Large subcutaneous hematomas
• Chronic constipation
• Colonic diverticula
• Pneumothorax/pneumohemothorax
• Nephrolithiasis/cystolithiasis
• Hydronephrosis
• Cryptorchidism in males
• Strabismus
• Refractive errors (myopia, astigmatism)
• Glaucoma / elevated intraocular pressure

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of mcEDS is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in CHST14 or DSE identified by molecular genetic testing (see Table 1) [Brady et al 2017, Malfait et al 2017].

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic CHST14 or DSE variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is characterized by multiple congenital contractures, progressive foot and ankle deformities, hypermobility of the small joints, recurrent dislocations, spinal deformities, characteristic craniofacial features, skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars), large subcutaneous hematoma, and ocular abnormalities [Brady et al 2017, Malfait et al 2017]. Additional organ systems can be involved including genitourinary, cardiovascular, neurologic, and gastrointestinal. To date, 70 individuals from 51 families have been identified with biallelic pathogenic variants in CHST14 (mcEDS-CHST14) [Minatogawa et al 2022b, Qian et al 2022, Ks et al 2024, Uemura et al 2024] and 15 individuals from nine families have been identified with biallelic pathogenic variants in DSE (mcEDS-DSE) [Minatogawa et al 2022a, Yoshikawa et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Skeletal features. Finger shape is characteristic (e.g., tapered, slender, cylindrical) (see Figure 1). Multiple congenital contractures affect the digits and feet. Over time progressive foot and ankle deformities (e.g., pes planus, valgus deformity of the ankle) (see Figure 2), hypermobility limited to the small joints, recurrent dislocations (e.g., shoulder, knee, elbow, hip), spinal deformities (scoliosis, kyphoscoliosis), and pectus excavatum, flat sternum with loss of natural thoracic curve, and reduced anteroposterior diameter of the thorax are noted. In individuals with mcEDS-CHST14, median age at the initial joint dislocation is six years, and 80% of individuals with dislocations have their initial episode by age ten years [Minatogawa et al 2022b]. Congenital contractures of the fingers become milder with age, though some impairment of finger extension and/or flexion persists (see Figure 1) [Minatogawa et al 2022b].

Figure 1.

Clinical photographs of hands of individuals with musculocontractural Ehlers-Danlos syndrome (mcEDS) 1st & 2nd row. Clinical photographs of three individuals with mcEDS-CHST14 [Minatogawa et al 2022b]

Figure 2.

Clinical photographs of feet of individuals with musculocontractural Ehlers-Danlos syndrome (mcEDS) 1st & 2nd row. Clinical photographs of two individuals with mcEDS-CHST14. Note clubfeet followed by progressive talipes deformities [Minatogawa (more...)

According to a single institution-based survey including 12 individuals with mcEDS-CHST14, eight individuals (67%) had scoliosis with a Cobb angle ≥10°, including one with severe scoliosis with a Cobb angle ≥45°; five individuals (42%) had thoracolumbar kyphosis with a kyphotic angle ≥20°, including three with severe thoracolumbar kyphosis with a kyphotic angle ≥50° accompanied by thoracic lordosis with a wedge-like vertebral deformity and anterior vertebral osteophyte at the thoracolumbar junction; six individuals (50%) had cervical kyphosis, two (17%) had atlantoaxial subluxation, and ten (83%) had cervical vertebral malformations [Uehara et al 2018].

According to a single institution-based survey including 12 individuals with mcEDS-CHST14 and one with mcEDS-DSE, 12 (92%) had a history of dislocation: shoulder in 11 and elbow in two. Four individuals (31%) had elbow osteoarthritis, and three (23%) had distal radioulnar joint osteoarthritis. The phalanges and metacarpals were thin, and the ratio of medullary cavity to metacarpal width decreased with age [Isobe et al 2022].

Craniofacial. The craniofacial features are distinctive and are common among individuals with both mcEDS-CHST14 and mcEDS-DSE. Craniofacial features include large fontanelle with delayed closure, downslanted and short palpebral fissures, hypertelorism, blue sclera, short nose with hypoplastic columella, low-set, posteriorly rotated ears, long philtrum, thin vermilion of the upper lip, small mouth, high palate, and micro- or retrognathia. Cleft lip and/or palate was reported in 3/50 individuals with mcEDS-CHST14. Some features become less evident or change with age: a round facial shape with micro- or retrognathia in early childhood becomes slender and elongates with a protruding jaw, crowded teeth, and facial asymmetry in adolescence or adulthood (see Figure 3) [Minatogawa et al 2022b].

Figure 3.

Craniofacial features of individuals with musculocontractural Ehlers-Danlos syndrome (mcEDS) 1st row. Composite images of 15 individuals with mcEDS-CHST14 (left, childhood; right, adolescence and adulthood) using Face2Gene facial recognition technology (more...)

Skin. Skin hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars are common in individuals with mcEDS-CHST14 (see Figure 4). These features are less common in individuals with mcEDS-DSE. Hyperalgesia to pressure is also frequent, especially in the upper arm. Recurrent subcutaneous infections were reported in 14/42 individuals with mcEDS-CHST14 and have not been reported in individuals with mcEDS-DSE; recurrent subcutaneous infections were typically accompanied by fistula formation (e.g., buttocks, elbows), which was reported in 11/37 individuals with mcEDS-CHST14 [Minatogawa et al 2022b].

Figure 4.

Clinical photographs of skin manifestations of musculocontractural Ehlers-Danlos syndrome (mcEDS) 1st–3rd row. Clinical photographs of six individuals with mcEDS-CHST14. Note marked hyperextensibility, atrophic scars, and fistulae [Minatogawa (more...)

Ophthalmologic. Refractive errors are common (e.g., myopia, astigmatism). Occasionally in individuals with mcEDS-CHST14, glaucoma or intraocular pressure is elevated and retinal detachment occurs. Median age of retinal detachment is 15.5 years. Six individuals with mcEDS-CHST14 were reported to be blind [Minatogawa et al 2022b].

Genitourinary. Cryptorchidism in males is common. Hypogonadism was also reported in 3/22 individuals with mcEDS-CHST14 [Minatogawa et al 2022b].

Urologic manifestations (hydronephrosis, bladder dysfunction, recurrent urinary tract infection, nephrolithiasis) have occasionally been observed. Recurrent urinary tract infection was only reported in those with mcEDS-CHST14 and occurred in 12/37 individuals. Nephrolithiasis or cystolithiasis was only reported in individuals with mcEDS-CHST14 [Minatogawa et al 2022b].

Cardiovascular. Large subcutaneous hematomas are common and typically involve the scalp, buttocks, thigh, leg, and knee. Median age at the initial episode is six years in individuals with mcEDS-CHST14. Large subcutaneous hematoma can result from minimal trauma and can proceed to life-threatening hypovolemic shock. Large subcutaneous hematoma development can produce significant pain and affect quality of life. In conjunction with delayed wound healing, large subcutaneous hematoma development has led to amputation of toes in some individuals. Immediate desmopressin and tranexamic acid treatment together with cooling under pressure of the injured site following minor trauma appears warranted. Cardiac valve abnormalities (e.g., mitral valve regurgitation/prolapse) and congenital heart defects (e.g., atrial septal defect) are occasionally observed. Enlargement of the ascending aorta was reported in only one individual with mcEDS-CHST14 [Minatogawa et al 2022b].

Neurologic. Delay in acquisition of motor skills is more common in children with mcEDS-CHST14 than in those with mcEDS-DSE, sometimes with elevated serum creatine kinase level. Hypotonia is also more common in children with mcEDS-CHST14 than in those with mcEDS-DSE. However, muscle weakness was reported in individuals with mcEDS-DSE (4/7 individuals). No significant intellectual disability was noted in individuals with mcEDS-CHST14 of school age or older [Minatogawa et al 2022b]. Intellectual disability was reported in only one individual with mcEDS-DSE [Minatogawa et al 2022a].

Structural brain abnormalities are reported in individuals with mcEDS-CHST14, including ventricular enlargement or asymmetry, hypoplasia of the septum pellucidum, and Dandy-Walker variant. No abnormalities were reported in the three individuals with mcEDS-DSE who had brain imaging [Minatogawa et al 2022a].

Gastrointestinal. Constipation is a common gastrointestinal manifestation. Inguinal and umbilical hernias were reported. Diverticula is occasionally seen and can be complicated by perforation and infection. Several individuals with mcEDS-CHST14 developed fatal colonic perforations. A male age 36 years died after multiple perforations despite intensive treatment [Qian et al 2022]; another individual age 37 years died from colonic perforation [Minatogawa et al 2022b]. Two sisters experienced perforations requiring extensive surgical interventions at ages 24 and 29 years [Kobayashi et al 2023].

Hearing. According to a single institution-based survey of individuals with mcEDS-CHST14 (18 ears from nine individuals), hearing loss was detected in 78% of ears (89% of individuals); hearing loss was typically sensorineural and bilateral, with mild-to-moderate severity, and of high frequency or low frequency [Kawakita et al 2023]. Hearing impairment was only reported in 1/9 individuals with mcEDS-DSE [Minatogawa et al 2022a].

Respiratory. Pneumothorax is a rare but important respiratory complication, reported in 4/40 individuals with mcEDS-CHST14 [Minatogawa et al 2022b].

Phenotype Correlations by Gene

The clinical phenotypes of mcEDS-CHST14 and mcEDS-DSE are similar. However, joint manifestations (recurrent/chronic joint dislocations, joint hypermobility), skin features (hyperextensibility, bruisability, fragility, atrophic scars), constipation, hypotonia, and gross motor delay are significantly less common in individuals with mcEDS-DSE than in those with mcEDS-CHST14 (p <0.01) [Minatogawa et al 2022a].

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Prevalence

To date, 70 individuals from 51 families have been identified with biallelic pathogenic variants in CHST14 [Minatogawa et al 2022b, Qian et al, 2022, Ks et al 2024, Uemura et al 2024] and 15 individuals from nine families have been identified with biallelic pathogenic variants in DSE [Minatogawa et al 2022a, Yoshikawa et al 2023].

Prevalence of mcEDS-CHST14 in Japan is estimated to be 1:2,000,000, based on the frequency of three founder variants (p.Pro281Leu, p.Phe209Ser, p.Tyr293Cys) (see Table 7).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with mcEDS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Avoid the following:

• Contact or competitive sports
• Upper arm sphygmomanometer and use of a tight tourniquet during blood collection in individuals with hyperalgesia to pressure

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

To date, only one pregnancy and delivery was recognized in a woman with mcEDS-CHST14 [T Kosho, personal experience]. Premature rupture of membranes, birth canal laceration, and excessive bleeding with vaginal delivery are predicted complications. Pregnancy and delivery in women with mcEDS should be managed in a perinatal center; planned cesarean section would be a reasonable approach.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for an mcEDS-related pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a CHST14 or DSE pathogenic variant and allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a CHST14 or DSE pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with mcEDS are obligate heterozygotes (carriers) for an mcEDS-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an mcEDS-related pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the mcEDS-related pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with mcEDS, particularly if both partners are of the same ancestry. CHST14 founder variants have been identified in the Japanese population (see Table 7).

Prenatal Testing and Preimplantation Genetic Testing

Once the mcEDS-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

DSE and CHST14 encode proteins involved in the biosynthesis of dermatan sulfate. DSE encodes dermatan sulfate epimerase (DSE), which converts glucuronic acid (GlcA) into iduronic acid (IdoA) by epimerizing the C-5 carboxy group of GlcA residues in the repeating disaccharide region of the chondroitin precursor chain, [GlcA–N-acetylgalactosamine (GalNAc)]_n, to form the disaccharide region of dermatan sulfate, [IdoA-GalNAc]_n [Kosho et al 2019]. CHST14 encodes dermatan 4-O-sulfotransferase 1 (D4ST1), which transfers a sulfate group from 3'-phosphoadenosine 5'-phosphosulfate to the C-4 hydroxy group of GalNAc residues in dermatan sulfate [Kosho et al 2019].

Skin fibroblasts from individuals with pathogenic variants in CHST14 or DSE showed lower D4ST1 or DSE activities than those from healthy controls [Kosho et al 2019]. Chondroitin sulfate was produced on the decorin core protein from skin fibroblasts of individuals with musculocontractural Ehlers-Danlos syndrome (mcEDS) caused by biallelic pathogenic variants in CHST14 (mcEDS-CHST14) [Kosho et al 2019]. Dermal collagen fibrils were tightly and regularly assembled in healthy controls; in contrast, they were dispersed in individuals with mcEDS-CHST14 [Hirose et al 2019]. Alteration of the side chain on decorin from dermatan sulfate (curved chains) to chondroitin sulfate (linear chains) caused this spatial disorganization of collagen networks [Hirose et al 2019].

Mechanism of disease causation. Loss of function

Author Notes

The Kosho Lab (Center for Medical Genetics Shinshu [CMGS] at Shinshu University Hospital, Department of Medical Genetics and Division of Clinical Sequencing, Shinshu University School of Medicine) performs integrated translational research on Ehlers-Danlos syndromes (EDS). CMGS has a strong reputation as an internationally recognized center of expertise for research, diagnostics, and clinical management related to a range of hereditary connective tissue disorders (HCTD), including, among others, EDS.

At the Kosho Lab, PI Prof Tomoki Kosho, MD, PhD, and Associate Prof Tomomi Yamaguchi, PhD, lead studies in the following areas of interest:

• Unraveling the molecular basis of HCTD, with a specific focus on EDS, and studying their natural history and genotype-phenotype correlations
• Elucidating molecular and physiologic mechanisms underlying HCTD pathogenesis, using an integrated approach of in vivo and in vitro techniques, on tissue samples of humans, patient-derived induced pluripotent stem (iPS) cells, and animal models (mice).

Tomoki Kosho (pj.ca.u-uhsnihs@ikomotk) is actively involved in clinical research regarding individuals with musculocontractural Ehlers-Danlos syndrome (mcEDS). Prof Kosho would be happy to communicate with persons who have any questions regarding diagnosis of mcEDS or other considerations.

Prof Kosho is also interested in hearing from clinicians treating families affected by mcEDS in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Tomomi Yamaguchi (pj.ca.u-uhsnihs@ihcugamay_t) to inquire about review of CHST14 or DSE variants of uncertain significance.

The Kosho Lab leads variable international collaborative clinical and basic studies on HCTD with multiple institutes, including the lab in the Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, that Dr Shuji Mizumoto belongs to.

Contact Dr Shuji Mizumoto (pj.ca.u-ojiem@otomuzim) to inquire about glycobiologic aspects.

Contact Dr Mendoza-Londono (ac.sdikkcis@azodnem.otrebor) to inquire about management of patients, especially in North America.

Acknowledgments

This work is supported by the endowed chair named "Division of Clinical Sequencing, Shinshu University School of Medicine," which is sponsored by BML, Inc and Life Technologies Japan Ltd, a subsidiary of Thermo Fisher Scientific Inc. The authors wish to thank the EDS Society and Japan Ehlers-Danlos Syndrome Fellowship Association (JEFA).

Revision History

• 15 May 2025 (sw) Review posted live
• 27 November 2024 (tk) Original submission

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