Clinical and molecular features of 66 patients with musculocontractural Ehlers−Danlos syndrome caused by pathogenic variants inCHST14(mcEDS-CHST14)

Abstract

BackgroundMusculocontractural Ehlers−Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated.MethodsWe collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations.ResultsSixty-six patients in 48 families (33 males/females; 0–59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype–phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE.ConclusionThis first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.

The Specific Role of Dermatan Sulfate as an Instructive Glycosaminoglycan in Tissue Development

“…D4ST encoded by carbohydrate sulfotransferase 14 (CHST14) catalyzes the transfer of a sulfate group from 3 -phosphoadenosine 5 -phosphosulfate to the C-4 hydroxy group of GalNAc residues in DS chains (Figure 2) [26,27]. EDS musculocontractural type 1 is caused by a variety of pathogenic variants in CHST14 [22][23][24]81,[87][88][89][90][91][92][93][94][95][96] (Table 2). The characteristic manifestations of the EDS musculocontractural type 1 were craniofacial features including large fontanelle with delayed closure, downslanting palpebral fissures, and hypertelorism; skeletal features including characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities, and recurrent joint dislocation; cutaneous features including hyperextensibility, fine/acrogeria-like/wrinkling palmar creases, and bruisability; refractive errors of vision, large subcutaneous hematomas, constipation, cryptorchidism, hypotonia, and motor developmental delay [96].…”

The Ehlers–Danlos Syndromes against the Backdrop of Inborn Errors of Metabolism

“…Prenatal ultrasound abnormalities sometimes seen in e.g., lysosomal storage diseases (hydrops fetalis) or peroxisome biogenesis disorders (brain anomalies and cystic renal disease), are extremely uncommon in EDS [ 6 ]. The lone exception are the congenital anomalies of the kidney and urinary tract (nephroptosis and ureteropelvic junction obstruction) sometimes observed in musculocontractural EDS (mcEDS) [ 7 ].…”

“…Central nervous system abnormalities have been reported only in mcEDS- CHST14 and spEDS- B3GALT6 and include ventricular enlargement, Dandy–Walker anomalies, hypoplasia of the septum pellucidum, hydrocephalus and a tethered spinal cord [ 7 , 12 ]. Intellectual disability is typically not present but has sporadically been reported in families with AR types of EDS.…”

“…The facial dysmorphisms in dEDS also combine into a recognizable appearance and include prominent and protuberant eyes with puffy, edematous eyelids and excessive periorbital skin, large fontanels and/or wide cranial sutures, micrognathia and gingival hyperplasia ( Figure 1 M) [ 10 ]. Finally, individuals with mcEDS present with large fontanels, downslanting palpebral fissures, hypertelorism, a short nose with hypoplastic columella, ear deformities, high-arched palate, long philtrum, thin upper lip vermilion, small mouth and microretrognathia ( Figure 1 J) [ 7 , 29 ].…”

“…Hearing loss is a key finding in heritable connective tissue disorders, such as osteogenesis imperfecta and Stickler syndrome but is also present in the majority of individuals with kEDS- FKBP14 or mcEDS and a third of the individuals with BCS [ 7 , 12 , 27 ]. Finally, cryptorchidism is present in the large majority of mcEDS- CHST14 individuals and should raise suspicion of mcEDS in a neonate with signs of connective tissue fragility and contractures [ 7 ].…”