A new Ehlers–Danlos syndrome with craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and multisystem fragility‐related manifestations

Abstract

We previously described two unrelated patients showing characteristic facial and skeletal features, overlapping with the kyphoscoliosis type Ehlers-Danlos syndrome (EDS) but without lysyl hydroxylase deficiency [Kosho et al. (2005) Am J Med Genet Part A 138A:282-287]. After observations of them over time and encounter with four additional unrelated patients, we have concluded that they represent a new clinically recognizable type of EDS with distinct craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and multisystem fragility-related manifestations. The patients exhibited strikingly similar features according to their age: craniofacial, large fontanelle, 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 micro-retrognathia in infancy; slender and asymmetric face with protruding jaw from adolescence; skeletal, congenital contractures of fingers, wrists, and hips, and talipes equinovarus with anomalous insertions of flexor muscles; progressive joint laxity with recurrent dislocations; slender and/or cylindrical fingers and progressive talipes valgus and cavum or planus, with diaphyseal narrowing of phalanges, metacarpals, and metatarsals; pectus deformities; scoliosis or kyphoscoliosis with decreased physiological curvatures of thoracic spines and tall vertebrae; cutaneous, progressive hyperextensibility, bruisability, and fragility with atrophic scars; fine palmar creases in childhood to acrogeria-like prominent wrinkles in adulthood, recurrent subcutaneous infections with fistula formation; cardiovascular, cardiac valve abnormalities, recurrent large subcutaneous hematomas from childhood; gastrointestinal, constipation, diverticula perforation; respiratory, (hemo)pneumothorax; and ophthalmological, strabismus, glaucoma, refractive errors.

Loss of dermatan‐4‐sulfotransferase 1 (D4ST1/ CHST14 ) function represents the first dermatan sulfate biosynthesis defect, “dermatan sulfate‐deficient adducted thumb–clubfoot syndrome”

“…The prominent feature of congenital foot malformations is present in all the patients they describe, delineated as clubfeet in ATCS and in its milder form as talipes equinovares. Furthermore, at least one of the symptoms of disturbed blood coagulation, delayed wound healing, ecchymoses, and hematoma formation that we described in ATCS was present in each of their patients [Dundar et al, 1997[Dundar et al, , 2001[Dundar et al, , 2009Janecke et al, 2001;Kosho et al, 2010]. Although there are minor differences in the clinical findings reported in each article dealing with CHST14 mutations, all are well within the range of expected clinical variability.…”

Discovery and Delineation of Dermatan 4-O-Sulfotransferase-1 (D4ST1)-Deficient Ehlers-Danlos Syndrome

“…Therefore, we tentatively proposed that the two patients represented a clinically recognizable subgroup of EDS type VIB [12]. Through their long-term clinical evaluation as well as four additional unrelated Japanese patients including one with parental consanguinity and another reported by Yasui et al [14], we concluded that they-four female patients and two male patients aged 4-32 years, represented a new clinically recognized type of EDS with distinct craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and multisystem fragility-related manifestations [15]. The disorder has been registered as EDS Kosho Type (EDSKT) in the London Dysmorphology Database (http://www.lmdatabases.com/index.html) and in POSSUM (http://www.possum.net.au/).…”

A new face and new challenges for Online Mendelian Inheritance in Man (OMIM®)

“…Sometimes what appears to be phenotypic diversity at a locus turns out, in fact, to be a single clinical entity. What was recently described as a ''new Ehlers-Danlos syndrome with craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and multisystem fragility-related manifestations'' [Kosho et al, 2010] was determined to have similar features to an existing entity in OMIM, adducted thumb-clubfoot syndrome (ATCS; MIM# 601776), which is due to mutations in CHST14 (MIM# 608429). Some of the patients reported by Kosho et al [2010] had been reported earlier [Kosho et al, 2005] as having Ehlers-Danlos syndrome VIb (EDS VIB).…”

“…In the original description of adducted thumb-clubfoot syndrome by Dundar et al [1997], the patients were very young, and joint contractures were the most prominent features. The patients reported by Kosho et al [2010] were older, and skin and joint laxity were the most prominent features.…”