A response to: Loss of dermatan-4-sulfotransferase 1 (D4ST1/CHST14) function represents the first dermatan sulfate biosynthesis defect, “dermatan sulfate-deficient Adducted Thumb–Clubfoot Syndrome”. Which name is appropriate, “Adducted Thumb–Clubfoot Syndrome” or “Ehlers–Danlos syndrome”?
We thank Janecke et al. [2011] for their letter about a recently recognized dermatan 4-O-sulfotransferase 1 (D4ST1) deficiency caused by loss-of-function CHST14 (MIM# 608429) mutations, independently found in an arthrogryposis syndrome “Adducted Thumb–Clubfoot Syndrome” (ATCS) [Dündar et al., 2009], a specific form of Ehlers-Danlos syndrome (EDS) as we have proposed (EDS, Kosho Type; EDSKT) [Miyake et al., 2010], and a subset of kyphoscoliosis type EDS without evidence of lysyl hydroxylase deficiency (EDS type VIB) coined as “Musculocontractural EDS” (MCEDS) [Malfait et al., 2010]. Janecke et al. [2011] proposed that these three conditions constitute a clinically recognizable and genetically identical type of connective tissue disorder and that the disorders should not be categorized into a form of EDS, but be termed collectively “Dermatan Sulfate-Deficient Adducted Thumb–Clubfoot Syndrome” to avoid possible confusion for both clinicians and researchers. The proposal is based on their clinical and molecular recognition of the disorder. First, the presence of multiple congenital malformations such as facial dysmorphism, cleft lip/palate, intestinal abnormalities, renal abnormalities, and features such as nephrolithiasis and muscle hypotonia in these patients are not typical in EDS, though features such as joint laxity, skin hyperextensibility/fragility, and bleeding diathesis are typical in EDS. Second, the molecular basis in the disorder is different from that in EDS.
EDS comprises a heterogeneous group of heritable connective tissue disorders, with the hallmarks being skin hyperextensibility, joint hypermobility, and tissue fragility affecting the skin, ligaments, joints, blood vessels, and internal organs [Steinmann et al., 2002]. Dominant-negative effects or haploinsufficiency of mutant procollagen α-chain genes or deficiency of collagen-processing enzymes have been found to cause EDS [Mao and Bristow, 2001]. In a revised nosology, EDS was classified into six major types [Beighton et al., 1998] and several other forms have also been identified based on the molecular and biochemical abnormalities [Abu et al., 2008; Giunta et al., 2008; Kresse et al., 1987; Schalkwijk et al., 2001; Schwarze et al., 2004].
Homozygous or compound heterozygous CHST14 mutations have been found in 11 patients aged 0 day to 6 years at the initial publication (from four families) with ATCS [Dündar et al., 1997, 2001, 2009; Janecke et al., 2001; Sonoda and Kouno, 2000], in six patients aged 2–32 years (from six families) with EDSKT [Kosho et al., 2005, 2010; Miyake et al., 2010; Yasui et al., 2003], and in three patients aged 12–22 years (from two families) with MCEDS [Malfait et al., 2010]. Lack of detailed clinical information from later childhood to adulthood in ATCS and lack of detailed clinical information from birth to early childhood in EDSKT and MCEDS have made it difficult to determine whether the three conditions would be distinct clinical entities or a single clinical entity with variable expressions and with different presentations depending on the patients' ages at diagnosis [Miyake et al., 2010], though the latter notion was suspected to be appropriate [Janecke et al., 2011; Malfait et al., 2010]. We, therefore, have just published an article in American Journal of Medical Genetics Part A, describing detailed clinical findings and courses of two additional unrelated EDSKT patients, aged 2 and 6 years, which could definitely unite the three conditions [Shimizu et al., 2011]. Furthermore, we have presented a comprehensive review of all reported patients with D4ST1 deficiency, which concludes that the three conditions constitute a clinically recognizable disorder, characterized by progressive multisystem fragility-related manifestations and various malformations and allows us to term the disorder “D4ST1-deficient EDS” [Shimizu et al., 2011]. The clinical manifestations are summarized in Table 1.
Craniofacial | Cardiovascular |
Large fontanelle (early childhood) | Congenital heart defects (ASD) |
Hypertelorism | Valve abnormalities (MVP, MR, AR, ARD) |
Short and downslanting palpebral fissures | Large subcutaneous hematomas |
Blue sclerae | Gastrointestinal |
Short nose with hypoplastic columella | Constipation |
Ear deformities (prominent, posteriorly rotated, low set) | Diverticula perforation |
Palatal abnormalities (high, cleft) | Respiratory |
Long philtrum and thin upper lip | (Hemo) pneumothorax |
Small mouth/microretrognathia (infancy) | Urogenital |
Slender face with protruding jaw (from school age) | Nephrolithiasis/cystolithiasis |
Asymmetric face (from school age) | Hydronephrosis |
Skeletal | Dilated/atonic bladder |
Marfanoid habitus/slender build | Inguinal hernia |
Congenital multiple contractures (fingers, wrists, hips, feet) | Cryptorchidism |
Recurrent/chronic joint dislocations | Poor breast development |
Pectus deformities (flat, excavated) | Ocular |
Spinal deformities (scoliosis, kyphoscoliosis) | Strabismus |
Peculiar fingers (tapering, slender, cylindrical) | Refractive errors (myopia, astigmatism) |
Progressive talipes deformilies (valgus, planus, cavum) | Glaucoma/elevated intraocular pressure |
Cutaneous | Microcornea/microphthalmia |
Hyperextensibility/redundancy | Retinal detachment |
Bruisability | Hearing |
Fragility/atrophic scars | Hearing impairment |
Fine/acrogeria-like palmar creases | Neurological |
Hyperalgesia to pressure | Ventricular enlargement/asymmetry |
Recurrent subcutaneous infections/fistula | Development |
Hypotonia/gross motor delay |
- a ASD: atrial septal defect; MVP: mitral valve prolapse; MR: mitral valve regurgitation; AR: aortic valve regurgitation; ARD: aortic rot dilation.
We have categorized D4ST1 deficiency into a form of EDS for substantial reasons. Clinically, the disorder satisfies all the hallmarks of EDS [Steinmann et al., 2002]. All patients we have encountered were diagnosed with EDS and have been managed as having generalized connective tissue fragility, such as preventing skin wounds, hematomas, joint dislocations, and progressive talipes and spinal deformities. Careful surgical suturing of torn skin and regular evaluations of internal organs (e.g., cardiac valve abnormalities, aortic root dilation, and bladder enlargement) and ocular abnormalities are also conducted. ATCS is surely a helpful term to detect and diagnose patients at birth, but it is indeed questionable whether the term would be appropriate for the lifelong management of patients with the disorder. Furthermore, clinical manifestations extending beyond the core features of EDS are considered not as excluding information from EDS as Janecke et al. [2011] have claimed, but as wide clinical variability in EDS such as muscle hypotonia and chronic pain in most of the types, talipes equinovarus and facial characteristics in vascular type, and congenital hip dislocation in arthrochalasia type [Beighton et al., 1998; Voermans et al., 2009].
Etiologically, multisystem fragility in D4ST1 deficiency was illustrated to be caused by impaired assembly of collagen fibrils resulting from loss of dermatan sulfate (DS) in the decorin glycosaminoglycan side chain [Miyake et al., 2010], which justifies terming the disorder a form of EDS. However, ultrastructural findings in the skin from patients with ATCS and MCEDS were not consistent with those in patients with EDSKT, characterized by intact collagen fibrils not assembled regularly or tightly [Miyake et al., 2010]. For patients with ATCS, the skin was assessed as normal [Dündar et al., 2009]. For those with MCEDS, most collagen bundles were found to be small sized, some of which were composed of variable diameter collagen fibrils separated by irregular interfibrillar spaces [Malfait et al., 2010]. Ultrastructural and glycobiological studies on the skin from other patients as well as those on other affected tissues such as bone, muscle, and intestine would be necessary to delineate the wide spectrum of pathophysiology. Involvement of other DS-containing proteoglycans such as biglycan should also be investigated. Various malformations observed in the disorder might not simply be explained by connective tissue fragility, as they are considered to be inborn errors of development [Dündar et al., 2009; Zhang et al., 2010].
Based on the clinical, molecular, ultrastructural, and glycobiological data to date, D4ST1 deficiency is characterized by a unique set of clinical features consisting of progressive multisystem fragility-related manifestations and various malformations (Table 1). Further clinical and etiological evidences would solve the problem regarding which name should be the most appropriate: “Dermatan Sulfate-Deficient Adducted Thumb-Clubfoot Syndrome” or “D4ST1-Deficient EDS.” Until then, we propose that the name “D4ST1-Deficient EDS (Adducted Thumb-Clubfoot Syndrome)” would be preferable.