Ehlers-Danlos · Connective tissue
Spondylodysplastic Ehlers-Danlos Syndrome · spEDS
Short stature with progressive spinal deformity. Three known molecular forms.
Description
Spondylodysplastic Ehlers-Danlos syndrome, spEDS, is an autosomal recessive connective tissue disorder defined by short stature that is progressive in childhood, muscle hypotonia, and skeletal dysplasia involving the vertebrae and long bones. The 2017 international classification (Malfait and colleagues, American Journal of Medical Genetics Part C, 2017) groups three molecular causes under one clinical heading. B4GALT7 and B3GALT6 encode galactosyltransferases that build the linker tetrasaccharide on which all proteoglycan glycosaminoglycan chains are assembled. SLC39A13 encodes the zinc transporter ZIP13, which moves zinc out of the endoplasmic reticulum and supports collagen and proteoglycan biosynthesis indirectly. The B4GALT7 form was reported by Quentin and colleagues in Proceedings of the National Academy of Sciences in 1990 and refined by Okajima and colleagues in the Journal of Biological Chemistry in 1999. The B3GALT6 form was described by Nakajima and colleagues and Malfait and colleagues in the American Journal of Human Genetics in 2013. The SLC39A13 form was identified by Giunta and colleagues in the American Journal of Human Genetics in 2008.
The 2017 criteria require the two universal major findings, short stature progressive in childhood and muscle hypotonia ranging from severe congenital to mild later-onset, plus bowing of the limbs, plus subtype-specific features. B4GALT7 disease produces a phenotype historically called progeroid EDS, with thin and wrinkled skin on the face and extremities, sparse scalp hair, and craniofacial features that suggest premature aging. B3GALT6 disease overlaps with B4GALT7 disease and adds kyphoscoliosis, joint contractures, and osteoporosis with fractures. SLC39A13 disease produces protuberant eyes with bluish sclerae, characteristic hand findings with tapering fingers, and severe muscle hypotonia.
Confirmation is by gene sequencing of B4GALT7, B3GALT6, or SLC39A13 with biallelic pathogenic variants. The B4GALT7 form has elevated frequency among people of Mauritian and Chagossian descent through a founder variant (Cartault and colleagues, European Journal of Human Genetics, 2015). Fewer than 50 cases per molecular subtype have been reported, and the combined worldwide total remains under a few hundred.
Treatments to date
Care is supportive and multidisciplinary. There is no approved disease-modifying therapy, no enzyme replacement, and no gene therapy in clinical use for any form of spEDS.
Orthopedic management addresses limb bowing, kyphoscoliosis, joint contractures, and the consequences of low bone density. Bracing is used for progressive spinal curves, and spinal surgery is considered when curves advance despite bracing or when pulmonary function declines. Long-bone deformity may require osteotomy. Bone density is monitored from childhood, and fractures are managed conservatively when possible because tissue fragility complicates fixation. Physical therapy targets stabilization of hypermobile joints and supports gross motor development in children with severe hypotonia.
Growth is monitored with the recognition that adult stature is reduced and that pharmacologic growth-promoting therapy has no established role. Cardiology assessment screens for aortic root dilation reported in B3GALT6 disease. Ophthalmology assessment screens for refractive errors and, in SLC39A13 disease, the protuberant eye and scleral findings. Skin care is conservative because of fragility and easy bruising in the progeroid phenotype.
No drug is approved by the FDA or EMA for spEDS. Research has focused on glycosaminoglycan biology and zinc homeostasis rather than on a near-term therapeutic.