Ehlers-Danlos Syndrome, Kyphoscoliotic Type

DISEASE CARD

Disease group Connective tissue disorders
DISEASE NAME EHLERS-DANLOS SYNDROME, KYPHOSCOLIOTIC TYPE
Synonymous EDS kyphoscoliotic type, Ehlers-Danlos syndrome oculo-scoliotic type, Ehlers-Danlos Syndrome Type VIA
Estimated prevalence -
OMIM 225400
Inheritance Autosomal recessive
Gene (s) PLOD 1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 or lysyl hydroxylase 1) (153454)

Definition

EDS kyphoscoliotic form is an autosomal recessive connective tissue disorder characterized by progressive kyphoscoliosis, joint laxity, muscle hypotonia, and, in some individuals, ocular problems. It is caused by deficient activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1: lysyl hydroxylase 1)

Clinical Description

The disorder is characterized by neonatal muscle hypotonia and joint hyperlaxity, which may cause mild delay in motor development. Thoracic kyphoscoliosis is commonly present at birth or may develop within the first year of life. It is usually progressive and adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease and recurrent pneumonia. Other skeletal manifestations include clubfoot, recurrent joint dislocations, a marfanoid habitus and osteoporosis.
Scleral fragility with rupture of the globe is present in a minority of affected patients. High myopia however is common, and most individuals have microcornea. Some individuals have glaucoma and/or retinal detachment.
Mitral valve prolapse is common. Moreover patients are at risk for arterial rupture of medium-sized arteries or aorta dilatation and dissection.Other features include tissue fragility, skin hyperextensibility, atrophic scarring and easy bruising.

Pathogenesis

This autosomal recessive disorder is caused by deficient activity of the enzyme procollagen-lysine 2-oxoglutarate 5 dioxygenase-1 (lysyl hydroxylase-1, PLOD), a posttranslational modifying enzyme in collagen biosynthesis. This enzyme is required for the hydroxylation of specific collagen lysines to produce hydroxylysines which act as precursors for the crosslinking process that is essential for the tensile strength of collagen. Deficiency of this enzyme results in a deficiency of hydroxylysine-based pyridinoline cross-links in types I and III collagen.

Diagnosis

The diagnosis of EDS, kyphoscoliotic form relies upon clinical evaluation.
It is confirmed by the demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by HPLC, a highly sensitive and specific test. Assay of lysyl hydroxylase enzyme activity in skin fibroblasts is also available. Molecular genetic testing of the PLOD1 gene that encodes the enzyme lysyl hydroxylase 1 is available on a research basis. Prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member.

Treatment

Affected individuals should be referred to an orthopaedic surgeon for management and follow-up of their kyphoscoliosis. Orthopaedic surgery is not contraindicated and should be performed as necessary.
In children with severe muscle hypotonia physical therapy evaluation is necessary in order to develop a plan for ongoing therapy to strengthen large muscle groups and prevent recurrent dislocations.
A baseline echocardiogram with aortic diameter measurement is recommended prior to the age of 10 years with follow-up studies timed according to whether an abnormal measurement is found. Patients with mitral valve prolapse require antibiotic prophylaxis for bacterial endocarditis. Aggressive control of the blood pressure in order to reduce the risk of arterial rupture is mandatory. Routine ophthalmological examination for management of myopia and early detection of glaucoma is necessary.