Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Ehlers-Danlos Syndrome kyphoscoliotic Type (EDS type VIB) [Q79.6]

OMIM numbers: 601776, 608429 (CHST14), 614557, 614505 (FKBP14)

Dr. rer. nat. Karin Mayer

Scientific Background

The autosomal recessive inherited kyphoscoliotic EDS type (EDS type VI) is genetically heterogeneous. Characteristic clinical symptoms include kyphoscoliosis, muscle hypotonia, hyperextensible, thin and easy bruisable skin, atrophic scarring, hypermobility of the joints and various ocular manifestations. Furthermore, different craniofacial abnormalities, joint contractures and wrinkled palms.

In the majority of patients the disease is caused by mutations in the PLOD1 gene, which encodes for the enzyme lysyl hydroxylase 1 (LH1) and is referred to as EDS type VIA. Deficiency of the enzyme LH can be detected by an increased cross link ratio of lysyl pyridinoline (LP) to hydroxylysyl pyridinoline (HP) in the urine.

A small number of patients with an identical clinical picture exhibit an unsuspicious LP/HP ratio in the urine and no PLOD1 mutation which is referred to as EDS type VIB. In some of these patients homozygous or compound heterozygous mutations in the CHST14 gene (carbohydrate sulfotransferase 14) were identified, which codes for the dermatan-4-sulfotransferase 1 (D4ST1). The clinical phenotype of these patients with D4ST1 deficiency is also referred to as musculocontractural type. Already in 2009 mutations in CHST14 were described as the cause of adducted thumb-clubfoot syndrome (ATCS). Since it currently remains unclear if they really represent distinct clinical entities, the term D4ST1 deficient EDS was proposed. So far only 8 missense and 3 frameshift mutations in the CHST14 gene are described in the literature.

In 2012, in regard to differential diagnosis to EDS type VIA and D4ST1 deficient EDS, another autosomal recessive EDS type with unsuspicious LP/HP ratio was described: EDSKMH. Besides progressive kyphoscoliosis, muscle hypotonia, joint hypermobility, hyperextensible skin, and myopathy, sensorineural hearing loss is especially characteristic for this type of EDS. The cause of EDSKMH are mutations in the FKBP14 gene, which codes for the FK506-binding protein 14, a member of the peptidyl-prolyl isomerases (PPIs). So far only 2 distinct homozygous / 2 compound heterozygous mutations in the FKBP14 gene have been described in 5 families.