A novel variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy and hearing loss – a differential diagnosis in floppy infant syndrome

M Baumann; C Giunta; C Bönnemann; S Quijano-Roy; F Muntoni; S Cirak; G Schreiber; R Bittner; M Colombi; M Rohrbach; B Steinmann; K Rostásy; B Krabichler; J Zschocke; C Fauth

doi:10.1055/s-0032-1307058

A novel variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy and hearing loss – a differential diagnosis in floppy infant syndrome

M Baumann ¹, C Giunta ², C Bönnemann ³, S Quijano-Roy ⁴, F Muntoni ⁵, S Cirak ⁵, G Schreiber ⁶, R Bittner ⁷, M Colombi ⁸, M Rohrbach ², B Steinmann ², K Rostásy ¹, B Krabichler ⁹, J Zschocke ⁹, C Fauth ⁹

¹Department of Paediatrics IV Paediatric Neurology and Inherited Metabolic disorders Innsbruck Medical University, Innsbruck, Austria
²Connective Tissue Unit, Division of Metabolism and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland
³National Institute of Neurological Disorders and Stroke, NIH Bethesda, Bethesda, United States
⁴Service de Pédiatrie Hôpital Universitaire Raymond Poincaré Garches, Centre National de Référence des Maladies Neuromusculaires, Garches, France
⁵Dubowitz Neuromuscular Centre, Institute of Child Health London, London, United Kingdom
⁶Department of Neuropaediatrics, Klinikum Kassel, Kassel, Germany
⁷Neuromuscular Research Department, Center of Anatomy & Cell Biology, Medical University of Vienna, Wien, Austria
⁸Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology University of Brescia, Brescia, Italy
⁹Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria

Abstract

Aims: We report on a novel autosomal recessive variant of Ehlers-Danlos syndrome (EDS) characterized by severe muscle hypotonia at birth, delayed motor development, joint hypermobility, hyperelastic skin, progressive scoliosis, myopathy and sensorineural hearing impairment.

Methods: The candidate gene was identified by linkage analysis in a large kindred of European descent and belongs to the family of FK506-binding proteins (FKBPs). FKBPs are involved in various biochemical processes including protein folding, protein trafficking and receptor signaling. Sequence analysis revealed a homozygous frameshift mutation in the candidate gene in all affected members of the index family.

Results: Based on the cardinal clinical characteristics of the disorder four additional individuals originating from different European countries were identified who carried either homozygous or compound heterozygous mutations in the gene. All affected individuals presented with severe generalized hypotonia at birth and marked muscle weakness which improved in infancy. Motor development was delayed and reduced muscle strength persisted into adulthood. Signs of primary muscle disease were identified by muscle MRI, histology and electron microscopy. Characteristic symptoms like joint hypermobility, skin hyperelasticity and follicular hyperkeratosis, but also occasional features like bladder diverticula, inguinal or umbilical herniae and subdural hygroma, reveal systemic connective tissue involvement.

Conclusion: Clinically the disorder shares many features with the kyphoscoliotic type of EDS (EDS VIA) and Ullrich congenital muscular dystrophy. Mutation analysis of this gene should be considered in all individuals with apparent kyphoscoliotic type of EDS and normal urinary pyridinoline excretion, in particular in conjunction with sensorineural hearing impairment. This novel disorder is a differential diagnosis to be considered in floppy infant syndrome and Ullrich congenital muscular dystrophy.

Ehlers-Danlos syndrome - myopathy - hearing impairment