A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history

Abstract

PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.MethodsWe report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.ResultsBased on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.ConclusionOur data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS.

Figure 1

Clinical phenotype of patients with FKBP14-kEDS. Consent for publication of patient photos was obtained for each subject. (a,b) P1 from the original publication showing wrist-drop of both hands in early infancy (a,b, age 2 and 6 weeks). (c) P3/FIII at age 10 years after surgical correction of the severe thoracolumbar scoliosis. (d) P2/FII at age 8 years after surgical correction of the progressive severe scoliosis. (e) P1/FI at age 8 years with pes planovalgus and rocker bottom feet. (f,g) P7/FV showing micrognathia (f, age 1 year), and hyperextensible skin (g, age 8 years). (h) P10/FVIII at age 12 years with pronounced pes valgus. (i) P12/FX at age 8 years presenting with pectus excavatum. (j–l) P13/FXI at age 5 years presenting with pectus excavatum, umbilical herniae, and wrinkly, redundant skin (j), pronounced criss cross pattern of the soles (k) and cutis marmorata (l). (m–o) P8/FVI at age 6 years (m,o), and 8 years (n) showing scoliosis (m), hyperkeratotic skin eruptions in the pressure areas under the thoracolumbar orthosis (o), and mild flexion contractures of the elbows (n).

Figure 2

Radiological findings. At the age of 50 years, P2 from Baumann et al. developed a dissection of the internal carotid artery. The perforation was located just above the right carotid artery bifurcation with formation of a pseudoaneurysm extending to the base of the skull. (a) Contrast-enhanced magnetic resonance angiography shows interruption of the right internal carotid artery (double arrowhead) and elongation and increased tortuosity of the extracranial vessels. Axial sections with (b) fat saturated T1 sequences and (c) time-of-flight angiography show the residual lumen of the right internal carotid artery (double arrowhead). Spinal magnetic resonance image at age 4 years in P6 from Baumann et al. shows an atlantoaxial subluxation with dens dislocation and myelocompression. (d) In sagittal T2-weighted imaging compression of the spinal canal and increased signal intensity of the myelon at the craniocervical junction as sign of myelopathy (double arrowhead). (e) Axial T1-weighted imaging shows dislocation of the dens with myelocompression (double arrowhead) and pannus proliferation around the dens.