Ehlers-Danlos Syndrome, Kyphoscoliotic Type, 2

A number sign (#) is used with this entry because of evidence that Ehlers-Danlos syndrome kyphoscoliotic type 2 (EDSKSCL2) is caused by homozygous or compound heterozygous mutation in the FKBP14 gene (614505) on chromosome 7p15.

Description

Ehlers-Danlos syndrome kyphoscoliotic type 2 is characterized by severe muscle hypotonia at birth, progressive scoliosis, joint hypermobility, hyperelastic skin, myopathy, sensorineural hearing impairment, and normal pyridinoline excretion in urine (Baumann et al., 2012).

For a discussion of genetic heterogeneity of the kyphoscoliotic type of EDS, see 225400.

Clinical Features

Baumann et al. (2012) reported a 16-year-old Austrian boy who was born with severe muscle hypotonia, paucity of antigravity movements, poor sucking, hypermobile joints, and slightly bluish sclerae. At 2 months of age, the first signs of spinal deformity developed. Muscle weakness and hypotonia improved over subsequent months, with unsupported sitting at 13 months and unassisted walking at 2.5 years. He underwent surgical repair of an inguinal hernia at 2 years of age, placement of subdural-peritoneal shunt for chronic subdural hygroma at 3 years of age, and repair of a large bladder diverticulum at 9 years of age. Bilateral high frequency sensorineural hearing impairment requiring a hearing aid was diagnosed at 6 years of age. Progression of scoliosis resulted in a restrictive ventilation disorder, with a forced vital capacity of 34%. Echocardiography and thoracoabdominal CT scan at 13 years of age showed no signs of cardiomyopathy or dilation of the aorta or other large vessels. At age 16, he had severe kyphoscoliosis and marked hypermobility of the large and small joints (Beighton score, 6/9), but no contractures. He had a characteristic handshake 'like a bag of little bones' due to seeming collapse of the musculoskeletal structure of the hand on pressure. His skin was thin, soft, and hyperelastic, with follicular hyperkeratosis but no signs of increased fragility or atrophic scars; he had 2 keloids in the left deltoid area, where a skin biopsy had been taken. There was no skin wrinkling of the palms. He was myopic with normal corneal diameter. The proband's father had a female cousin who had severe muscle hypotonia and weakness at birth, scoliosis from age 2 years, and moderate bilateral high frequency sensorineural hearing impairment requiring hearing aids at 6 years of age. In her fifth decade, she developed progressive weakness of the lower limbs, and at 48 years of age, had difficulty climbing stairs and could not do toe or heel walking. Clinical examination showed a moderate degree of muscular atrophy in the legs and intrinsic hand muscles, without sensory deficit. She had marked instability of the knees and her Beighton score was 6/9. Her skin was soft and hyperelastic with easy bruisability, without abnormal scarring. She was myopic with normal corneal diameter. She had an older sister who was born with hypotonia, developed mild but progressive kyphoscoliosis and follicular hyperkeratosis, and died unexpectedly at 12 years of age from aortic rupture. Baumann et al. (2012) identified 4 additional patients from 4 unrelated families of Italian, French, Turkish, and German origin with similar presentations. Radiography showed mild to moderate osteopenia in all patients, but no increased bone fragility. Electromyopathy showed a myopathic pattern in adolescence and adulthood, but results obtained in infancy were mostly reported as normal. Histopathologic features of muscle biopsies ranged from nonspecific mild myopathic changes with increased variation in muscle fiber diameter to more pronounced changes with profound fiber atrophy and proliferation of fatty tissue. Electron microscopy of patient fibroblasts showed dilated cisterns filled with flocculent material, and immunofluorescence experiments demonstrated disturbed distribution and assembly of several extracellular matrix (ECM) components, including collagens type I and type III and fibronectin as well as their receptors. Baumann et al. (2012) noted that the disorder shared many features with the kyphoscoliotic form of EDS (225400) and Ullrich congenital muscular dystrophy (254090).

Aldeeri et al. (2014) studied a 3-year-old boy in whom slow feeding and floppiness were evident shortly after birth. At 19 months of age, he had just taken his first steps and was observed to be borderline microcephalic with subtle dysmorphic features, including sloping forehead, square nasal root, mild hypotelorism, epicanthal folds, and hypotonia. He also had excessively redundant umbilical skin. At 2.5 years of age, he was making 2-word sentences and exhibited an immature waddling gait. He had appreciable skin laxity, with a Beighton score of 8/9. No specific mention was made of kyphoscoliosis or hearing loss, but at age 3 the child had an 'abnormal gait' and 'only 50% of his speech was understandable by strangers.' No hearing test was reported. Echocardiography revealed patent ductus arteriosus. Electromyography showed myopathic changes; muscle biopsy showed a predominance of type I fibers.

Dordoni et al. (2016) described an 8-year-old Italian boy with Ehlers-Danlos syndrome and compound heterozygous mutations in the FKBP14 gene (see MOLECULAR GENETICS) who had mixed hearing loss, mild nonprogressive kyphoscoliosis, and muscle hypotonia. In addition to these cardinal features of EDSKSCL2, at age 6 years he had left hypogastric artery pseudoaneurysm rupture. Thoracic and abdominal magnetic resonance angiography did not reveal any other arterial malformations. Also at age 6, flexion/extension x-rays of the cervical spine showed asymptomatic atlantoaxial instability, with enlarged atlantoaxial distance in flexion. The authors suggested that cerebrovascular monitoring is warranted in patients with FKBP14-associated EDS.

Giunta et al. (2018) reported a cohort of 17 individuals with kyphoscoliotic Ehlers-Danlos syndrome and the follow-up of 3 previously reported patients, and provided an extensive overview of the disorder and its natural history. In a summary (Table 2) of features present in the 17 patients reported by Giunta et al. (2018) and 6 reported by Baumann et al. (2012), all reported patients had soft-textured skin, small-joint hypermobility, foot deformities, muscle hypotonia at birth, poor head control in infancy, improving weakness over time, and delayed motor development. More than two-thirds of these 23 patients presented with hyperextensible skin, hypermobile large joints, progressive kyphoscoliosis, and hearing impairment. Muscle atrophy was present in 63%, cardiac valve anomalies in 40%, vascular anomalies in 30%, visual refraction anomalies in 60%, and hernias in 47%. A variety of other features were associated with a minority of patients.

Diagnosis

Based on the frequency of clinical features of 23 patients with EDSKSCL2 reported to that time, Giunta et al. (2018) stated that the major diagnostic criteria are (i) severe generalized hypotonia at birth with marked muscle weakness that improves in infancy, and delayed gross motor milestones; (ii) early-onset progressive kyphoscoliosis; (iii) joint hypermobility without pronounced contractures; (iv) foot deformities; and (v) normal or decreased ratio of lysyl pyridinoline to hydroxylysyl pyridinoline in urine. Minor criteria include (i) hyperelastic skin with follicular hyperkeratosis, easy bruising, and occasional abnormal scarring; (ii) myopathy as seen clinically by reduced strength and endurance and confirmed in some patients by histology and muscle imaging; and (iii) hearing impairment that is predominantly sensorineural and may not be present in all individuals.

Mapping

Using genomic DNA from 23 members of an Austrian family segregating autosomal recessive Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss, Baumann et al. (2012) performed a genomewide scan followed by haplotype analysis and autozygosity mapping and identified only 2 linkage regions for which the 2 affected individuals were homozygous identical by descent, on chromosomes 7p15.1 and 16q12.2. The 670,554-bp homozygous linkage interval on chromosome 7 was flanked by SNPs rs767430 and rs2709800, whereas the 724,063-bp region on chromosome 16 was flanked by SNPs rs211085 and rs1486733.

Molecular Genetics

In 2 affected individuals from an Austrian family with Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss, Baumann et al. (2012) sequenced the candidate gene FKBP14 (614505) and identified homozygosity for a 1-bp insertion (614505.0001). Analysis of FKBP14 in 4 additional unrelated probands with EDSKMH from Italian, Turkish, French, and German families revealed homozygosity for the 1-bp insertion in 3 and compound heterozygosity for the insertion and a 19-bp deletion (614505.0002) in 1.

In a 3-year-old boy with Ehlers-Danlos syndrome and myopathy, Aldeeri et al. (2014) performed exome sequencing and identified homozygosity for a 4-bp splice site deletion in the FKBP14 gene (614505.0003).

In an 8-year-old Italian boy with EDSKSCL, Dordoni et al. (2016) sequenced the FKBP14 gene and identified compound heterozygosity for the recurrent 1-bp duplication (614505.0001) and a 3-bp deletion (614505.0004). His unaffected parents were each heterozygous for 1 of the mutations.