TRPV4 related skeletal disorders
Heterozygous mutations in the transient receptor potential cation channel, subfamily V, member 4 gene (TRPV4) have been shown to be responsible for spondyloepiphyseal dysplasia, Maroteaux type (MIM 184095), brachyolmia type 3 (MIM 113500), spondylometaphyseal dysplasia, Kozlowski type (SMDK; MIM 184252), metatropic dysplasia (MIM 156530), parastremmatic dwarfism (MIM 168400), and digital arthropathy-brachydactyly, familial (FDAB; MIM 606835). This gene encodes a channel molecule involved in calcium ion homeostasis.
Spondyloepiphyseal dysplasia, Maroteaux type, also known as pseudo-Morquio syndrome, type 2 is an autosomal dominant skeletal dysplasia. Affected individuals have a normal birth weight and length but display progressive shortening of the trunk resulting in extreme short stature. Additional findings include platyspondyly, brachydactyly, genu valgum, cubitus valgus, broad pelvis, enlarged joints and dysplastic changes of the femoral neck.
Brachyolmia type 3 is an autosomal dominant disorder. It is characterized by a normal length at birth and the development of short-trunk short stature early in childhood due to marked platyspondyly. Vertebrae may also display overfaced pedicles. Additionally, patients typically have scoliosis, kyphosis, mild brachydactyly and mildly shortened limbs with proximal femoral epiphyseal abnormalities. Some have delayed carpal ossification and some display mild femoral metaphyseal changes.
Spondylometaphyseal dysplasia, Kozlowski type is another postnatal short stature disorder. Inheritance is autosomal dominant. Affected individuals share findings with brachyolmia, autosomal dominant but display a more severe phenotype. Patients have significant progressive kyphoscoliosis, metaphyseal irregularities, short neck, pectus carinatum and genu varus. Additional findings include generalized platyspondyly, odontoid hypoplasia, short square ilia, flat acetabular roofs, wide femoral epiphyseal plates and markedly delayed carpal bone ossification. Patients are usually diagnosed after age two when a waddling gait is noticed.
Metatropic dysplasia is an autosomal dominant disorder. Newborns display a long narrow trunk that evolves into a progressive and severe kyphoscoliosis and a coccygeal tail due to excessive coccyx ossification. Limbs are foreshortened. Facial features include a prominent forehead and squared-off jaw. Other findings may include odontoid hypoplasia, cervical myelopathy and deafness. Radiological findings include wafer-like vertebral bodies in newborns and a halberd (battleax) shaped pelvis. Brachydactyly with delayed carpal ossification and flared proximal and distal femoral metaphyses may also be seen. Mutations in TRPV4 have been described in both non-lethal and lethal forms of metatropic dysplasia.
Parastremmatic dwarfism is an autosomal dominant disorder recognized in the first 6 to 12 months of life. It is characterized by symmetric deformities of the legs, severe genu valgum, bowed long bones with twisting along the axis, a short neck, kyphoscoliosis, contractures and reduced adult height. Full manifestations occur by 10 years of age. Radiographs show coarse bone trabeculations with areas of irregular, dense stippling and streaking giving the metaphyses of the long bones a unique "woolly" appearance. Platyspondyly, a lace-like border of the iliac crests and metaphyseal flaring have also been noted.
Familial digital arthropathy-brachydactyly is an aggressive, autosomal dominant osteoarthropathy with clinical findings confined to the hands and feet. Patients appear normal at birth but exhibit changes in the proximal articular surfaces of the distal interphalangeal joints during the first decade. Eventually all interphalangeal, metacarpophalangeal and metatarsophalangeal joints are affected by the progressive arthropathy resulting in brachydactyly and deformity of the middle and distal phalanges. The hands are usually more affected than the feet.
TRPV4 related neuromuscular disorders
Spinal muscular atrophy, distal, congenital nonprogressive (MIM 600175), scapuloperoneal spinal muscular atrophy (SPSMA; MIM181405), and hereditary motor and sensory neuropathy, type IIC (HMSN2C; Charcot-Marie-Tooth neuropathy, type 2C; CMT2C; MIM 606071) are autosomal dominant disorders of the peripheral nervous system caused by mutations in the transient receptor potential cation channel, subfamily V, member 4 gene (TRPV4). Although distinct, all of these disorders are characterized by proximal and distal muscle weakness and wasting.
Congenital distal spinal muscular atrophy is a nonprogressive lower motor neuron disorder with variable findings that are primarily restricted to the lower part of the body. Severely affected individuals have paralysis of the upper and lower leg muscles, associated muscle atrophy, weakness of the pelvic girdle and trunk muscles resulting in scoliosis and decreased or absent reflexes without sensory abnormalities. Arthrogryposis is a common finding.
SPSMA is a more severe disorder characterized by congenital absence of muscles, progressive scapuloperoneal atrophy with distal weakness and amyotrophy. Some individuals have laryngeal palsy resulting in a hoarse voice and respiratory stridor, facial paresis, weakness of both the proximal and distal muscles of the upper and lower limbs, scoliosis and hip dysplasia. SPSMA seems to be more severe and progressive in males and in succeeding generations (anticipation).
HMSN2C shares features with both congenital distal spinal muscular atrophy and SPSMA, including distal limb weakness and muscle atrophy due to peripheral neuropathy. However, HMSN2C patients have foreshortened life expectancy in severely affected patients due to respiratory failure resulting from intercostal muscle and diaphragm involvement. A further distinction is distal sensory impairment. Additional features may include, vocal cord paresis with hoarse voice, eye muscle palsy, shoulder girdle muscle atrophy, wasting of hand muscles with impaired manual dexterity, involvement of proximal limb muscles, foot drop, areflexia/hyporeflexia, and bladder urgency with incontinence. Patients with HMSN2C may have difficulties with activities of daily living and may become wheelchair bound.
The TRPV4 gene encodes a cation channel protein that mediates calcium influx in response to various stimuli including hypotonicty, mechanical stress and heat. TRPV4 mutations have been identified in several families whose members have phenotypes consistent with one or more of the above disorders. The mutations all result in amino acid substitutions in the region of the ankyrin domains of TRPV4. The ankyrin region is thought to regulate protein-protein interactions and to be involved in TRPV4 channel assembly.