Metatropic dysplasia (ORPHA:2635)
Metatropic dysplasia (MTD) is a rare spondyloepimetaphyseal dysplasia characterized by a long trunk and short limbs in infancy followed by severe and progressive kyphoscoliosis causing a reversal in proportions during childhood (short trunk and long limbs) and a final short stature in adulthood.
Epidemiology
The prevalence is unknown. Approximately 81 cases have been reported in the literature to date.
Clinical description
The phenotypic spectrum of MTD is variable with severe cases being lethal in utero, or shortly after birth, and others having only milder skeletal changes. Infants present at birth with a long trunk and short limbs. Craniofacial abnormalities can also be noted and include a prominent forehead, midface hypoplasia, and a squared-off jaw. Some are born with an elongation of the coccyx and rarely reported additional findings include sensorineural hearing loss. Rapidly progressive kyphoscoliosis appears during childhood and a reversal in proportions is seen with a shortening of the trunk and relatively long extremities. Kyphoscoliosis can lead to thorax deformities and to a decrease in pulmonary function and respiratory distress that can be fatal. The small joints are usually hypermobile while contractures of the large joints are not uncommon and are usually progressive. Severe kyphoscoliosis and possible atlantoaxial instability can lead to myelopathy. Adults reach an average height of 107-135 cm. Intelligence is normal.
Etiology
MTD is due to mutations in the transient receptor potential vanilloid 4 (TRPV4) gene (12q24.1) encoding a polymodal Ca2+ permeable cation channel found in a variety of tissues. Mutations in this gene cause an increase in calcium in the chondrocytes and consequently disrupted endochondral ossification and the clinical manifestations of MTD.
Diagnostic methods
Diagnosis is based on clinical and radiological findings. Radiological findings include short diaphyses with wide metaphyses, marked platyspondyly, precocious calcification of hyoid and cricoid cartilage, halberd shaped pelvis, severe hypoplasia of the anterior part of the first cervical vertebrae and squared-off, irregular calcaneal bones. Radiological manifestations change at different ages. Molecular genetic testing can identify a mutation in the TRPV4 gene, confirming diagnosis.
Differential diagnosis
Differential diagnoses include mucopolysaccharidosis type IV and other types of spondylometaphyseal dysplasia, in particular spondylometaphyseal dysplasia, Kozlowski type (see these terms), an allelic disorder that shows important overlap with mild MD cases.
Antenatal diagnosis
Prenatal diagnosis is possible through genetic testing and prenatal assessment (with a 3D computed tomography scan or ultrasound) and should be offered when a mutation in the family is known.
Genetic counseling
MTD is inherited autosomal dominantly and genetic counseling is possible. Parents with MTD have a 50% risk of passing the disease on to their offspring. Many cases occur de novo, but in families with no history of the disease, germline mosaicism cannot be excluded.
Management and treatment
Treatment is targeted at possibly avoiding the progression of skeletal deformity and maintaining pulmonary function. Standard practice includes bracing until skeletal maturity is reached. A conservative approach is usually preferred, but surgical procedures (i.e. corrective spine surgery with posterior fusion) can be successful in some cases in halting deformity. Preoperative evaluation of pulmonary function is mandatory before any invasive procedure is considered. Regular follow-up should monitor for any breathing difficulties or signs of myelopathy. A tracheostomy and long-term ventilatory support may be necessary in severe cases.
Prognosis
The prognosis varies on the severity of the disease. Life expectancy is not usually affected unless there are respiratory complications.

                            Last update: 
                            January 2014


                            - Expert reviewer(s): 
                            Dr Elena ANDREUCCI