INPPL1-Related Opsismodysplasia

Excerpt

Clinical characteristics: INPPL1-related opsismodysplasia is characterized by prenatal-onset short stature, short, bowed limbs, characteristic facial features (relative macrocephaly, prominent forehead, midface retrusion, depressed nasal bridge, short nose, anteverted nares, relatively long philtrum), narrow thorax, small hands and feet, delayed epiphyseal mineralization, metaphyseal cupping, and platyspondyly. Complications include increased risk of fractures, cervical spine abnormalities, scoliosis, bone pain, respiratory issues, and delayed gross motor skills. Some individuals have cardiac or kidney manifestations. Prognosis is variable with perinatal demise in some infants.

Diagnosis/testing: The diagnosis of INPPL1-related opsismodysplasia is established in a proband with characteristic clinical and radiographic features and biallelic pathogenic variants in INPPL1 identified by molecular genetic testing.

Management: Targeted therapy: Intravenous bisphosphonate therapy has improved bone mineral density and gross motor function in two individuals with INPPL1-related opsismodysplasia.

Supportive care: Cervical spine complications should be managed by specialists familiar with skeletal dysplasias involving the spine including an orthopedist and neurosurgeon; surgical stabilization should be performed to prevent progressive myelopathy; management of scoliosis per orthopedist with surgery when indicated; management of hypophosphatemia, renal phosphate wasting, and bone demineralization per endocrinologist; treatment of respiratory insufficiency per pulmonologist; vaccines to prevent respiratory illnesses; CPAP and surgical management as needed for sleep apnea; feeding therapy with modification of fluid or food texture as needed for swallowing difficulties; aerodigestive evaluation for endoscopy and surgery as needed; management of cardiac manifestations per cardiologist; management of renal manifestations per nephrologist and/or urologist; amplification/hearing device and/or surgery when indicated for hearing impairment; social work and family support.

Surveillance: Flexion/extension cervical spine MRI every three months until cervical instability can be excluded in those with instability, risk of cervical cord compression, or limited radiograph interpretation; then MRI every two to three years, preoperatively, and when indicated. Clinical examination for scoliosis every six to 12 months with radiographs when indicated; endocrinology evaluation for hypophosphatemia and renal phosphate wasting every six to 12 months and when indicated; DXA scan when indicated; pulmonary function studies, chest radiographs, swallowing evaluation, and sleep study every six to 12 months and when indicated per pulmonologist; swallowing evaluation as indicated to evaluate for aspiration; developmental assessment to assess gross motor skills annually or as needed; rehabilitation medicine, physical therapy, and occupational therapy consultations when indicated to evaluate function and need for adaptive devices and to support activities of daily living and mobility; clinical cardiac examination with frequency per cardiologist; audiology evaluation annually or as needed; ENT and orthodontic evaluations as needed; assess family and social work needs at each visit.

Agents/circumstances to avoid: Individuals with cervical spine instability or who are at risk for cervical spine instability should avoid extreme neck flexion and extension, contact sports, and other at-risk activities. Individuals with bone demineralization should avoid contact sports and other activities associated with an increased risk for fractures.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of targeted therapy.

Genetic counseling: INPPL1-related opsismodysplasia is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an INPPL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the INPPL1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.