Clinical characteristics: NOTCH3-related lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through spinal foramina), distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies. Neurologic sequelæ of the meningoceles depend on size and location and can include neurogenic bladder, paresthesia, back pain, and/or paraparesis. Other neurologic findings can include Chiari I malformation, syringomyelia, and rarely, hydrocephalus. Additional findings of LMS include developmental delay, mixed or conductive hearing loss, and cleft palate. Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones. Infants may demonstrate feeding difficulties with poor weight gain.
Diagnosis/testing: The diagnosis of NOTCH3-related LMS syndrome is established in a proband with consistent clinical findings and a heterozygous pathogenic variant in NOTCH3.
Management: Treatment of manifestations: Surgical intervention of lateral spinal meningoceles is generally avoided, but may be necessary due to neurologic manifestations secondary to meningocele size and location. Symptomatic treatment of neurologic sequelae of lateral meningoceles (neurogenic bladder, paresthesias, back pain, and/or paraparesis) provided as needed. As needed: timely supportive interventions to optimize development; management by specialists in chronic pain management or rehabilitation medicine; physiotherapy to reduce the risk for joint subluxation and dislocation. Routine management of: cleft palate, cardiovascular issues, genitourinary abnormalities, ophthalmologic issues, hearing loss, feeding difficulties.
Surveillance: Close clinical and radiographic monitoring for progressive neurologic symptoms and increase in meningocele size; an initial yearly scan to monitor for stability and subsequent spacing to every two years if meningoceles are small in size. Ongoing monitoring by the appropriate subspecialists for developmental, musculoskeletal, cardiovascular, genitourinary, gastrointestinal, ophthalmologic, and/or hearing issues.
Genetic counseling: All probands reported to date with NOTCH3-related LMS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo NOTCH3 pathogenic variant. Each child of an individual with NOTCH3-related LMS has a 50% chance of inheriting the pathogenic variant. Once the NOTCH3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for NOTCH3-related LMS are possible.
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