Clinical characteristics: MBTPS1-related spondyloepimetaphyseal dysplasia with elevated lysosomal enzymes (MBTPS1-SEMD) is characterized by postnatal-onset short stature, chest deformity (pectus carinatum or pectus excavatum), kyphosis and/or scoliosis, reduced bone density, inguinal hernia, protruding abdomen, cataracts, developmental delay, and dysmorphic facial features (prominent forehead, prominent cheekbones, retromicrognathia, wide mouth, and large, prominent ears). Additional features can include waddling or staggering gait, craniosynostosis, mild intellectual disability, and seizures. Imaging findings include diffuse osteopenia, copper-beaten appearance of the skull, dysplasia of multiple thoracolumbar vertebrae, long bones with small and irregular epiphyses and mildly enlarged and irregular metaphyses, hip dysplasia with small fragmented sclerotic femoral heads, and short metacarpals and metatarsals with small epiphyses. Increased concentration of multiple lysosomal hydrolase enzymes can be identified in plasma and dried blood spots.

Diagnosis/testing: The diagnosis of MBTPS1-SEMD is established in a proband with characteristic clinical and radiographic findings, elevated lysosomal hydrolase enzymes in plasma or dried blood spots, and biallelic pathogenic variants in MBTPS1 identified by molecular genetic testing.

Management: Treatment of manifestations: Management of kyphoscoliosis, scoliosis, and hip dysplasia per orthopedist; vitamin D and calcium for reduced bone density; treatment of craniosynostosis per craniofacial specialist; surgical repair per surgeon and/or gastroenterologist for hernia; surgical removal of cataract per ophthalmologist; physical therapy to maximize mobility and reduce the risk for later-onset orthopedic complications; developmental and educational support.

Surveillance: Annual growth assessment, orthopedic evaluation, ophthalmological evaluation, and assessment of developmental progress and educational needs; clinical assessment for hernia as needed.

Agents/circumstances to avoid: In children with significant kyphoscoliosis, sports that place stress on the spine (e.g., heavy lifting, weight-bearing exercises) should be avoided.

Pregnancy management: Although no pregnancies have been reported in individuals with MBTPS1-SEMD, pregnancy and delivery may be complicated in individuals with significant short stature and skeletal dysplasia; delivery by cesarean section may be necessary.

Genetic counseling: MBTPS1-SEMD is inherited in autosomal recessive manner. If both parents are known to be heterozygous for an MBTPS1 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 MBTPS1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.