Schimke Immunoosseous Dysplasia

Clinical characteristics: Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease. The majority of tested individuals have T cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated.

Diagnosis/testing: The diagnosis of SIOD is established in a proband with the characteristic clinical, laboratory, and radiographic features and/or biallelic pathogenic variants in SMARCAL1 identified on molecular genetic testing.

Management: Treatment of manifestations: Treatment of scoliosis and kyphosis per orthopedist; pain management and hip replacement as needed in older individuals for degenerative hip disease; standard treatments for osteopenia; consider cyclosporin A, tacrolimus, or corticosteroids for renal disease; renal transplantation as indicated using mild immunosuppressive therapy; acyclovir for recurrent herpetic infections and/or shingles; imiquimod and cidofovir for severe disseminated cutaneous papilloma virus infections; vaccine protocol (avoidance of live vaccines as for T cell immunodeficiency); consider antibiotic prophylaxis for Pneumocystis jirovecii pneumonia; granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for neutropenia; hematopoietic stem cell transplantation as indicated; immunosuppressive therapy for those with autoimmune manifestations; thrombopoietin receptor agonists; transfusions when indicated for thrombocytopenia and/or anemia; standard treatment of dental manifestations; developmental support as needed; medical therapy for migraine headaches as needed; agents that improve blood flow or decrease coagulability to treat transient ischemic attacks or strokes; blood pressure control; levothyroxine for hypothyroidism; treatment of malignancy per oncologist.

Surveillance: Annually: monitor growth; monitor for scoliosis/kyphosis and hip degeneration; monitor renal, immune, and hematologic status; assess for enteropathy, dental issues, and developmental concerns; assess for headaches or neurologic abnormalities; thyroid function studies; complete blood count with differential, complete metabolic panel, T and B cell flow cytometry, abdominal ultrasound, and clinical evaluation for lymphadenopathy to monitor for malignancy. At each visit: monitor blood pressure.

Agents/circumstances to avoid: Avoid hypertension; heat, stress, and lack of sleep; and live attenuated immunizations in those who are T cell deficient. Use DNA-damaging anti-cancer therapies with caution due to evidence of susceptibility to genotoxic agents.

Genetic counseling: SIOD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a SMARCAL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic SMARCAL1 pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SMARCAL1 pathogenic variants. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.