Sphingosine Phosphate Lyase Insufficiency Syndrome

Excerpt

Clinical characteristics: Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is characterized by varying combinations of steroid-resistant nephrotic syndrome (ranging from nonimmune fetal hydrops to adolescent onset), primary adrenal insufficiency (with or without mineralocorticoid deficiency), testicular insufficiency, hypothyroidism, ichthyosis, lymphopenia/immunodeficiency, and neurologic abnormalities that can include developmental delay, regression / progressive neurologic involvement, cranial nerve deficits, and peripheral motor and sensory neuropathy.

Diagnosis/testing: The diagnosis of SPLIS is established in a proband with at least one suggestive finding and biallelic pathogenic variants in SGPL1 identified by molecular genetic testing.

Management: Treatment of manifestations: Multidisciplinary management of steroid-resistant nephrotic syndrome, endocrine involvement, immunodeficiency, poor weight gain / feeding issues, developmental delay / intellectual disability, neurologic involvement, hearing loss, ichthyosis.

Surveillance: Routine follow up as requested by specialty care providers and routine monitoring of development progress and educational needs.

Agents/circumstances to avoid: Nephrotoxic medications; medications that require renal excretion (individuals with renal insufficiency); live vaccines, exposure to infectious agents, and transfusion products that have not been irradiated.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and awareness of agents and circumstances to avoid.

Genetic counseling: SPLIS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SGPL1 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 SGPL1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.