Weaver Kathryn Nicole, Sullivan Bonnie, Hildebrandt Friedhelm, Strober Jonathan, Cooper Megan, Prasad Rathi, Saba Julie
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Children's Mercy Kansas City, Kansas City, Missouri
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 identified by molecular genetic testing.
Multidisciplinary management of steroid-resistant nephrotic syndrome, endocrine involvement, immunodeficiency, poor weight gain / feeding issues, developmental delay / intellectual disability, neurologic involvement, hearing loss, ichthyosis. Routine follow up as requested by specialty care providers and routine monitoring of development progress and educational needs. 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. 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.
SPLIS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an 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 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.
鞘氨醇磷酸裂解酶缺乏综合征（SPLIS）的特征是多种症状的不同组合，包括激素抵抗性肾病综合征（范围从非免疫性胎儿水肿到青少年发病）、原发性肾上腺功能不全（伴或不伴盐皮质激素缺乏）、睾丸功能不全、甲状腺功能减退、鱼鳞病、淋巴细胞减少/免疫缺陷以及神经学异常，后者可包括发育迟缓、退化/进行性神经受累、颅神经缺陷以及周围运动和感觉神经病变。
诊断/检测：在一个先证者中，如果通过分子基因检测发现至少有一项提示性发现以及双等位基因致病性变异，即可确立SPLIS的诊断。
对激素抵抗性肾病综合征、内分泌受累、免疫缺陷、体重增加不良/喂养问题、发育迟缓/智力残疾、神经受累、听力丧失、鱼鳞病进行多学科管理。按照专科护理人员的要求进行常规随访，并对发育进展和教育需求进行常规监测。避免使用肾毒性药物；需要经肾脏排泄的药物（肾功能不全者）；活疫苗、接触传染源以及未经过辐照的输血产品。为受影响个体的明显无症状的年长和年幼高危同胞明确基因状态是合适的，以便尽早识别那些将从及时开始治疗中获益的个体，并了解应避免的药物和情况。
SPLIS以常染色体隐性方式遗传。如果已知父母双方均为某一致病性变异的杂合子，受影响个体的每个同胞在受孕时有25%的几率受到影响，50%的几率为无症状携带者，25%的几率不受影响且不是携带者。一旦在受影响的家庭成员中确定了致病性变异，就可以对高危亲属进行携带者检测、对高风险妊娠进行产前检测以及进行植入前基因检测。
