Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is characterized by varying combinations of steroid-resistant nephrotic syndrome, primary adrenal insufficiency (with or without mineralocorticoid deficiency), testicular insufficiency, immunodeficiency, and neurologic abnormalities, and may also include primary hypothyroidism and ichthyosis. Patients may have only one of the typical manifestations (such as renal or peripheral nerve involvement) and still have SPLIS.
To date, 46 individuals with sphingosine phosphate lyase insufficiency syndrome (SPLIS) have been reported around the world.
The range of renal involvement extends from nonimmune fetal hydrops at the severe end to delayed evidence of nephrosis for many years after diagnosis or no renal involvement after years of follow up, as observed in two sibs in their twenties and thirties. Typically, the nephrotic syndrome is congenital or occurs during infancy, is unresponsive to steroids, and progresses rapidly to end-stage renal disease within one year. The oldest age of diagnosis of nephrotic syndrome among the 46 reported individuals is 18 years.
Six affected individuals underwent renal transplantation: two at age five years; one at age five years and again at age 12 years; and one at age eight years. Age at transplant of the other two individuals was not provided; however, at time of last update one was age 8.4 years and the other 17.5 years.
Primary adrenal insufficiency may occur with or without adrenal calcifications, and may present as an Addisonian crisis requiring emergent treatment with corticosteroid and electrolyte replacement therapy. All individuals with primary adrenal insufficiency have glucocorticoid deficiency; some also have mineralocorticoid deficiency.
Testicular insufficiency is suspected in newborns with micropenis, cryptorchidism, or microorchidism. Hormone studies show low baseline levels of testosterone, no increase in testosterone levels in response to human chorionic gonadotropin (HCG), exaggerated gonadotropin response to luteinizing hormone-releasing hormone test in early infancy, low müllerian inhibitory factor, and low serum levels of inhibin B.
Hypothyroidism. The age of onset is unknown. Endocrine studies show low or normal T4, high TSH. Thyroxine replacement is necessary.
Lymphopenia. Among individuals with SPLIS, the lower incidence of lymphopenia compared to nephrotic syndrome, adrenal insufficiency, and neurologic defects may be due to failure to recognize and report the presence of asymptomatic lymphopenia in the earliest descriptions of this disorder.
Lymphopenia, usually with residual T cell function, with or without other lymphocyte deficiencies.
Cranial nerve deficits can affect cranial nerves III, IV, VI manifesting as ptosis, strabismus, esotropia, and/or amblyopia.
Developmental delay. Some children demonstrate normal development for a period of time and achieve expected milestones as indicated by Denver Developmental Screening Test, followed by impaired acquisition of new skills. For the majority of reported individuals, detailed information about developmental progression is not available.
Regression / progressive neurologic changes. Some individuals demonstrate normal development for a period of time without signs of neurologic impairment, followed by delay in gross motor, language, and social skill development, and subsequently by a loss of skills and function (gait, language, and social interaction). This regression is often associated with progressive MRI changes and can progress to generalized hypotonia, seizures, and death.
• One individual was hospitalized on numerous occasions due to gastrointestinal symptoms with no identified infectious etiology.
• In some instances, affected infants were below normal weight, often in association with severe illness requiring hospitalization. Failure to thrive may be the presenting complaint, and may be associated with adrenal insufficiency, nephrotic syndrome, or poor feeding.
• Rare skeletal abnormalities have been observed (craniotabes, short stature, rachitic rosary sign, scoliosis, asymmetric skull). Scoliosis may be secondary to neurologic defects.
• Rarely: intestinal malrotation; pericardial effusion, dilated cardiomyopathy, dysmorphic features (hypertelorism, down-slanting palpebral fissures).
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