Typically congenital or infantile-onset, often associated with focal segmental glomerulosclerosis.

⚬ T-cell lymphopenia or pan lymphopenia. Low absolute lymphocyte counts; low CD3, CD4, CD8 T-cell subsets with or without low absolute B- and NK-cell counts⚬Low-to-normal immunoglobulins
⚬ Abnormal TREC (T-cell receptor excision circle) newborn screening test (on occasion)
⚬ Normal or impaired T-cell functional assays, proliferation, and response to vaccinations

⚬ Cranial nerve deficits
⚬ Sensorineural hearing loss
⚬ Developmental delay
⚬ Regression / progressive neurologic involvement
⚬ Upper motor neuron involvement presenting as weakness and/or spasticity
⚬ Lower motor neuron involvement including motor and sensory neuropathy
⚬ Seizures (generalized or complex partial)

Increased sphingosine-1-phosphate and/or other sphingolipids on plasma metabolic analysis. In most individuals, specialized tests were obtained by tandem mass spectrometry-based analysis under research protocols. However, accumulation of sphingolipid intermediates may be detected on a comprehensive plasma/serum metabolomics profiling test designed to capture a broad range of small molecules.

Enlarged kidneys or adrenal glands, calcifications of adrenal gland.

⚬ Primary adrenal insufficiency (low cortisol with normal or high ACTH). Typically, glucocorticoid deficiency; some individuals also have mineralocorticoid deficiency.
⚬ Testicular insufficiency (increased gonadotropins, poor response to LH stimulation); typically manifest in newborns as micropenis and cryptorchidism or microorchidism
⚬ Primary hypothyroidism (low-to-normal free thyroxine levels with increased thyroid stimulating hormone)

Ichthyosis, often generalized and present at birth. Acanthosis/hyperpigmentation including conjunctival hyperpigmentation can also be seen.

Nonspecific abnormalities can include structural brain anomalies (most commonly agenesis or dysgenesis of the corpus callosum) abnormal deep gray nuclei, involvement of dopaminergic neurons, microcephaly, prominent involvement of basal ganglia, cortical atrophy, and/or progressive worsening and expansion of brain lesions observed on T2-weighted or FLAIR images.

It is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). There may be family history of unexplained fetal loss or nonimmune fetal hydrops. Absence of a known family history does not preclude the diagnosis.