Sphingosine Phosphate Lyase Insufficiency Syndrome
Summary
Clinical characteristics.
Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is characterized by varying combinations of steroid-resistant nephrotic syndrome (ranging from non-immune 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/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.
Diagnosis
Suggestive Findings
Sphingosine phosphate lyase insufficiency syndrome (SPLIS) should be suspected in individuals with any combination of the following clinical, laboratory, and imaging findings and family history.
Clinical findings
- Steroid-resistant nephrotic syndrome. Typically congenital or infantile-onset, often associated with focal segmental glomerulosclerosis
- Endocrine
- 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)
- Immunodeficiency
- 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
- Neurologic abnormalities including:
- 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)
- Skin. Ichthyosis, often generalized and present at birth. Acanthosis/hyperpigmentation including conjunctival hyperpigmentation can also be seen.
Laboratory findings. 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 [Guerrero et al 2018]. Increased plasma sphingosine/dihydrosphingosine ratio may be observed.
Imaging findings
- Brain MRI. 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 [Martin et al 2020]. One individual had generalized cortical atrophy, simplified gyral pattern, hypoplastic temporal lobe, and cerebellar hypoplasia [Bamborschke et al 2018].
- Abdominal ultrasound. Enlarged kidneys or adrenal glands, calcifications of adrenal gland
Family history 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.
Establishing the Diagnosis
The diagnosis of sphingosine phosphate lyase insufficiency syndrome (SPLIS) is established in a proband with at least one suggestive finding and biallelic pathogenic variants in SGPL1 identified by molecular genetic testing (see Table 1).
Note: Identification of biallelic SGPL1 variants of uncertain significance (or identification of one known SGPL1 pathogenic variant and one SGPL1 variant of uncertain significance) does not establish or rule out a diagnosis of SPLIS.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of SPLIS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
Single-gene testing. Sequence analysis of SGPL1 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step typically is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; to date, however, such variants have not been identified as a cause of this disorder.
A steroid-resistant nephrotic syndrome, hereditary neuropathy, or primary adrenal insufficiency multigene panel that includes SGPL1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of sphingosine phosphate lyase insufficiency syndrome, some panels for steroid-resistant nephrotic syndrome, hereditary neuropath,y and/or primary adrenal insufficiency may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date such variants have not been identified as a cause of this disorder.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Sphingosine Phosphate Lyase Insufficiency Syndrome
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| SGPL1 | Sequence analysis 3 | All reported 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Atkinson et al [2017], Janecke et al [2017], Lovric et al [2017], Prasad et al [2017], Bamborschke et al [2018], Linhares et al [2018], Saygili et al [2019a], Saygili et al [2019b], Settas et al [2019], Zhao et al [2020]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
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 (Table 2).
To date, 46 individuals with sphingosine phosphate lyase insufficiency syndrome (SPLIS) have been reported [Atkinson et al 2017, Janecke et al 2017, Lovric et al 2017, Prasad et al 2017, Bamborschke et al 2018, Linhares et al 2018, Saygili et al 2019a, Settas et al 2019, Taylor et al 2019, Maharaj et al 2020, Zhao et al 2020]. Of note, the individual reported by Taylor et al [2019] is also included in the report by Zhao et al [2020]. The following description of the phenotypic features of SPLIS is based on these reports.
Table 2.
Features of Sphingosine Phosphate Lyase Insufficiency Syndrome
| Feature | # of Persons | Comment | |
|---|---|---|---|
| Steroid-resistant nephrotic syndrome | 37/46 | ||
| Endocrine | Primary adrenal insufficiency | 31/46 | 5 who also had mineralocorticoid deficiency 1 |
| Testicular insufficiency | 8/26 w/cryptorchidism &/or micropenis | ||
| Hypothyroidism | 6/46 | ||
| Immunodeficiency | 31/46 | ||
| Neurologic abnormalities | 22/46 |
| |
| Sensorineural hearing loss | 8/45 | ||
| Ichthyosis/acanthosis | 13/46 | ||
- 1.
Prasad et al [2017], Linhares et al [2018], Maharaj et al [2020]
Nephrotic Syndrome
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 [Atkinson et al 2017]. 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 [Lovric et al 2017].
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.
Pathology of renal biopsies is usually consistent with glomerulosclerosis, especially with focal segmental glomerulosclerosis and ultrastructural finding of podocyte foot-process effacement. Three affected individuals had collapsing variant focal segmental glomerulosclerosis, a subclassification associated with rapid disease progression [Zhao et al 2020]. Some individuals had a pathologic diagnosis of diffuse mesangial sclerosis. Focal tubular dilation, diffuse IgM staining, foci of calcification, lipid or hyaline droplets, perivascular sclerosis, and hypertrophic blood vessel walls have been reported in some renal biopsies.
Endocrine Involvement
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.
Most individuals with adrenal insufficiency have become symptomatic in the first decade of life. The oldest reported age of onset was 11 years [Lovric et al 2017].
Adrenal calcifications or enlargement, which may be seen prenatally, are likely a risk factor for adrenal insufficiency [Janecke et al 2017, Zhao et al 2020].
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.
Multiple individuals with SPLIS have experienced frequent infections including several whose cause of death was related to infection [Lovric et al 2017, Bamborschke et al 2018, Saygili et al 2019b, Zhao et al 2020]. Most individuals who died of sepsis had experienced prolonged hospitalizations, complex courses, and other risk factors for infection.
To date, two individuals with SPLIS have had abnormal TREC (T-cell receptor excision circle) on newborn screening. In one, absolute lymphocyte count was low with distorted distribution of naive to memory cells and low B and NK cell counts; IgG levels were not determined; immune response to vaccinations was protective. In the other, absolute lymphocyte count was low with low absolute CD3 T cells and normal B and NK cell counts; IgG levels were low; immune response to vaccinations was not determined [Zhao et al 2020].
Neurologic Abnormalities
Cranial nerve deficits can affect cranial nerves III, IV, VI manifesting as ptosis, strabismus, esotropia, and/or amblyopia.
Cranial nerve VIII involvement manifests as sensorineural hearing loss. The loss may be congenital or diagnosed later in the first decade; it can be progressive and severe, and unilateral or bilateral (e.g., bilateral, upward sloping with air-bone gap at 500 Hz).
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.
Age of onset of deterioration and type of first manifestation are variable, in some cases as young as 12 months (case 4 in Zhao et al [2020]) and as old as 25 years (ptosis [Lovric et al 2017]). Some individuals have no reported neurologic impairment.
Peripheral neuropathy manifestations can be any of the following:
- Acute or subacute onset
- Mononeuropathy or polyneuropathy involving upper or lower limbs, often distal
- Median or ulnar paralysis
- Absent reflexes
- Sensory neuropathy, transient pain, loss of vibration sense
- Spontaneous resolution that is complete or with residual deficits
- Progression leading to muscle wasting, contractures, scoliosis, hemiparesis
In two sisters who had no other manifestations of SPLIS, the following were observed [Atkinson et al 2017]:
- Nerve conduction studies showed undetectable compound muscle and sensory nerve action potentials;
- EMG showed spontaneous activity and a neuropathy pattern;
- Axonal neuropathy was demonstrated by axonal disintegration on sural nerve biopsy in one sib.
Seizures. Generalized and complex partial seizures may be associated with adrenal insufficiency, hypoglycemia, or progressive neurologic disease.
Microcephaly (n=4). Usually reported without details or neuroradiologic measurements of brain size. In one individual with additional brain developmental defects, occipitofrontal head circumference was recorded at 31.5 cm at age two weeks (i.e., <3rd centile) [Bamborschke et al 2018].
Other
- 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).
Ichthyosis/acanthosis. Ichthyosis may present at birth or later. Hyperpigmentation has been a presenting manifestation in numerous individuals usually as a consequence of primary adrenal insufficiency. Skin biopsies have shown thinned epidermis with hyperkeratosis and decreased granular layer of skin.
Abnormalities noted prenatally in 14/15 pregnancies included nonimmune hydrops, adrenal calcifications, and increased nuchal translucency. There have been several instances of intrauterine fetal demise.
Genotype-Phenotype Correlations
Genotype-phenotype correlations are not fully defined for SPLIS.
Intrafamilial variability is observed as the clinical manifestations and age of onset can vary within the same family in which affected individuals have the same SGPL1 pathogenic variants. For example, some can be a fetal loss, whereas others develop manifestations in infancy or later in childhood.
Prevalence
The prevalence of SPLIS is unknown. To date, approximately 46 individuals with SPLIS have been reported. The total number of reported individuals depends on whether or not sibs of index cases whose presentations are consistent with the diagnosis of SPLIS (but without molecular genetic confirmation) were counted.
Differential Diagnosis
Table 3.
Genes of Interest in the Differential Diagnosis of Sphingosine Phosphate Lyase Insufficiency Syndrome
| Gene(s) | DiffDx Disorder(s) | MOI | Features of the DiffDx Disorder | |
|---|---|---|---|---|
| Overlapping w/SPLIS | Distinguishing from SPLIS | |||
| ALDH3A2 | Sjögren-Larsson syndrome 1 | AR | Ichthyosis; intellectual disability; abnormal brain MRI | Spasticity; lack of kidney involvement |
| GBA | Gaucher disease type 2 | AR | Ichthyosis; nonimmune hydrops; abnormal brain MRI | Hepatosplenomegaly; pancytopenia |
| LAMB2 | Pierson syndrome (OMIM 609049) | AR | Steroid-resistant nephrotic syndrome; developmental delay | Microcoria |
| LIPA | Lysosomal acid lipase deficiency | AR | Adrenal calcifications | Hepatic fibrosis & cirrhosis; intestinal malabsorption |
| LMX1B | Nail-patella syndrome | AD | Steroid-resistant nephrotic syndrome; sensorineural hearing loss | Nail dysplasia; hypoplastic or absent patellae; eye anomalies |
| NPHS1 NPHS2 PLCE1 | Congenital nephrotic syndrome types 1, 2, & 3 (OMIM 256300, 600995, 610725) | AR | Steroid-resistant nephrotic syndrome | Absence of additional syndromic findings |
| SMARCAL1 | Schimke immunoosseous dysplasia | AR | Steroid-resistant nephrotic syndrome; T-cell lymphopenia | Spondyloepiphyseal dysplasia; numerous lentigines |
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; SPLIS = sphingosine phosphate lyase insufficiency syndrome
- 1.
Cho et al [2018]
Table 4.
Differential Diagnosis of Clinical Findings Associated with Sphingosine Phosphate Lyase Insufficiency Syndrome
| Clinical Finding | Distinguishing Features | Comment |
|---|---|---|
| Motor/sensory neuropathy | Often autosomal dominant | See Charcot-Marie-Tooth Hereditary Neuropathy Overview. |
| Congenital ichthyosis | Acanthosis may be observed in SPLIS. |
|
| Nonimmune hydrops | Enlarged/hemorrhagic adrenals | Many genetic conditions are assoc w/fetal hydrops (e.g., chromosome anomalies, RASopathies, & lysosomal storage disorders). 1 |
| Primary adrenal insufficiency | Adrenal calcifications, hypothyroidism, cryptorchidism, & micropenis may be assoc w/primary adrenal insufficiency. |
|
| Primary immunodeficiency / T-cell lymphopenia (CD4 & CD8) w/or w/o low B & NK cells | Persons w/SPLIS have lymphopenia w/↓ T cells & frequently low B & NK cells; however, T-cell function & vaccine responsiveness is generally retained in SPLIS (vs in persons w/SCID). |
|
| Steroid-resistant nephrotic syndrome (SRNS) | High incidence of collapsing variant FSGS in SRNS 4 | >50 monogenic causes of SRNS have been identified 5; disease is largely limited to kidneys in many affected persons. |
PNP = purine nucleoside phosphorylase; SCID = severe combined immunodeficiency; SPLIS = sphingosine phosphate lyase insufficiency syndrome
- 1.
Mardy et al [2019]
- 2.
Flück [2017], Buonocore & Achermann [2020]
- 3.
Tangye et al [2020]
- 4.
Collapsing variant FSGS is a pathologic diagnosis given when one or more glomeruli show segmental or global obliteration of the glomerular capillary lumen due to collapse of the glomerular basement membrane associated with podocyte hypertrophy and hyperplasia. It is most often seen in association with severe nephrotic syndrome and rapid progression to end-stage renal disease.
- 5.
Preston et al [2019]
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with sphingosine phosphate lyase insufficiency syndrome (SPLIS), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 5.
Recommended Evaluations Following Initial Diagnosis in Individuals with Sphingosine Phosphate Lyase Insufficiency Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Steroid-resistant nephrotic syndrome | Referral to nephrologist |
|
| Primary adrenal insufficiency | Endocrinology referral |
|
| Hypothyroidism | Serum TSH & free T4 | |
| Testicular insufficiency | Age-related lab investigations: luteinizing hormone, follicle-stimulating hormone, testosterone, serum inhibin B, anti-müllerian hormone | |
| Immunodeficiency |