SPLIS (Sphingosine-1-Phosphate Lyase Insufficiency)

Sphingosine phosphate lyase insufficiency syndrome: steroid-resistant nephrotic syndrome with adrenal insufficiency (NPHS14), RENI syndrome and juvenile neuropathic form due to biallelic SGPL1 variants

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

0.1. Identification of the Entity

0.2. Quick-Reference Clinical Data

1. Introduction

1.1. Clinical Background and Molecular Discovery

The association between congenital nephrotic syndrome and adrenal calcifications was described before its cause was known. According to the review by Ron and colleagues, clinically compatible pictures were reported in 1990 in three Native American patients, in 2005 in India and in 2014 in an Arab family from Israel, whose molecular diagnosis was only established in 2017 [13]. These descriptions remained isolated because the combination of nephropathy, endocrinopathy and neurological involvement was not recognised as a single entity.

In March 2017, three groups independently published the identification of biallelic loss-of-function variants in SGPL1. Lovric and colleagues, through exome sequencing, identified nine recessive variants in seven families with SRNS and, variably, ichthyosis, adrenal insufficiency, immunodeficiency and neurological deficits; they demonstrated reduction or absence of the protein and of enzymatic activity, subcellular mislocalisation of the mutant forms, lack of complementation in yeast lacking the orthologous gene and a nephrocyte phenotype resembling nephrotic syndrome in Drosophila [14]. Prasad and colleagues started from primary adrenal insufficiency and described eight patients from five families with four homozygous variants, including c.665G>A p.(Arg222Gln), and showed that the Sgpl1−/− mouse reproduces the altered adrenal cortical zonation and the glomerular phenotype [15]. Janecke and colleagues described three children from two consanguineous families with congenital nephrotic syndrome, hypogonadism and adrenal calcifications detected prenatally, with homozygous truncating variants and marked elevation of S1P and sphingosine in blood and fibroblasts [16].

In the same year, Atkinson and colleagues identified, in a nuclear family with acute- or subacute-onset axonal peripheral neuropathy and episodes of recurrent mononeuropathy, compound heterozygosity in SGPL1 and proposed sphingosine phosphate lyase deficiency as the cause of a distinct form of Charcot-Marie-Tooth disease [17]. This report extended the spectrum to a juvenile form without nephropathy, which the chapter on disorders of sphingolipid metabolism in Saudubray's textbook describes alongside the severe early-onset forms [18].

1.2. The Gene and the Enzyme before Human Disease

The first sphingosine phosphate lyase gene was cloned in the yeast Saccharomyces cerevisiae (BST1, from bestowed of sphingosine tolerance) by Julie Saba's group in 1997; the murine homologue was cloned in 1998 and the human gene was mapped by synteny to chromosome 10 [1, 7]. In 2005, Schwab and colleagues showed that pharmacological inhibition of the enzyme by the food colourant 2-acetyl-4-tetrahydroxybutylimidazole increases S1P more than a hundredfold in lymphoid tissues and causes lymphopenia, establishing that the S1P gradients maintained by the lyase govern lymphocyte egress from lymphoid organs [7]. The lymphopenia of patients, described more than a decade later, confirmed this function in humans [10].

1.3. Nomenclature and Definition

The disease has received several designations depending on the starting point of the groups that described it. Lovric and colleagues named it nephrotic syndrome type 14 (NPHS14), placing it in the phenotypic series of monogenic nephrotic syndromes [14, 19]; OMIM adopted the name RENI syndrome (renal, endocrine, neurological and immune), keeping NPHS14 and SPLIS as alternative titles [3]; Saba's group proposed the designation sphingosine phosphate lyase insufficiency syndrome (SPLIS), which is the one used by GeneReviews and by most recent series [1, 20]. Orphanet uses the descriptive designation familial steroid-resistant nephrotic syndrome with adrenal insufficiency (ORPHA:506334) [4].

SPLIS designates the disease caused by biallelic pathogenic or likely pathogenic SGPL1 variants in an individual with at least one suggestive finding, which is the operational definition of GeneReviews and of the largest published series [1, 2]. The definition includes fetal forms with hydrops, congenital and infantile forms with SRNS and PAI, forms with isolated PAI for years, isolated SRNS and isolated juvenile axonal neuropathy [2, 17, 21, 22]. SPLIS is a sphingolipidosis, but it is not a lysosomal storage disease: the enzyme is in the endoplasmic reticulum and catalyses the last step in the degradation of all sphingolipids [1, 11].

1.4. Nosological Framework

SPLIS is listed as a syndromic form among the genetic causes of steroid-resistant nephrotic syndrome and as a cause of primary adrenal insufficiency with predominant glucocorticoid deficiency. The present article covers the disease as a whole.

2. Molecular Genetics and Pathophysiology

2.1. The SGPL1 Gene and Sphingosine-1-Phosphate Lyase

SGPL1 is located at 10q22.1 and encodes sphingosine-1-phosphate lyase 1, an integral protein of the outer membrane of the endoplasmic reticulum that functions as a homodimer [1, 2]. The gene has 15 exons, with the initiation codon in exon 2, and the MANE Select reference transcript is NM_003901.4, which encodes the protein NP_003892.2 [2, 6]. Expression is ubiquitous; in humans it is moderate in the adrenal cortex and kidney and high in the testis and thyroid, and in the mouse kidney the enzyme is found in podocytes and in mesangial and endothelial cells, colocalised with endoplasmic reticulum markers [7]. According to the review by Ron and colleagues, expression is particularly high in the thymus and jejunum and is present in T and B lymphocytes and in granulocytes [13].

The enzyme depends on pyridoxal phosphate (PLP), the active form of vitamin B6, which binds covalently to lysine 353 [2, 11]. The reaction irreversibly cleaves the bond between carbons 2 and 3 of the phosphorylated sphingoid bases, of which S1P is the main one, generating phosphoethanolamine and a long-chain fatty aldehyde (hexadecenal) [2, 5, 20]. It is the only exit route from sphingolipid metabolism: all degraded sphingolipids converge on sphingosine, which is phosphorylated to S1P by sphingosine kinase and only then cleaved by the lyase, linking sphingolipid metabolism to that of glycerophospholipids [2, 18, 23].

2.2. Consequences of Loss of Function

S1P is a lipid mediator that circulates bound to albumin and high-density lipoproteins and acts through five G protein-coupled receptors (S1PR1 to S1PR5), expressed in most cells [1, 20]. Loss of lyase activity has consequences at several levels, described by GeneReviews and by the reviews of Saba's group [1, 2]. The first is the accumulation of S1P and of upstream sphingolipids (sphingosine, sphinganine, ceramides, hexosylceramides and lactosylceramides), some of which are cytotoxic and are candidates to explain the neurological component [1]. The second is the disturbance of S1P gradients between lymphoid tissues and lymph and blood, which blocks the egress of T lymphocytes from the thymus and peripheral lymphoid organs and causes lymphopenia with a predominance of memory over naive cells [1, 3]. The third is podocyte injury, with altered morphology and foot process effacement [1, 14]. The fourth is the lack of the reaction products, such as specialised ceramides and long-chain aldehydes needed for the skin barrier and axonal integrity [1, 24]. The fifth is the disruption of adrenal development and acute steroidogenesis by the accumulated intermediates [1, 15].

Animal models support these mechanisms. The Sgpl1-null mouse has compromised adrenal cortical zonation, defective expression of steroidogenic enzymes, mesangial hypercellularity, glomerular fibrosis, complete foot process effacement, absent slit diaphragms, hypoalbuminaemia and albuminuria; it also has raised lipids and cholesterol, which shows that the lyase participates in hepatic lipid homeostasis [2, 3]. CRISPR deletion of SGPL1 in human H295R adrenocortical cells abolishes cortisol production, which is restored by the wild-type enzyme but not by the p.(Asp350Gly) variant [25]. In human keratinocytes lacking SGPL1, S1P, sphingosine and ceramides accumulate, differentiation is accelerated, the stratum corneum becomes thickened and retained and E-cadherin junctions disaggregate, which links ichthyosis to the sphingolipid imbalance, to excessive S1P signalling and to calcium regulation [26]. In Drosophila, neuronal reduction of the orthologue alters the neuromuscular junction and causes progressive degeneration of chemosensory neurons [17].

Two 2026 studies refined the model. Majcher and colleagues showed, with isotopic labelling, that lyase-deficient cells can maintain near-normal S1P through feedback on de novo synthesis by the ORMDL-ceramide axis and diversion of excess ceramides to glycosphingolipids; intracellular S1P accumulates when this compensation is overwhelmed by sphingolipid overload or when it fails, and in the kidney of the Sgpl1−/− mouse the accumulated S1P activates the Rho/ROCK pathway and disorganises the epithelial cytoskeleton [27]. Khan and colleagues generated a mouse with the R222Q variant by gene editing and observed, on a pyridoxine-poor diet, inactivation of the enzyme, S1P accumulation, proteinuria, glomerulosclerosis and podocyte loss, prevented by inhibition of S1P production or of the RhoA/ROCK pathway [28]. The clinical implication is that a normal plasma S1P does not exclude the deficiency [27].

2.3. Inheritance

SPLIS is autosomal recessive. In all patients in Keller's series with family studies, the variants were biallelic and the parents were asymptomatic carriers [2]. GeneReviews mentions rare cases in which one of the variants arose de novo in the proband (unpublished data from J. Saba) and points out that apparent homozygosity may result from an undetected deletion of the other allele or from uniparental isodisomy [1]. The sources consulted do not describe dominant inheritance or a phenotype in carriers. A 2026 report attributed multisystem amyloidosis with IgA-κ monoclonal gammopathy in a 53-year-old man to a heterozygous SGPL1 variant [29]; the case does not meet the definition of SPLIS, the causal relationship was not demonstrated and GeneReviews maintains that heterozygotes are asymptomatic [1].

2.4. Variant Spectrum

Variants are distributed across almost all exons, with a predominance in the central PLP-binding domain (exons 10 to 12) [2, 11]. They include missense, nonsense and splicing variants, small insertions and deletions and, rarely, intragenic deletions (one reported) [1, 2]. The biochemical effects range from absence of mRNA (nonsense-mediated decay) to production of mRNA without stable protein, through misfolding, and to protein present with reduced activity owing to lower affinity for the substrate or the cofactor [2]. In Keller's series, 21 of the 45 variants were considered complete loss of function, because of a catastrophic effect on mRNA or protein synthesis or substitution of lysine 353 [2]. The following table brings together the variants of clinical or historical significance, normalised in VariantValidator on the MANE transcript and checked against ClinVar on 31 October 2026.

There are nomenclature errors in the literature that should be recognised. In the adrenal phenotype table of Maharaj and colleagues, several R222Q patients are described as “c.664C>T”; in VariantValidator, c.664C>T corresponds to p.(Arg222Trp) and the R222Q variant is c.665G>A [6, 23]. The p.(Arg340Trp) variant was published on transcript NM_003901.3, with no numbering difference relative to NM_003901.4 [6, 19]. The p.(Tyr15Cys) variant, very frequent in some populations, is probably benign [2], and the p.(Val21Leu) variant, found in heterozygosity in patients with adrenal insufficiency, has an allele frequency of 0.09 in ExAC and was considered unrelated to the disease [3].

2.5. Genotype-Phenotype Correlations

The correlations are not fully defined, but Keller's series of 76 patients identified consistent patterns [1, 2]. Five missense variants (R222Q, Y416C, R340W, S346I and R222W) account for 75% of cases, and the median age at last assessment (which serves as a survival measure) was 8.0 years for R222Q (range 2.9–19), 6.2 years for Y416C (1.7–12), 3.67 years for R340W (1.25–5.7), 0.1 years for S346I (0–0.5) and 0.09 years for R222W (0–0.42) [2]. Of the 13 R222Q homozygotes, 11 were alive (77%, or 80% excluding the transplanted), versus 41% of non-transplanted patients with other variants; five had no kidney disease at the time of analysis and, in the rest, nephropathy always appeared after the first year [2]. In the 21 patients with two complete loss-of-function variants, excluding transplanted survivors, only 28% were alive, with no statistical difference from the others; patients with insertions or deletions had a survival of 30% [1, 2].

The proposed structural explanation is that residue 222 of each chain of the dimer stabilises the catalytic site: glutamine breaks hydrogen bonds and reduces the affinity for PLP, whereas tryptophan adds a steric clash that distorts the active site further; the S346I substitution, although distant from the catalytic site, destabilises the protein about ten times more than R222Q [2, 11]. This gradation of residual activity is consistent with the observation that mice with 10% to 20% of normal activity are healthy, except for lymphopenia [11].

On the endocrine axis, the R222Q variant is almost always associated with isolated glucocorticoid deficiency: of the five patients with adrenal insufficiency without nephrotic syndrome in Maharaj's review, four were R222Q homozygotes and one a p.(Asp350Gly) homozygote [23]. The six patients with all three endocrinopathies (adrenal, gonadal and thyroid), all with nephrotic syndrome, had variants distributed outside the PLP-binding domain [23].

2.6. Penetrance, Expressivity and Allelic Disorders

In the published series, all individuals with biallelic pathogenic variants had at least one manifestation, but expressivity is highly variable, including within the same family: with the same genotype, one sibling may die in utero and another manifest the disease in childhood [1]. Two siblings with isolated neuropathy still had no renal involvement at 39 and 42 years [1]. Sedillo's series accepts that there may be individuals with a biallelic genotype without disease through compensatory mechanisms, but considers this possibility unlikely [8]. GeneReviews does not recognise other phenotypes associated with biallelic germline SGPL1 variants; the axonal neuropathy described by Atkinson is treated as part of the spectrum and not as a separate allelic disorder [1, 17]. The coexistence of another monogenic disease may aggravate the picture, as in a Gambian newborn with homozygous SGPL1 and STAT1 variants who presented with severe combined immunodeficiency and died at six weeks [33].

3. Clinical Spectrum and Manifestations by System

3.1. Overview and Data Sources

Clinical information comes from case reports, systematic reviews and an international retrospective series; no prospective studies have been published. The largest series is that of Keller and colleagues, which brought together 76 patients with a molecular diagnosis, published or communicated between 2017 and 2023, from 22 countries (including the USA, Canada, Argentina, Brazil, the United Kingdom, Spain, France, Germany, Turkey, Iran, Pakistan, Saudi Arabia, Morocco, China, India and Australia) [2]. In this series, the sex ratio was 1.1:1, 45 variants were found in 23 ethnicities or nationalities, there was consanguinity in 61% and a family history in 56%, 54% presented in the first year of life, 22% had a prenatal diagnosis or findings and 50% were alive at last assessment [2]. The systematic review by Pournasiri and colleagues, with 55 patients in 19 articles, obtained similar proportions: 70.9% consanguinity, 52.7% family history and 54.9% onset in the first year [34]. The frequencies by system from the 2026 GeneReviews update, which bring together 76 published patients, are shown in the following table [1].

The differences between sources reflect different denominators and definitions; lymphopenia, in particular, was under-reported in the first descriptions because it was an asymptomatic finding, and the targeted analysis by Gharagozlou found immunodeficiency in 93% of patients with immunological data [1, 10].

3.2. Age at Presentation and Initial Organ

Presentation ranges from the prenatal period to 15 years in Keller's series, in which the latest-presenting patient had isolated peripheral neuropathy [2]. The kidney is usually the first organ involved and often coincides with adrenal insufficiency or neurological signs [2]. The table shows the age of the first sign by organ in that series.

Source: Keller 2024, Table 3 [2].

3.3. Prenatal Period

GeneReviews records prenatal abnormalities in 15 pregnancies (non-immune hydrops, adrenal calcifications and increased nuchal translucency) and four fetal deaths [1]. In Keller's series, prenatal findings also included oligohydramnios, polyhydramnios, skin oedema, adrenal haemorrhage and brain developmental defects; no patient with prenatal findings survived to three years [2]. In Pournasiri's review, all patients with a prenatal diagnosis (27.5%) died, at a median age of 2 months (interquartile range, IQR, 1.4–5.3) [34]. The most severe form combines fetal hydrops, brain malformations, congenital nephrotic syndrome and adrenal calcifications [18, 32].

3.4. Kidney

Renal involvement ranges from non-immune fetal hydrops to nephrosis diagnosed many years later, and some patients never develop it [1]. In many, proteinuria is present at birth or earlier; the latest known onset of SRNS is at 25 years, with rapid progression to ESKD [1]. All patients in Keller's series with quantified proteinuria had nephrotic-range proteinuria (protein/creatinine ratio ≥2 mg/mg) [2]. The time between first detection of proteinuria and ESKD ranged from less than one month to 60 months, with a median of 30 months; the six patients diagnosed after the first year progressed in 24 to 60 months, and of those diagnosed in infancy, eight progressed in six months or less and seven between 11 and 60 months [2]. In Pournasiri's review, ESKD occurred in 36.5% at a median age of 6 months (IQR 1.4–42.6) [34].

Biopsy usually shows glomerulosclerosis, mainly focal segmental glomerulosclerosis (FSGS), with effacement of podocyte foot processes on electron microscopy [1]. Three patients had the collapsing variant of FSGS, associated with rapid progression, and diffuse mesangial sclerosis is found in congenital cases [3, 11]. Also described were IgA nephropathy in one patient, IgM nephropathy with glomerulosclerosis and tubulointerstitial lesions in one of the Chinese twins, focal tubular dilatation, diffuse IgM deposits, foci of calcification, lipid or hyaline droplets, perivascular sclerosis and thickening of vessel walls [1, 3]. Janecke's patients had vascular changes compatible with a vascular maturation defect similar to that of the Sgpl1-null mouse [16].

Isolated SRNS, without extrarenal manifestations during 53 and 60 months of follow-up, was described in Chinese identical twins compound heterozygous for two intronic variants; both died of kidney failure [22]. In those authors' review, the 29 previously published patients with nephropathy all had extrarenal manifestations [3].

3.5. Adrenal

Primary adrenal insufficiency may be the first manifestation, as an Addisonian crisis requiring emergency corticosteroids and electrolytes [1]. All patients with PAI have glucocorticoid deficiency and some also have mineralocorticoid deficiency [1]. In the endocrinological review by Maharaj and colleagues (50 patients published up to February 2022, 13 of them from the London cohort), PAI was present in 32 (64%), with a male predominance of 1.7:1; the median age at presentation was 1 year in boys (0–6.5) and 0.55 years in girls (0.17–11), and 81% presented in the first two years [23]. Ten of the 32 (31%) had mineralocorticoid deficiency [23]. The temporal relationship with nephropathy varied: in 12 of 27 patients nephrotic syndrome preceded PAI (median 0.3 years), in eight the diagnosis was simultaneous and in seven nephrotic syndrome appeared after PAI, at a median of 1.9 years and up to 12.5 years [23]. The latest known onset of PAI is at 42 years [1].

Adrenal calcifications were present in 69% of the 13 patients with imaging described in Maharaj's review and in five more without a biochemical diagnosis of insufficiency; they can be seen prenatally and are probably a risk factor for PAI [1, 23]. The clinical presentations described include hyperpigmentation, raised adrenocorticotropic hormone (ACTH), hypoglycaemia, hypocalcaemia with seizures and severe hyponatraemia [3, 19].

3.6. Thyroid and Gonads

Primary hypothyroidism was described in 17 patients in Maharaj's review, with mildly raised thyrotropin (TSH) (8 to 29 mIU/L in cases with published values), low free thyroxine (T4), a structurally normal thyroid on ultrasound and goitre in a single patient [23]. It usually appears in infancy, but may be diagnosed later (12 years in one case); 67% of patients with hypothyroidism had PAI and nephrotic syndrome, but it also occurs without nephropathy, and all required continued levothyroxine after treatment of adrenal insufficiency [23]. Urinary loss of thyroid hormone-binding proteins, common to any nephrotic syndrome, does not by itself explain the cases without nephropathy [9, 23].

Primary testicular failure was described in nine boys, all with bilateral cryptorchidism and seven with micropenis, which suggests lower androgen exposure from the second trimester; there are no reports of hypospadias [23]. Hormonal studies show raised basal gonadotropins, an exaggerated response to luteinising hormone (LH)-releasing hormone, no testosterone response to human chorionic gonadotropin (hCG), low anti-Müllerian hormone (AMH) and low inhibin B [1, 23]. All these boys also had PAI, adrenal calcifications and nephrotic syndrome, and most died in infancy [23]. In girls, no pubertal delay has been described; two adolescents had menarche and adequate AMH, and one had bilateral non-neoplastic ovarian calcifications at 13 years [23, 25].

3.7. Immunity

Lymphopenia results from the block in lymphocyte egress and mainly affects T cells [1, 10]. In the analysis by Gharagozlou and colleagues, which brought together 46 evaluable patients out of 78 known, 43 (93%) had immunodeficiency, defined by lymphopenia, hypogammaglobulinaemia or low T or B subsets, which corresponds to 55% of all known cases [10]. The table summarises the altered parameters.

Source: Gharagozlou 2024, Table 1 [10].

The infections described include sepsis and septic shock in 11 patients (Serratia marcescens and coagulase-negative staphylococci), respiratory infections due to respiratory syncytial virus and enterovirus, gastroenteritis and peritonitis (including recurrent Clostridioides difficile), oral candidiasis and viraemias due to BK virus after transplantation, Epstein-Barr virus and adenovirus [10]. Hypogammaglobulinaemia may result from the lack of T-cell help, the reduction in B cells and nephrotic protein loss [10]. In Zhao's series, the four patients tested had a protective vaccine response, although two had low total IgG, which distinguishes SPLIS from severe combined immunodeficiency, in which T-cell function is abolished [1, 11]. Infection was the second cause of death in Keller's series [2]. The risk of lymphoid neoplasia associated with chronic lymphopenia is an open question [10].

3.8. Nervous System

Neurological involvement was present in 43% of patients in Keller's series and in about half of patients in Maharaj's review, including patients without nephropathy [2, 23]. Developmental delay may follow a period of normal development [1]. Some patients have regression: after normal acquisitions, motor, language and social delay appears, followed by loss of walking, language and interaction, often with worsening lesions on magnetic resonance imaging (MRI), which may progress to generalised hypotonia, seizures and death; deterioration began between 12 months and 25 years [1]. Other patients never had a neurological deficit; the oldest patient in Prasad's series had a normal examination and MRI at 17.5 years [1, 3].

Cranial nerve deficits affect the III, IV and VI nerves, with ptosis, strabismus, esotropia and amblyopia [1]. Involvement of the VIII nerve causes sensorineural hearing loss that is congenital or diagnosed in the first decade, sometimes progressive and severe, unilateral or bilateral [1]. All current participants in the natural history study have some degree of hearing loss, including middle ear disease, mild conductive hearing loss and mild high-frequency sensorineural hearing loss [1]. Peripheral neuropathy may have an acute or subacute onset, be a mononeuropathy or a distal polyneuropathy, cause median or ulnar palsy, areflexia, transient pain and loss of vibration sense, regress spontaneously with or without sequelae or progress to atrophy, contractures, scoliosis and hemiparesis [1]. In the two siblings described by Atkinson, motor and sensory action potentials were undetectable, electromyography showed spontaneous activity and a neuropathic pattern and sural nerve biopsy showed axonal disintegration [1, 17]. Also described were upper motor neuron involvement with weakness and spasticity, generalised and complex partial seizures (associated with adrenal insufficiency, hypoglycaemia or progressive neurological disease), microcephaly in four patients and retinopathy [1, 3, 11].

Martin and colleagues reviewed the MRIs of four new patients and of the published cases and described a recurrent pattern: isolated dysgenesis of the corpus callosum, prominent involvement of the globus pallidus, thalamus and dentate nucleus, and progressive atrophy with worsening lesions [35]. GeneReviews adds involvement of the deep grey nuclei and dopaminergic neurons and expansion of T2 and FLAIR lesions [1]. A patient with hydrops had generalised cortical atrophy, a simplified gyral pattern, hypoplastic temporal lobes, cerebellar hypoplasia and pontine hyperintensity [32]. A Saudi boy homozygous for R222Q with isolated PAI had basal ganglia changes compatible with a degenerative process, without neurological symptoms [21], and a Turkish infant with ptosis had asymmetric enhancement of the cavernous sinus and orbital apex and thinning of the optic nerves [36].

3.9. Skin

Ichthyosis may be present at birth or appear later, and is often generalised [1]. Acanthosis and hyperpigmentation, including conjunctival hyperpigmentation, also occur; hyperpigmentation may be the presentation of PAI [1]. Among patients with a described skin phenotype, 94% had ichthyosis, acanthosis or hyperpigmentation [26]. Biopsy shows a thinned epidermis with hyperkeratosis and a reduced granular layer [1].

3.10. Growth, Feeding, Digestive Tract and Metabolism

Poor weight gain is frequent and may be the presentation, associated with adrenal insufficiency, nephrotic syndrome or feeding difficulties; several patients had food intolerance and aversion requiring tube feeding, and others had postprandial abdominal pain [1]. Raised transaminases, intestinal malrotation and repeated admissions for digestive symptoms without an infectious cause have been described [1]. In the London cohort there was no consistent evidence of intrauterine growth restriction (birth weight from the 1st to the 98th centile), but two girls followed to final height reached standard deviations of −3.67 and −3.02, and at least three patients with chronic kidney disease had tertiary hyperparathyroidism, one with parathyroidectomy [23]. Hypertriglyceridaemia and hypercholesterolaemia are described laboratory findings, partly attributable to nephrotic syndrome and partly to the role of the lyase in lipid homeostasis [2, 13].

3.11. Heart, Skeleton and Others

Cardiac manifestations are occasional: dilated cardiomyopathy, cardiomegaly, atrial and ventricular dilatation, aortic sinus dilatation, pericardial effusion, hypertrophy of the left ventricular papillary muscles, bradyarrhythmias, congestive heart failure, left ventricular hypertrophy, ventricular septal defect and tetralogy of Fallot [1]. Skeletal abnormalities are rare (craniotabes, short stature, rachitic rosary, scoliosis, asymmetric skull), sometimes secondary to the neurological disease, and mild dysmorphic features such as hypertelorism and downslanting palpebral fissures [1]. Anaemia, retinal changes and increased bone cortex have also been described [2].

3.12. Natural History and Treated Disease

Most survival data come from patients who received only supportive treatment. In Keller's series, the median age at death was 0.6 years (0–8.6) and the known causes of death in 30 patients were ESKD with or without poor weight gain (9), sepsis or infection (6), cardiorespiratory failure (4), fetal death with heart failure (2), fetal death of unknown cause (2), sudden death (2), post-transplant complication (1), cerebral oedema (1), congestive heart failure or arrhythmia (1), hypovolaemic shock (1) and unspecified cause (1) [2]. In Pournasiri's review, 49.1% of patients with known outcome had died at a median age of 5 months, mainly after ESKD (23%) or sepsis and septic shock (23%) [34]. The eight patients in Keller's series without renal involvement were all alive, aged 0.17 to 32 years at last assessment [2]. Data on treated disease (kidney transplantation and pyridoxine) are scarce and come from retrospective comparisons in small groups [2, 11].

4. Clinical Recognition and Warning Signs

4.1. When to Suspect It

The combination of congenital or infantile steroid-resistant nephrotic syndrome with primary adrenal insufficiency is the presentation most suggestive of the disease, and Linhares and colleagues consider it sufficient for clinical recognition [1, 19]. SPLIS should, however, also be considered when only one of the organs is involved, because PAI may precede nephropathy by years and because there are forms of isolated SRNS and isolated neuropathy [17, 21–23]. GeneReviews recommends suspecting it in the presence of any combination of the clinical, laboratory and imaging findings listed in the table, especially with a family history compatible with recessive inheritance (affected siblings, consanguinity, unexplained fetal losses or non-immune hydrops), stressing that the absence of a family history does not exclude the diagnosis [1].

4.2. Emergency Signs

Adrenal crisis is the most immediate emergency: vomiting, diarrhoea, dehydration, hypotension, hyponatraemia, hyperkalaemia and hypoglycaemia, sometimes with seizures, as in the Brazilian case in which the first manifestation was a crisis at 5 months with sodium of 109 mEq/L and a seizure [12, 19]. The Endocrine Society recommends treating with intravenous stress-dose hydrocortisone before results are known when symptoms are severe (strong recommendation) [12]. Other urgent situations are the hypovolaemia or fluid overload of congenital nephrotic syndrome, thrombosis, severe infections in a lymphopenic patient and rapid neurological deterioration [1, 10, 37]. Starting levothyroxine may precipitate an adrenal crisis in a patient with unrecognised PAI, by increasing cortisol metabolism, which is relevant in a disease that combines both deficiencies [12].

4.3. Newborn Screening

There is no specific newborn screening for SPLIS. Screening for severe combined immunodeficiency by quantification of T-cell receptor excision circles (TREC) detected seven patients [1], and in Gharagozlou's series TREC were low or absent in seven of eight newborns tested, which suggests greater sensitivity than the lymphocyte count for neonatal lymphopenia [10]. The sensitivity of TREC screening for SPLIS has not been established [13]. An abnormal TREC with preserved T-cell function justifies sequencing of SGPL1 [13].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no consensus clinical criteria [1]. The diagnosis is established in a proband with at least one suggestive finding and biallelic pathogenic or likely pathogenic SGPL1 variants [1]. Biallelic variants of uncertain significance (VUS), or one pathogenic variant with a VUS, neither confirm nor exclude the diagnosis [1].

5.2. Supporting Biochemical Study

Plasma S1P and other sphingolipids are raised in many patients. In a series of 13 children with a molecular diagnosis compared with 96 paediatric controls, seven plasma analytes (phosphorylated and non-phosphorylated sphingoid bases, ceramides, hexosylceramides and lactosylceramides) were consistently raised, and this profile normalised with cofactor supplementation in a subgroup (unpublished data from J. Saba cited by GeneReviews) [1]. An increased plasma sphingosine/sphinganine (dihydrosphingosine) ratio has been described since the first reports [1, 17, 18]. Zhao and colleagues observed raised S1P in three of four patients and proposed the S1P/dihydro-S1P ratio as an aid in the interpretation of missense VUS [11]. These assays are performed by tandem mass spectrometry, mainly in a research setting; a comprehensive plasma metabolomic profile may capture the intermediates [1]. The observation that cells can compensate for the deficiency and keep S1P near normal [27] and the lack of published paediatric reference values limit the value of a normal result.

Studies in skin fibroblasts (enzyme activity, protein expression and sphingolipid profile) are useful for evaluating VUS [1]. In fibroblasts, the in vitro response to pyridoxine correlated with the clinical response in two patients, which led the authors to propose its use to predict treatment response [11]. No biochemical test confirms the diagnosis on its own [5].

5.3. Organ Assessment

The characterisation of each organ follows the general rules of each specialty. PAI is confirmed by the corticotropin stimulation test, with 250 µg in adults and children aged 2 years or older, 125 µg in children under 2 years and 15 µg/kg in infants, intravenously, with sampling at 30 or 60 minutes; a peak cortisol below 500 nmol/L (18 µg/dL), assay-dependent, indicates insufficiency [12]. When the test is not possible, a morning cortisol below 140 nmol/L (5 µg/dL) with raised ACTH is suggestive, and an ACTH more than twice the upper limit with low cortisol is compatible with PAI; renin and aldosterone should be measured simultaneously to assess mineralocorticoid deficiency [12]. SRNS is defined by the absence of complete remission after four weeks of full-dose prednisolone, and the International Pediatric Nephrology Association (IPNA) recommends quantifying proteinuria by the protein/creatinine ratio before classifying the disease [9]. In the newborn with congenital nephrotic syndrome, the joint working group of ERKNet and the European Society for Paediatric Nephrology (ERKNet-ESPN) recommends an extrarenal assessment targeted at the syndromic forms (neurological, visual, auditory, dysmorphic and genital) [37].

5.4. Genetic Testing

GeneReviews describes two approaches [1]. The first is gene-targeted: sequencing of SGPL1 and, if only one variant or none is detected, deletion and duplication analysis; or a multigene panel that includes SGPL1 and the genes of the differential diagnosis. The second is exome or genome sequencing, which does not require choosing the gene. Sequencing detects more than 98% of the pathogenic variants described, and only one intragenic deletion has been reported [1]. This percentage describes the proportion of known variants detectable by the method and not the clinical sensitivity of the test in a patient with suspected disease.

The renal guidelines recommend genetic testing in all children with primary SRNS (moderate recommendation), with priority for familial cases, cases with extrarenal manifestations and preparation for transplantation, by a comprehensive panel that includes all known genes — the IPNA gene table includes SGPL1 with the phenotype “PAI and SRNS” [9]. ERKNet-ESPN recommends comprehensive genetic screening as the first line in all patients with congenital nephrotic syndrome and reserves kidney biopsy for sporadic non-syndromic disease without a molecular diagnosis [37]. On the endocrine side, the recommendation to determine the aetiology of all PAI [12] and the reports of isolated PAI due to SGPL1 led several authors to call for the inclusion of the gene in PAI and SRNS panels [21, 23, 34]. Sedillo and colleagues noted in 2024 that the gene was not included in many commercial targeted panels [8]. In a patient with severe immunodeficiency, full analysis of the immunodeficiency panel prevented a second diagnosis (STAT1) from being missed [33].

5.5. Test Limits and Interpretation

Exon sequencing may not detect deletions or duplications of one or more exons, and apparent homozygosity may correspond to hemizygosity due to a deletion of the other allele; parental studies resolve this ambiguity [1]. Deep intronic or splicing variants outside the canonical regions, such as c.1298+6T>C, may fall outside the analysis or be classified as VUS [1, 22]. The classification of many missense variants is still uncertain: in Keller's series, several were included as VUS and p.(Arg340Trp) remains a VUS in ClinVar despite having been found in homozygosity in patients from three countries [2, 30]. Yang and colleagues point out that a negative test does not exclude genetic SRNS because databases are continuously being updated [22]. The report should state the gene, the transcript with version (NM_003901.4), Human Genome Variation Society (HGVS) nomenclature, zygosity, classification according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria and the recommendation for parental studies [1, 9].

5.6. Practical Algorithm

5.7. Prenatal and Preimplantation Diagnosis

Once the two familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible [1]. In the absence of a familial diagnosis, ultrasound abnormalities (non-immune hydrops, adrenal calcifications, increased nuchal translucency) should lead to including SGPL1 in the genetic investigation of hydrops, alongside chromosomal causes, RASopathies and lysosomal diseases [1, 32, 38].

6. Differential Diagnosis

6.1. Comparative Table

6.2. Main Differentials

In the face of congenital or infantile steroid-resistant nephrotic syndrome, the differential with the non-syndromic forms (NPHS1, NPHS2, PLCE1) rests on a systematic search for extrarenal signs, because SPLIS may present in the kidney before any other organ and because the twins described by Yang had no extrarenal manifestations [1, 22]. The other syndromic forms are distinguished by their own markers: microcoria in Pierson syndrome, skeletal dysplasia and lentigines in Schimke syndrome, which shares T lymphopenia with SPLIS, and nail and patellar abnormalities in nail-patella syndrome [1]. Adrenal insufficiency, present in about two thirds of patients, is not part of the picture of any other listed form of monogenic SRNS, and Linhares and colleagues considered it exclusive to NPHS14 among the nephrotic syndromes [19]. The collapsing variant of FSGS is disproportionately frequent in SPLIS [1].

In the face of adrenal calcifications in a fetus or newborn, the diagnosis most sought is lysosomal acid lipase deficiency, which shares adrenal calcification and dyslipidaemia; SPLIS is distinguished by nephrotic syndrome, progressive renal dysfunction and, in some patients, hypogonadism, ichthyosis and immunodeficiency [13, 23]. The distinction has direct therapeutic and prognostic consequences, because acid lipase deficiency has had enzyme replacement therapy with sebelipase alfa since 2015 [13]. The differential of non-immune fetal hydrops is broad (chromosomal causes, RASopathies, lysosomal diseases and others) and the presence of enlarged, haemorrhagic or calcified adrenals points towards SPLIS [1, 38].

In the face of primary adrenal insufficiency, adrenal calcifications, hypothyroidism, cryptorchidism and micropenis are clues to SPLIS, but isolated glucocorticoid PAI is a recognised presentation, especially in R222Q homozygotes, and nephropathy may appear up to 12.5 years later [1, 21, 23].

In the face of T lymphopenia detected on newborn screening, SPLIS is distinguished from severe combined immunodeficiency because T-cell function and vaccine response are generally preserved; combined T, B and natural killer (NK) cell deficiencies with impaired function suggest adenosine deaminase or purine nucleoside phosphorylase deficiency [1, 11]. Given the possibility of two coexisting diseases, the immunodeficiency panel should be analysed in full [33].

7. Treatments and Risk Management Strategies

7.1. Principles and Initial Assessment

There are no clinical practice guidelines for SPLIS; the GeneReviews recommendations are based on the authors' experience, and decisions for each organ rely on the guidelines for the respective disease: primary adrenal insufficiency (Endocrine Society, British Society for Paediatric Endocrinology and Diabetes — BSPED — and National Institute for Health and Care Excellence — NICE), paediatric SRNS (IPNA) and congenital nephrotic syndrome (ERKNet-ESPN) [1, 9, 12, 37, 39, 40]. None of these guidelines addresses the combination of nephropathy, endocrinopathy and immunodeficiency, and follow-up requires a coordinated multidisciplinary team [1]. After diagnosis, GeneReviews recommends the initial assessment summarised in the table [1].

Source: GeneReviews 2026, Table 5 [1].

7.2. Targeted Therapy: Pyridoxine

Pyridoxine is the precursor of PLP, the lyase cofactor, and may act as a pharmacological chaperone, improving the folding and stability of some mutant forms, as in other diseases due to PLP-dependent enzymes [11, 41]. The expected benefit is therefore limited to alleles with residual activity and reduced affinity for the cofactor, with the p.(Arg222Gln) variant as the model [1, 41]. Complete loss-of-function variants (truncating, canonical splicing or lysine 353 variants) have no rational basis for response [2, 41].

The clinical evidence is retrospective and limited to a few patients. In the series of Zhao and colleagues, four patients already in kidney failure received supplementation at the discretion of their attending physicians, without a uniform regimen [11]. In an R222Q homozygote, oral pyridoxine at 5 mg/kg/day significantly increased the absolute lymphocyte count and percentage; in a compound heterozygote NM_003901.4:c.605C>T p.(Ser202Leu)/c.1247A>G p.(Tyr416Cys) (S202L/Y416C), oral PLP at 30 mg/kg/day was followed by a rise in IgG from 1.77–3.89 g/L to 7.5 g/L in four months (with discontinuation of intravenous immunoglobulins), improvement in CD3, CD4 and CD8 subsets, a fall in plasma S1P and hair growth, and was later replaced by pyridoxine at 8 mg/kg/day because of persistently raised liver enzymes, which improved [11]. Two patients, one homozygous for NM_003901.4:c.1079G>T p.(Gly360Val) (G360V) and the other compound heterozygous c.868T>C p.(Phe290Leu)/c.993C>G p.(Tyr331Ter) (F290L/Y331*), did not respond and died months later [11]. The authors stressed that the difference in outcome may be due to infections, drugs (anticonvulsants alter the bioavailability of vitamin B6) and genotypes and that a prospective study with a standardised regimen is needed [11]. In 2026, Khan and colleagues reported, in an R222Q patient, neurological improvement, normalisation of plasma S1P and increased enzyme activity in fibroblasts after pyridoxine, and in the R222Q mouse a pyridoxine-rich diet prevented the onset of nephropathy [28]. Keller's review points out that R222Q patients have better survival whatever the treatment, which makes it difficult to attribute their favourable course to it [2].

The main risk is the neurotoxicity of high-dose pyridoxine, which causes distal sensory and motor neuropathy overlapping with the neuropathy of SPLIS itself; GeneReviews considers it essential to perform nerve conduction studies before starting and periodically during treatment, and suggests monitoring plasma sphingolipids in a specialised or research laboratory to assess the response [1]. Seizures in infants are associated more with deficiency than with excess of vitamin B6, and GeneReviews suggests a trial of pyridoxine in the presence of seizures [1].

The GeneReviews dose is outside the SmPC conditions of either Portuguese medicine: the indication is different, Benadon® is contraindicated in children under 12 years and in renal impairment (frequent in SPLIS), and the SmPC limits doses of 300 mg/day or more to five months, a value that the GeneReviews maximum (200 mg/day) does not reach, although in SPLIS supplementation is prolonged [1, 42]. The Piridoxina Labesfal SmPC allows similar weight-based doses in pyridoxine-dependent seizures, which corresponds to an analogous condition of cofactor dependence [43]. The adverse effects described in the SmPCs are nausea, vomiting, peripheral neuropathy, polyneuropathy, paraesthesiae and photosensitivity, and overdose may cause drowsiness, raised aspartate aminotransferase and reduced serum folate, generally reversible on discontinuation [42].

7.3. Adrenal Insufficiency: Maintenance Replacement

Glucocorticoid replacement is with hydrocortisone, managed by paediatric endocrinology [1]. The Endocrine Society suggests, in children, hydrocortisone in three or four doses with an initial daily dose of 8 mg/m² of body surface area, adjusted to individual need and monitored clinically by growth velocity, weight, blood pressure and energy level, and advises against adjustment by hormone measurements (weak recommendations) [12]. NICE indicates 8 to 10 mg/m²/day in three to four doses in children and infants with PAI, with the largest dose in the morning, and 15 to 25 mg/day from 16 years [40]. BSPED adopts about 8 mg/m²/day as the physiological dose [39]. None of the three sources defines a maximum maintenance dose in children; the practical limit is given by the signs of overdosage [12, 39, 40]. Overdosage manifests as weight gain with growth deceleration or Cushingoid signs, and underdosage as nausea, anorexia, weight loss, lethargy and hyperpigmentation [12].

In patients with confirmed aldosterone deficiency, the Endocrine Society recommends fludrocortisone with an initial dose of 100 µg/day in children, which is not adjusted to body surface area, and sodium chloride supplements of 1 to 2 g/day (17 to 34 mmol/day), divided across feeds, in the neonatal period and up to 12 months [12]. NICE indicates fludrocortisone 50 to 300 µg/day in children and 50 to 200 µg/day in infants, adjusted to the response and to salt supplements [40]. Monitoring is by salt craving, postural hypotension, oedema, electrolytes and renin; hypertension on fludrocortisone requires dose reduction [12]. Infants should be seen at least every three to four months, with attention to blood pressure in the first year, when sensitivity to mineralocorticoids increases [12]. In SPLIS, the assessment of volume status and blood pressure is complicated by nephrotic syndrome and chronic kidney disease, and hypertension may be of renal origin, as in the Brazilian case in which there was difficult-to-control hypertension on dialysis [19].

The medicines available in Portugal include Hidrocortisona Generis 10 mg and Hidrocortisona Roussel 10 mg tablets, Hidrocortisona Generis 100 mg powder for solution for injection and Inocort® 0.1 mg (fludrocortisone acetate) [44–47]. For small paediatric doses, Alkindi® (hydrocortisone granules, capsules for opening of 0.5, 1, 2 and 5 mg) has been authorised in the European Union since 9 February 2018 for replacement in adrenal insufficiency from birth to 18 years [48]. In the United States, Khindivi® (hydrocortisone oral solution 1 mg/mL) is indicated in paediatric patients aged 5 years or older [49].

Starting levothyroxine may precipitate an adrenal crisis by increasing cortisol metabolism, and cytochrome CYP3A4 inducers (carbamazepine, mitotane, St John's wort) increase cortisol clearance and require higher doses [12]. In SPLIS, in which PAI and hypothyroidism coexist in many patients, adrenal function should be assessed before starting levothyroxine, and anticonvulsant treatment should be taken into account in the hydrocortisone dose [12, 23].

7.4. Sick Days, Adrenal Crisis and the Perioperative Period

All families should have written sick-day instructions, a steroid emergency card and medical identification, an injectable hydrocortisone kit and training in its use [1, 12, 40]. The reference doses for children and adolescents, intravenously (IV) or intramuscularly (IM), are given in the table; BSPED is the most detailed paediatric source and NICE refers to it below 16 years [39, 40].

In the absence of hydrocortisone, prednisolone is the alternative and dexamethasone the least preferred, because it has no mineralocorticoid activity [12]. Adrenal crises occurred at 6.6 to 8.3 per 100 patient-years in series of patients with PAI, with a mortality of 0.5 per 100 patient-years in a prospective study, and the most frequent triggers were gastroenteritis and other infections [12]; these figures come from mainly adult populations and not from patients with SPLIS, in whom the frequency of infections is higher [10].

Volume replacement in adrenal crisis poses a problem specific to this disease. The PAI guidelines recommend normal saline boluses, whereas ERKNet-ESPN recommends avoiding intravenous fluids and normal saline in congenital nephrotic syndrome and basing albumin infusion on clinical signs of hypovolaemia [12, 37, 39]. No guideline addresses the combination; emergency hydrocortisone is not in question, but the volume and type of fluids must be decided case by case, with clinical assessment of intravascular volume and the involvement of nephrology [9, 37]. GeneReviews recommends assessing adrenal function before any major procedure, even in patients without known PAI [1].

7.5. Kidney: Nephrotic Syndrome, Dialysis and Transplantation

SPLIS is, by definition, steroid-resistant, and IPNA recommends discontinuing calcineurin inhibitors and prednisolone when a monogenic form of SRNS is identified (moderate recommendation), maintaining renin-angiotensin-aldosterone system blockade [9]. This blockade, with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), should be started as soon as SRNS is diagnosed, at the maximum tolerated doses, and IPNA prefers ramipril and ARBs because they do not accumulate in renal failure [9]; in the newborn with congenital nephrotic syndrome, ERKNet-ESPN recommends it from four weeks of age [37]. In the Iranian case published in 2025, treatment with corticosteroids and ciclosporin did not prevent progression to ESKD and death from sepsis [31].

Supportive measures follow the nephrotic syndrome guidelines. IPNA suggests loop diuretics in severe oedema after excluding hypovolaemia and 20–25% albumin, 0.5–1 g/kg over 4 to 8 hours, with intravenous furosemide 1–2 mg/kg midway or at the end, in refractory oedema or symptomatic hypovolaemia; preventive anticoagulation in patients with previous thromboembolism; oral calcium in hypocalcaemia; and levothyroxine in hypothyroidism [9]. ERKNet-ESPN recommends, in congenital nephrotic syndrome, avoiding central venous catheters and, when they are unavoidable, maintaining prophylactic anticoagulation; furosemide 0.5–2 mg/kg per dose up to six times a day (maximum 10 mg/kg/day, and no more than one week above 6 mg/kg/day) only in overload with preserved renal function; amiloride rather than spironolactone as a potassium-sparing agent; indometacin 0.5 to 3 mg/kg/day as an adjunct, stopped if there is no benefit within 2 to 4 weeks; a diet with 130 kcal/kg/day, 4 g/kg/day of protein and reduced salt; growth hormone in persistent growth failure; and unilateral or bilateral nephrectomy in severe complications [37]. Nephrotoxic drugs should be avoided and renally eliminated drugs adjusted [1].

In Keller's series, 25 patients reached ESKD: seven received palliative care only, nine dialysis only and nine were transplanted [2]. The median age at last assessment was 1.3 years (IQR 5.6) in the palliative group, 4.4 years (IQR 7.4) in the dialysis group and 8 years (IQR 7) in the transplanted group; transplantation was associated with significantly longer survival than palliative care (p=0.004), and dialysis alone did not differ significantly from palliative care [2]. These comparisons are retrospective, with small groups and potential selection bias, because transplanted patients had to survive until transplantation; one of the transplanted patients was also receiving pyridoxine [2]. On peritoneal dialysis, the Brazilian case had four catheter-associated peritonitis episodes and difficult-to-control hypertension [19]; in Gharagozlou's review, catheter-associated infections and peritonitis are among the infections described [10].

GeneReviews brings together the experience of 14 transplanted patients (unpublished data from J. Saba): ten are alive and four have died [1]. In the detailed follow-up of ten, transplantation was performed between 3 and 22 years of age, between 11 months and 5 years after the start of dialysis, with living related and unrelated donors, deceased donors and paired exchange; only one had native nephrectomy; vascular anatomy was difficult in two recipients and led to abandonment of transplantation in two others; induction and maintenance immunosuppression were generally the usual ones, with reduction in several because of the immunodeficiency; there was one recurrence and severe complications such as a neurological catastrophe and encapsulating peritonitis, and quality of life improved in patients without complications [1]. An R222Q homozygote transplanted at 7 years had graft rejection and died at 8 [2]. A patient in the London cohort received two transplants, at 5 and 12 years, and had normal puberty [23]. Keller and colleagues consider transplantation a life-prolonging intervention in ESKD and note that the hypothesis of graft injury from circulating sphingolipids has, so far, no supporting evidence; IPNA recommends measuring proteinuria before transplantation in patients with residual function and discussing the risk of recurrence with the family [2, 9].

7.6. Thyroid and Gonads

Hypothyroidism is treated with levothyroxine, which all the patients described by Maharaj required on a continuing basis [1, 23]; IPNA recommends treating when TSH exceeds 10 mU/L with low free T4 and monitoring TSH between 4.5 and 10 mU/L with normal free T4 [9]. In patients with PAI, starting levothyroxine may precipitate an adrenal crisis if glucocorticoid replacement is not assured [12].

In infants with micropenis, GeneReviews suggests considering testosterone to increase penile length and allow voiding while standing; at puberty, considering the need for testosterone; and counselling about the possible reduction of spermatogenesis and sperm cryopreservation [1, 23]. The sources consulted do not give testosterone doses specific to SPLIS, and its use follows the protocols for micropenis and pubertal induction in primary hypogonadism.

7.7. Immunity and Infection Prevention

Immunological follow-up includes the lymphocyte count and, every 6 to 12 months, T, B and NK subsets, IgG, IgA and IgM and vaccine responses [1, 10]. Most patients have normal or near-normal T-cell function, but, if proliferation is impaired, GeneReviews recommends considering avoidance of live vaccines [1]. Intravenous or subcutaneous immunoglobulins may be considered depending on the history and results [1]; IPNA and ERKNet-ESPN suggest them when IgG is low and there are recurrent or severe infections (weak IPNA recommendation) [9, 37]. In Gharagozlou's review, patients received co-trimoxazole (4), fluconazole (2), immunoglobulins (3), penicillin, azithromycin, aciclovir and, some, protective isolation and Pneumocystis jirovecii prophylaxis; the impact of these measures is not known [10]. Keller and colleagues consider it necessary to study whether antibiotic prophylaxis and immunoglobulins alter the course, given that infection is the second cause of death [2]. Blood products should be irradiated [1]; in the practice described by Gharagozlou they were generally irradiated and leucodepleted, except when immunity was considered preserved [10]. After kidney transplantation, immunosuppression worsens vulnerability to infections, such as the BK viraemia described in one transplant recipient [10].

7.8. Neurology, Development, Senses, Skin, Nutrition and Heart

Treatment of the other manifestations is supportive and follows Table 7 of GeneReviews [1]. In seizures, electrolyte abnormalities and hypoglycaemia should be excluded, and the data do not allow a specific antiepileptic to be recommended; GeneReviews suggests considering a trial of pyridoxine [1]. Tone abnormalities (hypertonia or dystonia) may be treated with baclofen, tizanidine, botulinum toxin, antiparkinsonian drugs or orthopaedic surgery, under specialist guidance; physiotherapy aims at mobility and prevention of contractures, scoliosis and hip dislocation, and occupational therapy at fine motor skills [1]. Dysphagia is assessed clinically and by a radiological swallowing study, with thickening or cooling of food and, in severe cases, nasogastric tube or gastrostomy; augmentative and alternative communication is useful when speech is compromised [1]. Hearing loss benefits from hearing aids and support at school; ocular deficits are treated with glasses and esotropia surgery; ichthyosis with topical emollients [1]. Poor weight gain requires a search for the cause (renal, neurological due to altered peristalsis, or endocrine) and may require enteral or parenteral nutrition [1]. Cardiac manifestations are followed by cardiology [1]. Palliative care and home support should be assessed on an ongoing basis, especially in early-onset forms [1, 2].

7.9. Agents and Circumstances to Avoid

GeneReviews recommends avoiding nephrotoxic drugs, renally eliminated drugs in renal failure, live vaccines and exposure to infectious agents (because of the immunodeficiency) and non-irradiated blood products [1]. To these are added, because of PAI, CYP3A4 inducers without adjustment of hydrocortisone and dexamethasone alone as replacement [12], and, because of pyridoxine, doses above those recommended and combination with levodopa [1, 43].

7.10. Pregnancy, Lactation and Transition

The sources consulted do not describe pregnancies in women with SPLIS. Fertility may be reduced in some patients [1]; two girls in the London cohort had spontaneous puberty with adequate ovarian reserve, and boys with testicular failure are at risk of reduced spermatogenesis [23]. In a pregnancy in a woman with PAI, the Endocrine Society recommends monitoring for signs of under- and over-replacement at least once per trimester and giving a stress dose in active labour, with 100 mg of intravenous hydrocortisone followed by 200 mg/24 hours, rapidly reducing to the previous dose after delivery [12]. The Benadon® SmPC contraindicates high-dose pyridoxine in pregnancy and breastfeeding, so targeted supplementation requires reassessment in these phases [42]. Transition to adult services involves simultaneously transferring nephrology (or transplant follow-up), endocrinology, immunology and neurology; NICE recommends reviewing information needs at transition periods and, from 16 years, following adult regimens in adrenal insufficiency [39, 40].

7.11. Regulatory Status

There is no medicine specifically authorised for SPLIS by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA), and searches of ClinicalTrials.gov found no registered interventional trials [50, 51]. All drugs used are used within the indication for the manifestation (hormone replacement) or off-label (pyridoxine).

7.12. Clinical Studies and Evidence

There are no randomised trials or prospective interventional trials. The evidence in favour of pyridoxine is limited to improvements in biomarkers in a few patients with residual-activity alleles, without a control group and with confounders declared by the authors themselves, and the better survival of R222Q homozygotes is independent of treatment [2, 11]. The advantage of transplantation over dialysis and palliative care comes from a non-randomised comparison in 25 patients [2]. The ongoing natural history studies are intended to serve as a historical control for future trials [2, 50].

7.13. Developments in the Last 12 Months (November 2025 to October 2026)

In April 2026, Majcher and colleagues published in the Journal of Clinical Investigation the study of a patient with the novel variant c.1084T>A p.(Ser362Thr) and of cell and mouse models, showing that lyase deficiency can be compensated by feedback on sphingolipid synthesis and diversion to glycosphingolipids and that the S1P accumulated in the kidney activates the Rho/ROCK pathway; the ROCK inhibitor fasudil attenuated the renal cytoskeletal defects in mice [27]. Level of evidence: preclinical.

In September 2026, Khan and colleagues published in the same journal (advance version of 24 September) the first mouse model of the R222Q variant, which only develops nephropathy when the diet is poor in pyridoxine; inhibition of S1P production or of the RhoA/ROCK pathway prevented the nephrosis, and in an R222Q patient pyridoxine was associated with neurological improvement and normalisation of plasma S1P [28]. Level of evidence: preclinical, with an isolated clinical observation.

Gene therapy with adeno-associated virus (AAV) remains at the preclinical stage. The AAV-SPL 2.0 version, with a CAG promoter, increased expression and activity by 30% in human embryonic kidney cells and prolonged the survival of Sgpl1-null mice treated at birth to at least five months, with normal neurodevelopment, 85% of normal weight gain in the first four months and delayed proteinuria, but the animals eventually developed nephrosis and glomerulosclerosis, which indicates the need for better renal targeting [52]. AAV9 gene therapy did not correct lymphopenia in the mouse, and the authors accept that treatment of the immunodeficiency may require lymphoid targeting or bone marrow transplantation [10]. There is no registered human gene therapy trial [50, 51].

In January 2026, a report was published of a 53-year-old man with multisystem amyloidosis and a heterozygous SGPL1 variant, which the authors linked to the disease [29]; given the recessive inheritance of SPLIS and the absence of a phenotype in carriers, this report does not change knowledge of the disease [1]. The review by Zhang and colleagues on new therapies for rare podocytopathies, published in 2026, places SPLIS among the monogenic podocytopathies, which account for about 30% of cases of SRNS or FSGS [53]. The full GeneReviews update of 9 April 2026 added the transplantation, immunology and prevalence data [1].

7.14. Divergences between Sources

8. Reproductive Options and Family Counselling

8.1. Inheritance and Recurrence Risks

SPLIS is transmitted in an autosomal recessive manner [1, 3]. The parents of a patient are as a rule heterozygotes, and molecular testing of both is recommended to confirm carrier status and calculate the recurrence risk reliably [1]. When both parents are carriers, each sibling of the proband has, at conception, a 25% chance of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier [1]. Carriers are not at risk of developing the disease [1]. Each sibling of the parents has a 50% chance of being a carrier [1]. The children of a patient are obligate carriers, and fertility may be reduced [1].

If only one parent is a carrier and paternity and maternity are confirmed, the second variant may have arisen de novo in the proband, which has been observed rarely, or in one of the parents as post-zygotic mosaicism [1]. If the proband appears homozygous, consideration should be given to a deletion of one or more exons undetected by sequencing, which mimics homozygosity, or to uniparental isodisomy of chromosome 10 [1].

8.2. Intrafamilial Variability and Counselling

Age at onset and manifestations may vary between siblings with the same variants: in the same family there may be a fetal loss and a sibling with onset in childhood [1]. Counselling should convey the average severity of the early-onset forms (mortality of about 80% before 5 years when nephropathy starts in the first year without transplantation) without presenting it as inevitable, because there are patients with a favourable course, especially R222Q homozygotes and patients without nephropathy [2]. Prenatal findings were always associated with early death in Keller's series [2].

8.3. Cascade Testing and Testing of Siblings

GeneReviews recommends clarifying the genetic status of apparently asymptomatic siblings, older and younger, in order to start treatment early and avoid risk agents [1]. IPNA suggests offering urinalysis to the siblings of patients with SRNS even before genetic testing [9]. Carrier testing in relatives requires prior identification of the proband's two variants [1]. Carrier testing should be offered to the partners of carriers and patients, especially when they share the same ancestry; in the North American Hutterite community, the p.(Tyr416Cys) variant is frequent in the Dariusleut branch [1].

8.4. Prenatal and Preimplantation Diagnosis

With the familial variants identified, prenatal diagnosis and preimplantation genetic testing are possible, and the ideal time to discuss these options is before pregnancy [1]. ERKNet-ESPN recommends early genetic counselling in families with a history of congenital nephrotic syndrome or with prenatal signs [37]. In a family with a second diagnosis, such as the newborn with SGPL1 and STAT1 variants, counselling must cover both risks and, in the case of STAT1, the possibility of haematopoietic stem cell transplantation in future siblings [33]. Decisions about the use of these tests are personal and may differ between families and professionals [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What Is Known about the Frequency

The true prevalence is unknown. Up to the 2026 GeneReviews update, 76 patients had been published, and the authors knew of 12 more unpublished [1]; Gharagozlou's immunological analysis counted 78 known patients [10]. The only population estimate is that of Sedillo and colleagues, who summed the allele frequencies of high-confidence pathogenic variants in genomic databases and corrected for consanguinity when known [8]. With gnomAD v2.1.1 (141,430 samples), the estimated prevalence was 0.015/100,000 (95% CI 0.010–0.021), corresponding to about 11,707 patients worldwide (credible interval 6288–19,699); with gnomAD v3.1.2 the estimate was 0.011/100,000 and 11,770 patients [8]. These figures describe expected genotypes and not diagnosed patients: the published cases represent less than 1% of those predicted, which the authors attribute to undiagnosed fetal and infant deaths, mild adult forms, lack of awareness of the disease and the absence of the gene from many panels [8]. The estimates depend on the variants included and may change with the reclassification of frequent VUS [8].

In the United States, the overall rate predicts about 71 patients, but extrapolation from the worldwide estimate predicts more than 500, and more than 1000 in the United States and the European Union together [8]. East Asia and South Asia would contribute more than 95% of the predicted cases, which contrasts with the origin of the published patients [8].

9.2. Distribution of Known Patients and Founder Populations

The published patients are concentrated in regions with high rates of consanguinity: Pakistan, the Middle East and North Africa, Turkey and the Hutterite colonies of southern Canada [2, 8]. The p.(Arg222Gln) variant has been found in Pakistani, Saudi and Turkish families, p.(Arg222Trp) in a Turkish family, p.(Ser346Ile) in a Moroccan family, c.7dup in Spanish Roma and p.(Arg340Trp) in patients from Brazil, Turkey, India and Iran [2, 7, 31].

The p.(Tyr416Cys) variant is a founder variant in the Hutterite community, an Anabaptist group that settled in North America in the 19th century and is divided into three branches (leut) [8]. All known Hutterite patients belong to the Dariusleut branch; in the analysis of 140 Lehrerleut, 150 Dariusleut and 100 Schmiedeleut individuals, 10 heterozygotes were found, all Dariusleut, giving a carrier frequency of 6.67% in that branch [1]. In 121 Hutterite genomes from South Dakota no pathogenic variants were found, which suggests that the variant is confined to one branch or one colony [8]. The variant exists in gnomAD in heterozygosity in 2 of 135,332 Europeans (allele frequency 0.00000739), and it is not known whether the Hutterite form is of European origin or results from an independent mutational event [1]. No pathogenic variants were found in the Amish or in the Saudi and Israeli datasets, which were small [8].

9.3. Portugal and Brazil

The sources consulted do not describe Portuguese patients. In Brazil, Linhares and colleagues, from Belo Horizonte, described in 2018 a family with non-consanguineous parents and two children affected by the homozygous p.(Arg340Trp) variant [19]; Keller's series includes Brazilian patients with this variant [2]. The rarity of published cases in the two countries does not allow the local frequency to be estimated.

9.4. Special Populations

The fetal and neonatal forms have the worst outcome and require early discussion of goals of care, including the possibility of kidney replacement therapy and palliative care [2, 13]. Transplanted patients add therapeutic immunosuppression to the immunodeficiency of the disease [1, 10]. Adults with mild forms, such as isolated neuropathy, may go undiagnosed because the disease is little known outside paediatrics [8]. In girls and women, ovarian function appears preserved in the few cases described [23].

9.5. Reference Networks and Patient Organisations

In Europe, follow-up involves the European Reference Networks ERKNet (kidney diseases, https://www.erknet.org), Endo-ERN (endocrine diseases, https://endo-ern.eu), ERN RITA (immunodeficiencies, https://ern-rita.org) and MetabERN (hereditary metabolic diseases, https://metab.ern-net.eu). GeneReviews lists as resources NephCure Kidney International, the American Kidney Fund and the Kidney Foundation of Canada, and mentions the family groups Kaya Girl Legacy and Team SPLIS [1]. The international registry (NCT04885179) and the natural history study (NCT06669949) of the University of California, San Francisco were recruiting in October 2026 [50, 51]. The Orphanet entry is at https://www.orpha.net/en/disease/detail/506334 [4].

10. Illustrative Clinical Case

Linhares and colleagues described in 2018 a Brazilian family from Minas Gerais [19]. The proband was the third daughter of healthy, non-consanguineous parents, born at term by caesarean section after an uncomplicated pregnancy, weighing 3370 g and measuring 49 cm (50th centile) with an Apgar score of 9; development was normal, with sitting and first words at 8 months and independent walking at 18 months.

At 5 months she was admitted with an adrenal crisis with vomiting, diarrhoea and dehydration. After hydration, generalised oedema appeared, with sodium of 109 mEq/L, calcium of 0.94 mmol/L and albumin of 1.1 g/dL, and a seizure attributed to the hyponatraemia. She improved with hydrocortisone, fludrocortisone and calcium carbonate. At 6 months she had proteinuria of 134 mg/dL, a protein/creatinine ratio of 7.05 and ACTH of 4610 pg/mL. Kidney biopsy at 8 months showed a mild increase in mesangial matrix and cellularity and focal tubular dilatation, immunofluorescence with diffuse mesangial IgM deposits and, on electron microscopy, diffuse and severe foot process effacement with little matrix expansion (figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC6070023/figure/sfx130-F2/).

Brain MRI at 2 years and 4 months was normal. At 2 years and 5 months she was admitted with worsening renal function (proteinuria of 284 mg/dL, ratio of 18.03) and hypertensive encephalopathy, and started peritoneal dialysis. She had total cholesterol of 434 mg/dL, low-density lipoprotein (LDL) cholesterol of 242.88 mg/dL, high-density lipoprotein (HDL) cholesterol of 81 mg/dL and triglycerides of 381 mg/dL, a normal blood count, TSH of 11.6 µIU/mL with free T4 of 2.53 ng/dL and parathyroid hormone of 220 pg/mL. The chest radiograph showed cardiomegaly and the echocardiogram mild dilatation of the aortic sinus, left atrium and left ventricle, hypertrophy of the left ventricular papillary muscles and a small pericardial effusion. She had four catheter-associated peritonitis episodes, difficult-to-control hypertension and a catheter change at 2 years and 9 months. At 3 years and 5 months she had respiratory failure followed by an adrenal crisis and cardiorespiratory arrest, and died three months later with bradyarrhythmia and congestive heart failure.

Her younger brother had had generalised oedema at 3 months; kidney biopsy at 4 months showed immature glomeruli with foot process effacement without slit diaphragms, tubular microcystic dilatation and diffuse interstitial fibrosis. At 8 months skin hyperpigmentation appeared and the work-up showed hyponatraemia, hyperkalaemia, hypoglycaemia and raised ACTH, with a diagnosis of Addison disease. He died at 1 year and 4 months, after vomiting and diarrhoea that within a few hours led to dehydration and shock. The older brother, aged 7, was healthy.

Exome sequencing identified in the proband the homozygous variant c.1018C>T p.(Arg340Trp) in exon 11 of SGPL1, absent from ExAC and confirmed by Sanger sequencing in the parents, both heterozygotes (pedigree and chromatograms in figure 1 of the article) [19]. In VariantValidator the variant is NM_003901.4:c.1018C>T, and in ClinVar it is classified as of uncertain significance, although its recurrence in homozygosity in patients from several countries and family segregation support pathogenicity [2, 6, 30].

The case brings together several features of the disease: PAI as the first manifestation, nephropathy months later, hyperpigmentation less marked in the sister treated early with hydrocortisone and fludrocortisone than in the brother, hypothyroidism, dyslipidaemia, the hyperparathyroidism of chronic kidney disease, cardiac involvement and the infectious complications of dialysis [1, 19]. The authors attributed to calcium carbonate the absence of the skeletal abnormalities described in other patients, a hypothesis without demonstration. The adrenal crisis triggered by intercurrent illness was the immediate cause of the brother's death and preceded his sister's, which underlines the importance of stress doses and of an emergency plan [12, 19, 39]. The later data of Keller indicate that kidney transplantation, which was not performed in this family, is associated with longer survival in ESKD [2].

A 2022 North American case illustrates the neonatal presentation: a newborn girl of Gambian ancestry with bilateral adrenal calcifications on prenatal ultrasound and intrauterine growth restriction had oliguria from birth, creatinine of 1.7, albumin of 1.8 g/dL, cholesterol of 294 mg/dL and triglycerides of 468 mg/dL on the second day, and a presumptively positive newborn screen for severe combined immunodeficiency on the third day [13]. The initial suspicion of lysosomal acid lipase deficiency was ruled out by enzyme activity and LIPA sequencing; the nephrotic syndrome panel revealed the homozygous variant c.932C>G p.(Pro311Arg), of uncertain significance. Because of pulmonary oedema she was intubated at 17 days; the family chose not to start dialysis and compassionate extubation took place at 19 days [13].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In the largest series, 50% of the 76 patients were alive at last assessment, and the factors with the greatest influence on survival were the age and organ of presentation, kidney transplantation and the genotype [2]. Among the 48 non-transplanted patients with nephropathy, the 30 with onset in the first year of life had a mortality of 81% before 5 years, a median survival of 3.0 months after onset and a median age of 0.4 years at last assessment; only 17% were alive [2]. In the 18 with onset after the first year, mortality before 5 years was 27%, median survival in the first two years was 20.4 months and the median age was 6.5 years; about 70% were alive [2]. The presence of PAI did not alter the survival of patients with nephropathy [2]. Prenatal findings were always associated with early death, and patients without nephropathy were all alive [2]. Survival by genotype was 77% in R222Q homozygotes, 66.7% with Y416C, 50% with R340W, 0% with S346I and R222W, 48% with the remaining variants and 30% with insertions or deletions [1, 2]. Survival appeared higher in boys (58% versus 37%, without statistical significance), a difference the authors attribute to the greater number of transplanted patients and R222Q homozygotes among them [2]. The most frequent causes of death were ESKD (30%) and infection (20%) [2]. Some patients live productively into the third and fourth decades [2].

11.2. Surveillance

There are no published surveillance guidelines; the table reproduces the GeneReviews recommendations, with additions from the guidelines for each organ [1].

Infants with PAI should be seen at least every three to four months to assess growth, blood pressure and general condition [12]. Transition to adult services requires continuity in all these areas [40].

12. Summary and Final Considerations

SPLIS is an autosomal recessive disease due to loss of function of sphingosine-1-phosphate lyase, the PLP-dependent enzyme that irreversibly degrades S1P in the last step of sphingolipid metabolism [1, 2]. The accumulation of S1P and other sphingolipids and the lack of the reaction products explain a multisystem picture that brings together steroid-resistant nephrotic syndrome with FSGS, primary adrenal insufficiency frequently with calcifications, hypothyroidism, testicular failure, T lymphopenia, ichthyosis, hearing loss, cranial nerve deficits, peripheral neuropathy and central nervous system involvement [1, 10, 23]. The spectrum ranges from fetal hydrops to isolated neuropathy in the young adult, and overall survival in the largest series was 50% [2].

Diagnosis depends on recognising the association between kidney, adrenal and lymphocytes, and also on the inclusion of SGPL1 in SRNS, adrenal insufficiency and immunodeficiency panels, because the disease may begin in a single organ [1, 9, 21]. Newborn screening by TREC detects some of the patients [10]. Prognosis depends mainly on the age of onset of nephropathy, the genotype and access to kidney transplantation: renal onset in the first year is associated with a mortality of about 80% before 5 years, R222Q homozygotes have the most favourable course and transplantation was associated with longer survival than dialysis or palliative care, with severe complications in some patients [1, 2].

Treatment is mainly supportive and coordinated between nephrology, endocrinology, immunology, neurology and genetics [1]. Glucocorticoid and mineralocorticoid replacement follows the PAI guidelines, with attention to stress doses, the start of levothyroxine and fluid management in the presence of nephrotic syndrome [12, 37, 39]. Pyridoxine, at a dose of 10 mg/kg/day up to 200 mg/day, is the only targeted therapy, with evidence limited to improvements in biomarkers in a few patients with residual-activity alleles and with a risk of neuropathy that requires monitoring of nerve conduction [1, 11]. The mouse models published in 2026 reinforce the response of the R222Q variant to pyridoxine and point to the Rho/ROCK pathway as a target, and AAV gene therapy remains at the preclinical stage [27, 28, 52]. The ongoing natural history studies are preparing the first clinical trials [50, 51].

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