A number sign (#) is used with this entry because of evidence that RENI syndrome (RENI) is caused by homozygous or compound heterozygous mutation in the SGPL1 gene (603729) on chromosome 10q21.

RENI syndrome (RENI) is an autosomal recessive form of steroid-resistant nephrotic syndrome with multisystemic manifestations. Most affected individuals present in infancy or early childhood with progressive renal dysfunction associated with focal segmental glomerulosclerosis (FSGS), resulting in end-stage renal disease within a few years. Other infants present with primary adrenal insufficiency. Some patients present in utero with fetal hydrops and fetal demise. Additional features of the disorder may include ichthyosis, acanthosis, adrenal insufficiency, immunodeficiency, and neurologic defects. In rare cases, patients present with isolated primary adrenal insufficiency (summary by Prasad et al., 2017; Lovric et al., 2017; Yang et al., 2023).

For a discussion of genetic heterogeneity of nephrotic syndrome and FSGS, see NPHS1 (256300).

Prasad et al. (2017) reported 8 patients from 5 unrelated families with a syndromic disorder characterized by early-onset primary adrenal insufficiency, which was often associated with hyperpigmentation and sometimes with adrenal calcifications. Four of the families were consanguineous, including a consanguineous Pakistani family previously reported by Ram et al. (2012). Most patients developed steroid-resistant nephrotic syndrome associated with FSGS on biopsy and partial effacement of podocytes on electron microscopy. Presenting features included hyperpigmentation, increased ACTH, hypoglycemia, and hypocalcemia with seizures. Four patients had ichthyosis, 4 had primary hypothyroidism, and 3 were found to have developmental delay with progressive neurologic abnormalities on follow-up. Neurologic abnormalities included ataxia, cognitive decline, loss of motor skills, impaired speech, and sensorineural hearing loss. One patient had retinopathy and complex partial seizures with subcortical changes on brain imaging. However, the oldest patient had normal brain imaging and neurologic function at age 17.5 years, demonstrating the variability of the extra-adrenal and extra-renal features. Less common features included increased serum triglycerides and lymphopenia. One patient had evidence of partial gonadal dysfunction manifest as cryptorchidism and micropenis. Mass spectrometry studies in 1 patient (patient 5) showed significantly increased levels of plasma ceramide and sphingolipid intermediates compared to heterozygous parents and controls. Immunologic workup of this lymphopenic patient showed increased memory T-cell species and decreased naive T-cell species, suggesting impaired egress of naive cells from lymphoid organs.

Lovric et al. (2017) reported 18 patients from 7 families with nephrotic syndrome with multisystemic manifestations. Most of the families were consanguineous, and their origins included Pakistan, Turkey, Spanish Roma, Morocco, and Europe. The severity of the features varied. Several patients had congenital nephrotic syndrome with fetal hydrops, fetal demise, or death within the first months of life, whereas others had onset of renal disease in the first months or years of life which progressed to end-stage renal disease (ESRD) necessitating renal transplant in childhood. Histologically, FSGS was the main finding, but diffuse mesangial sclerosis was found in cases with congenital nephrotic syndrome. At least 2 unrelated patients had a milder renal phenotype, with onset of nephrotic syndrome in the late teens. Early-onset adrenal insufficiency and ichthyosis were common, and about half of the patients had a severe immunodeficiency manifest as lymphopenia and recurrent bacterial infections. Detailed immunologic workup of 1 patient showed reduced levels of circulating lymphocytes with an overrepresentation of T cells with a memory phenotype over naive T cells. About half of patients also had variable neurologic deficits, including microcephaly, seizures, sensorineural deafness, hypotonia, developmental delay, and peripheral neuropathy. Some patients had variable dysmorphic features or bony defects.

Janecke et al. (2017) reported 3 male patients from 2 unrelated consanguineous families with congenital nephrotic syndrome and adrenal calcifications. One of the families was of Arab descent and was originally reported by Schreyer-Shafir et al. (2014). All of the patients showed adrenal calcifications either on prenatal ultrasound or soon after birth. They had adrenal insufficiency, hypogonadism with small penis and cryptorchidism or absent testes, and progressive nephrotic syndrome associated with massive proteinuria and hypoalbuminemia. Hypogonadism was associated with testicular dysfunction and abnormal testosterone levels and response. One child died suddenly at age 7 weeks, and renal autopsy showed FSGS.

Settas et al. (2019) described a 5.5-year-old boy who presented at the age of 2 years with hypoglycemia and seizures and was diagnosed with primary adrenal insufficiency (isolated glucocorticoid deficiency). A brain MRI showed basal ganglia abnormalities suggestive of a degenerative process; however, the patient had no neurologic symptoms. The urinalysis had normal protein level, and no other findings of nephrotic syndrome were seen. He and a paternal first cousin were homozygous for the same SGPL1 variant; the only features described in the cousin were right amblyopia, right hearing loss, right arm paralysis progressing to hemiparesis, and kidney failure requiring hemodialysis.

Maharaj et al. (2022) reported a 15-year-old girl who presented at 9 months of age with fever, seizures, hyperpigmentation, and ichthyosis. Laboratory testing showed marked hypercortisolemia with high plasma ACTH levels. Mineralocorticoid deficiency was also observed, with a raised plasma renin concentration. Treatment with hydrocortisone and fludrocortisone were initiated. Brain MRI showed increased bilateral parietooccipital uptake suggestive of meningoencephalitis. She later had revision of a neck mass, believed to be a thyroglossal cyst, and developed primary hypothyroidism. Pelvic ultrasound showed ovarian calcifications, but she underwent puberty without treatment. Renal function, including measurement of urine protein-creatinine ratio, remained normal. She was small for gestational age at birth and remained small with a final height of -3.67 SD.

Yang et al. (2023) reported 2 Chinese identical twin girls with isolated steroid-resistant nephrotic syndrome. No extrarenal manifestations were seen during the 60 and 53 months of follow-up, at which time the twins developed end-stage renal disease and died after stopping treatment. One of the twins had a renal biopsy, which showed IgM nephropathy with glomerulosclerosis and interstitial tubular lesions. Yang et al. (2023) identified 29 additional patients in the literature with SGPL1 variants causing nephrotic syndrome. All 29 children reported in the literature had extrarenal manifestations. Of the 31 patients, adrenal insufficiency was seen in 22 (75.9%), with neurologic manifestations in 16 (55.2%), immunodeficiency in 14 (48.3%), failure to thrive in 10 (34.5%), adrenal calcification in 5 (17.2%), and gonadal dysfunction in 5 (17.2%).

The transmission pattern of RENI in the families reported by Prasad et al. (2017) and Lovric et al. (2017) was consistent with autosomal recessive inheritance.

In 8 patients from 5 unrelated families with RENI, Prasad et al. (2017) identified homozygous loss-of-function mutations in the SGPL1 gene (see, e.g., 603729.0001-603729.0004). All but one of the families was consanguineous. The mutations were found by whole-exome or Sanger sequencing and segregated with the disorder in the families. Cellular expression assays of several of the mutations showed that they resulted in decreased stability of the protein and almost complete absence of enzyme activity, consistent with a loss of function. Prasad et al. (2017) discussed how SGPL1 deficiency, which regulates levels of the signaling molecule S1P, can have systemic tissue-specific effects, including modulating steroidogenesis and potentially adrenal development, playing a role in podocyte-based glomerular toxicity, and causing changes in ceramide, which may affect the skin barrier leading to ichthyosis.

In patients from 7 unrelated, mostly consanguineous families of various ethnic origins with RENI, Lovric et al. (2017) identified homozygous or compound heterozygous mutations in the SGPL1 gene (see, e.g., 603729.0001; 603729.0004-603729.0006). The mutation in the first family was found by a combination of homozygosity mapping and whole-exome sequencing; subsequent mutations were found by whole-exome sequencing or Sanger sequencing. All mutations segregated with the disorder in the families. The mutation spectrum included frameshift, splice site, and missense mutations, and all were associated with reduced or absent SGPL1 protein and/or enzyme activity. Detailed functional studies of 2 of the missense mutations (R222Q, 603729.0001 and S346I, 603729.0006) showed a loss-of-function effect, with reduced protein levels, enzyme activity, impaired degradation of long-chain sphingosine, and altered subcellular localization. Disease-associated variants were unable to rescue growth defects in yeast or abnormalities in Drosophila deficient in Sgpl1. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, and patient fibroblasts showed reduced cell migration compared to controls. Lovric et al. (2017) noted that inactivation of SGPL1 enzyme can result in accumulation of various bioactive sphingolipid intermediates, including phosphorylated and nonphosphorylated sphingoid bases and ceramides. Conditioned medium from patient fibroblast cultures showed significantly elevated C22:0, C24:0, and C24:1 ceramides compared to controls. Changes in local S1P concentration and gradient between tissues and lymph and blood were postulated to affect T-cell egress. The syndromic features resulting from SGPL1 mutations indicated the pivotal role of S1P metabolism in multiple tissues including kidney.

In 2 unrelated male patients, both born of consanguineous parents, with RENI, Janecke et al. (2017) identified homozygous truncating mutations in the SGPL1 gene (603729.0007 and 603729.0008). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in blood and fibroblasts from 1 of the patients.

Settas et al. (2019) screened 21 patients with clinical features of primary adrenal insufficiency and identified 2 patients with homozygosity and 2 with heterozygosity for variants in the SGPL1 gene. The 2 patients with a homozygous mutation (R222Q; 603729.0001) included a 5.5-year-old boy, born to consanguineous Saudi Arabian parents, with RENI syndrome and his 15-year-old cousin for whom clinical details were limited, including only amblyopia of the right eye, right-sided hearing loss, right arm paralysis, and kidney failure requiring hemodialysis. The 2 patients with heterozygosity had a missense variant (c.61G-T; V21L) that had an allele frequency of 0.09 in ExAC; the authors posited that this variant was unrelated to their adrenal insufficiency.

In a 15-year-old girl, born to consanguineous Turkish parents, with RENI syndrome, Maharaj et al. (2022) identified a homozygous missense mutation in the SGPL1 gene (D350G; 603729). The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in her parents. Examination of SGPL1 protein levels with immunoblotting showed decreased expression of the D350G variant. CRISPR-engineered human adrenocortical cells with SGPL1 knockout showed minimal cortisol output.

In 2 Chinese identical twin girls with isolated steroid-resistant nephrotic syndrome, Yang et al. (2023) identified compound heterozygous intronic mutations in the SGPL1 gene (603729.0003 and 603729.0009). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were intronic. Each parent carried one of the mutations. From a review of the literature, Yang et al. (2023) identified 29 additional patients with SGPL1 variants causing nephrotic syndrome. Including their 2 patients, age of onset ranged from 1 day to 19 years. Exon variants were seen in 27 (87.1%) and intron variants in 4 (12.9%). In 25 (80.6%) patients, homozygosity was seen, whereas compound heterozygosity was seen in 6 (19.4%). Fifteen patients had homozygous missense variants, 8 had homozygous frameshift variants, 2 had homozygous truncation variants, and 6 had compound heterozygous variants.

Prasad et al. (2017) found that adrenal cortical zonation was compromised in Sgpl1-null mice. Steroidogenesis also appeared to be disrupted. Kidneys from mutant mice showed mesangial hypercellularity and glomerular fibrosis, which recapitulated the main characteristics of NPHS14.

Lovric et al. (2017) found that the kidneys of Sgpl1-null mice showed complete foot process effacement and absence of slit diaphragms. Mutant mice also showed hypoalbuminemia and increased urinary albumin/creatinine ratio. Cultured podocytes from Sgpl1-null mice did not show evidence of increased apoptosis or abnormalities in cell migration. However, knockdown of Sgpl1 in rat mesangial cells showed impaired reduced migration, which could be partially rescued by certain S1PR antagonists. Studies of Drosophila with deficiency of Sply, the ortholog of SGPL1, showed a reduction of nephrocyte foot process density and reduced albumin uptake compared to controls. Mutant flies also showed evidence of altered lipid metabolism due to disruption of the sphingolipid catabolic pathway.