Little is known about the molecular pathogenesis of congenital nephrotic syndrome in association with primary adrenal insufﬁciency. Most recently, three groups found concurrently the underlying genetic defect in the gene sphingosine-1-phosphate lyase 1 (SGPL1) and called the disease nephrotic syndrome type 14 (NPHS14). In this report we have performed whole-exome sequencing and identiﬁed a new homozygous variant in SGPL1, p.Arg340Trp, in a girl with nephrotic syndrome and Addison’s disease. Her brother died previously with the same phenotype and hyperpigmentation of the skin. We reviewed the reported cases and concluded that NPHS14 is a clinically recognizable syndrome. The discovery of this syndrome may contribute to the diagnosis and description of additional patients who could beneﬁt from treatment, genetic counseling and screening for related comorbidities. Until now, patients with congenital nephrotic syndrome associated with primary adrenal insufﬁciency have been treated as having two different diseases; however, the treatment for patients with NPHS14 should be unique, possibly targeting the sphingolipid metabolism. Key words: adrenal insufﬁciency, glomerular disease, nephrotic syndrome, sphingolipidosis, sphingolipids lesion characterized by sclerosis and podocyte foot process Introduction effacement in a few capillary segments of glomeruli . In the Congenital nephrotic syndrome (CNS) is a chronic kidney disease last 15 years, variants in >40 genes have been discovered to cause whose symptoms appear before and immediately after birth: SRNS . massive proteinuria with resulting hypoalbuminemia, which in Primary adrenal insufficiency (PAI) is defined as the inability turn causes edema . Patients with a lack of response to stand- to produce sufficient glucocorticoids and/or mineralocorticoids ardized corticosteroid therapy are diagnosed with steroid-resist- in the adrenals, which leads to feedback stimulation of the reg- ant nephrotic syndrome (SRNS) . SRNS typically manifests ulatory hypothalamus–pituitary axis and the renin–angioten- histologically as focal segmental glomerulosclerosis (FSGS), a sin–aldosterone loop . Consequently, a short corticotropin Received: August 5, 2017. Editorial decision: September 25, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/462/4621377 by Ed 'DeepDyve' Gillespie user on 07 August 2018 SGPL1 deficiency-caused nephrotic syndrome type 14 | 463 Fig. 1. (A) Pedigree of the probands family. (B) Fragments of sequence chromatograms are shown for SGPL1. Red arrows indicate the position of the variant. (C) Part of the SGPL1 gene showing that the variant is located in a region well conserved throughout evolution (Alamut Visual 2.9.0). test is recommended to establish the diagnosis. If this is not At 8 months of age, renal biopsy showed mild increasing of possible, an initial screening procedure comprising the meas- the mesangial matrix and cellularity. It was noted as focal tubular urement of morning plasma adrenocorticotropic hormone dilatation (Figure 2A–C). Direct immunofluorescence showed dif- (ACTH) and cortisol levels is recommended . Manifestations fuse staining for immunoglobulin M in the mesangial area of adrenocortical insufficiency, or Addison’s disease, include (Figure 2D). The ultrastructural findings were mainly diffuse foot weakness, fatigue, anorexia, abdominal pain, weight loss, process effacement and little matrix expansion (Figure 2E–H). orthostatic hypotension and salt craving; characteristic hyper- Nuclear magnetic resonance (NMR) of the brain at 2 years pigmentation of the skin occurs with primary adrenal failure [6, and 4 months of age was normal. At 2 years and 5 months of 7]. The spectrum of genetic defects in patients with PAI has age, she was hospitalized again because her renal function increased in recent years with the use of next generation worsened (protein level 284 mg/dL, protein:creatinine ratio sequencing methods, and variants in 50 genes have been 18.032) and she presented hypertensive encephalopathy; perito- reported . neal dialysis was started. Total cholesterol was very high (434 Until recently, the molecular mechanisms that could explain mg/dL), low-density lipoprotein cholesterol was 242.88 mg/dL, the association between CNS and PAI were unknown. However, in high-density lipoprotein cholesterol was 81 mg/dL and triglycer- March 2017, two articles reported variants in the gene for ide was 381 mg/dL. Blood count was normal. Thyroid- sphingosine-1-phosphate (S1P) lyase 1 (SGPL1, OMIM 603729) as stimulating hormone (TSH) level was 11. 600 mUI/mL, free thyro- theculprit of this phenotypein27patients from12families[8, 9]. xine (T4) was 2.53 ng/dL and parathyroid hormone (PTH) was Simultaneously, another research group reported three children high (220.0 pg/mL). A chest X-ray showed cardiomegaly and an from two unrelated consanguineous families with variants in echocardiogram showed mild dilation of the sinus aorta, mild SGPL1 . Herein we report a new family with a new variant in left atrial and left ventricular dilation, left ventricular papillary SGPL1 and review the previously reported patients. muscle hypertrophy and small pericardial effusion. She presented with recurrent peritonitis related to the dialy- sis catheter (four episodes) and multiple episodes of difficult-to- Case report control systemic arterial hypertension. At 2 years and 9 months The proband (II-3) was a 3-year-old girl diagnosed with neph- of age, the dialysis catheter was changed. At 3 years and 5 months, she was hospitalized with respiratory failure, followed rotic syndrome and Addison’s disease (Figure 1A). She was the third child of healthy non-consanguineous parents. She was by adrenal crisis and cardiorespiratory arrest. She died 3 months later with bradyarrhythmia and congestive heart delivered at term, by cesarean section, after an uneventful preg- nancy. Birthweight was 3370 g (50th centile), length 49 cm (50th failure. A 7-year-old sibling was healthy (II-1), while a younger sibling centile) and the Apgar score was 9. Her development was nor- mal, as she sat and spoke at 8 months of age and walked inde- presented a similar clinical history (II-2); he has been described in detail in a previous publication . In brief, he presented gener- pendently at 18 months of age. She was hospitalized at 5 months of age with adrenal crisis alized edema at 3 months of age. At 4 months of age he under- went renal biopsy, which showed mild increasing of the with vomiting, diarrhea and dehydration. When hydrated, she presented generalized edema accompanied by hyponatremia mesangial matrix, immature glomeruli with foot process efface- ment without slit diaphragm formation, tubular microcystic dila- (109 mEq/L), hypocalcemia (0.94 mmol/L) and hypoalbuminemia (1.1 g/dL) with improvement after she started on steroid tation and diffuse interstitial fibrosis. Hyperpigmentation of the skin was first noted at 8 months of age. Laboratory evaluation replacement of hydrocortisone, fludrocortisone and calcium carbonate (CaCO ). At this hospitalization, she presented con- revealed hyponatremia, hyperkalemia, hypoglycemia and high ACTH and was diagnosed with associated Addison’s disease. He vulsive crisis related to hyponatremia. At 6 months of age, urin alysis revealed proteinuria (134 mg/dL) and a protein:creatinine died at age 1 year and 4 months with diarrhea and vomiting, which in a few hours led to dehydration and shock. ratio of 7.05. Her ACTH level was very high (4610 pg/mL). Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/462/4621377 by Ed 'DeepDyve' Gillespie user on 07 August 2018 464 | N.D. Linhares et al. Fig. 2. Light and immunoﬂuorescence microscopy. (A) Hematoxylin and eosin, magniﬁcation 40, observing focal tubular dilatation. (B and C) Masson’s trichrome and periodic acid–Schiff stains, magniﬁcation 40, showing a thin glomerular basement membrane with mild increasing of the mesangial matrix and cellularity. (D) Direct immunoﬂuorescence for immunoglobulin M presenting diffuse mesangial staining. Electron microscopy. (E) Discrete increasing of the mesangial matrix (see asterisk). (F, G and H) Diffuse and severe foot process effacement (see arrows). Genomic DNA was isolated from peripheral blood of the pro- position c.1018C>T (p.Arg340Trp; NM_003901.3). The c.1018C>T band and her parents using a modified salting out procedure . variant was not present in the ExAC database. SGPL1 was ana- Whole-exome sequencing was performed by the Centre for Applied lyzed by Sanger sequencing as described . The c.1018C>T Genomics, Hospital for Sick Children, Toronto, ON, Canada, using variant was confirmed in samples from the proband and her the SureSelect Human All Exon kit V5 (Agilent Technologies, Santa parents (Figure 1B). To analyze the impact of the candidate var- Clara, CA, USA) and the HiSeq 2500 Sequencer (Illumina, San Diego, iant, Alamut Visual version 2.9.0 software (Interactive CA, USA). Variants were narrowed down using a software developed Biosoftware, Rouen, France) was used. It showed that the var- in-house called Mendel, MD  and the ENLIS Genome Research iant was located in a well-conserved region throughout evolu- software (Enlis Genomics, Berkeley, CA, USA). tion in SGPL1 orthologues (Figure 1C) and it had in silico Exome analysis resulted in identification of the candidate pathogenic characteristics as assessed by the prediction pro- missense homozygous variant in SGPL1, located in exon 11, grams SIFT (‘deleterious’; score ¼ 0.00), PolyPhen-2 (‘probably Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/462/4621377 by Ed 'DeepDyve' Gillespie user on 07 August 2018 SGPL1 deficiency-caused nephrotic syndrome type 14 | 465 Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/462/4621377 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Table 1. Clinical features of patients with variants in SGPL1 Features (1) (2) (3) (4) Total Family 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Patient 1 2 3 1 2 1 2 3 1 2 3 4 1 2 3 4 5 1 1 1 2 3 1 1 1 2 1 1 2 1 1 2 Mutation a b, c d e f g h, i d d j k a l m n Sex MM F F F M MM F F F F F F F F M M MM M F M F F M M M M F gg g g Foetal diseases FH FH FH FH FH, Age at diagnosis 4 y 7 m 10 m 2 y 1 y 19 y 3 y 2 y 1 m 3 m 1 m 1 m 2 m 18 y 8 m 1 y 1 y 1 y 6 m 10 m 4 m 9 y 6 w 2 d 1 w 4 m 5 m Age at renal 5 5/12& 8 5 ? 5& transplant (years) Age of death 8 y 2.9 y 5 m 2 m 6 m 1 m 3 m 7 w 3 m 1 y 3 y Nephrotic syndrome þ þ þ þ þ þ þ þ þþ þþ þ þ þ þ þ þ þ þ þ þþ þþ 25/28 f ff f f ff f Adrenal deﬁciency þ þþ þ þ þ þ þ þ þ þ þþþ þ þ þ þ þþ 24/26 Skin abnormalities þ þ þ þ þ þ þ þ þ þ þþþ þ þ þ þ 17/18 Neurologic defects þ þ þ þ þ þþ þ þ þ þ 11/19 Immunodeﬁciency þ þ þþ þ þ þ þ þþ 10/12 Hypothyroidism þ þ þ þþ þþ 7/10 Genital abnormalites þ þ þþ 4/6 Skeletal abnormalities þþ þ 3/5 Muscular hypotonia þþ 2/4 (1) Lovric et al. ; (2) Prasad et al. ; (3) Janecke et al. ; (4) this report. Mutations: a, p.Ser3Lysfs*11; b, p.Ile88Thrfs*25; c, p.Arg278Glyfs*1; d, p.Arg222Gln; e, p.Arg222Trp; f, p.Ser346Ile; g, p.Tyr416Cys; h, p.Ser202Leu; i, p.Ala316Thr; j, p.Phe545del; k, p.Ser65Argfs*6; l, p.Arg505*; m, p.Leu312Phefs*30; n, p.Arg340Trp. M, male; F, female; FH, fetal hydrops; m, months; y, years; w, weeks; d, days; ?, patient had renal transplantation, but the age at which it was performed was not speciﬁed; &, performed a retransplant. þ, present; , absent; blank, not reported. Skin abnormalities include ichthyosis, acanthosis, hyperpigmentation, scaly lesions and calcinosis cutis. Neurologic defects include developmental delay, ptosis, strabismus, abnormal gait, ataxia, sensorineural deafness, seizures, microcephaly, corpus callosum hypoplasia, peripheral neuropathy, contrast enhancement of cerebellar structures and bilateral globus pallidus, medial thalamic nucleus and central pons. Immunodeﬁcienies include lymphopenia, deﬁciency of cellular immunity, multiple bacterial infection, hypogammaglobulinemia, thrombocytopenia and anemia. Genital abnormalities include cryptorchidism and hypogonadism. Skeletal abnormalities include craniotabes, rachitic rosary, asymmetric skull, scoliosis and short stature. Adrenal calciﬁcations. Fetal demise. 466 | N.D. Linhares et al. damaging’; score ¼ 1.00) and MutationTaster (‘disease causing’; S1P receptors or even a lack of phosphoethanolamine produc- P ¼ 1). tion [8–10]. Informed consent was obtained according to current ethical and legal guidelines. The Research Ethics Committee of the Treatment Hospital das Clı ´nicas of Universidade Federal de Minas Gerais (CAEE 22487913.4.0000.5149) and the National Research Ethics No curative treatment is available for patients with SRNS; con- Committee (778.728) approved the study protocol. The study sidering the 32 patients reported until now with NPHS14 was conducted in accordance with the Declaration of Helsinki. (including the 2 patients reported here), only 6 of them were post–renal transplant, and 2 of these patients required a second renal transplant and 1 died 3 years later [8, 9]. In contrast, adre- Discussion nal insufficiency is potentially life-threatening: in PAI, minera- In this study we report a patient with CNS and PAI caused by a locorticoid replacement therapy is necessary to prevent sodium loss, intravascular volume depletion and hyperkalemia . new homozygous variant in p.Arg340Trp in SGPL1. To date, 13 different variants in SGPL1 in 14 families have been reported Targeting S1P metabolism may be a form of treatment for patients with NPHS14 . An S1P receptor antagonist [FTY720 (Table 1). The reported patients present a variable phenotype including CNS and PAI with a combination of skin abnormal- (fingolimod)] and a humanized monoclonal S1P antibody (LT1009) are available and they might represent a means to ities, neuronal dysfunction, immunodeficiency, hypothyroid- ism, skeletal abnormalities, muscular hypotonia and genital deplete S1P levels in patients with NPHS14 [10, 20, 21]. In addi- tion, SGPL1 enzyme replacement therapy may be a potential abnormalities [8–10]. Our patient had been treated since she was 5 months old with CaCO and we believe that it prevented therapeutic intervention, similar to the one used for Gaucher disease and Fabry disease [22, 23]. the development of skeletal abnormalities described in the other patients. In addition, contrary to her brother, our patient expressed only mild hyperpigmentation since she used hydro- Conclusions cortisone and fludrocortisone early. In this report, exome analysis found a new variant in SGPL1 that In most cases, nephrotic syndrome manifested as CNS or in the first year of life shows no response to steroid therapy and causes a novel sphingolipidosis, NPHS14. We conclude that this syndrome is clinically diagnosed, combining CNS and PAI, rapidly progresses to end-stage renal disease . Histologically, the main finding was FSGS, but diffuse mesangial sclerosis and among other features. SGPL1 sequencing should be considered in patients with this phenotype. Although many clinical find- foci of calcification were also found [8–10]. This syndromic form of CNS was called nephrotic syndrome type 14 (NPHS14) by ings of this syndrome have been documented in other NPHSs, adrenal insufficiency is so far exclusive to NPHS14. Lovric et al. . The literature review suggests that the distinc- tive phenotype in patients with NPHS14 is CNS combined with PAI. Acknowledgements Immunofluorescence experiments in mice revealed that We are grateful to the patients and their family. Their coop- SGPL1 is localized in the endoplasmic reticulum of renal glomer- eration made this work possible. ular cells, most specifically in podocytes and mesangial and endothelial cells . SGPL1-deficient mice recapitulated the main characteristics of the human disease with abnormal adre- Funding nal and renal morphology [8, 9]. In Drosophila, Sply mutants, N.D.L. was supported by a fellowship from Conselho which lack SGPL1, led to a phenotype reminiscent of podocyte Nacional de Pesquisa (CNPq). S.D.J.P. receives support as a changes in human nephrotic syndrome . SGPL1 is the intracellular enzyme responsible for the irrever- Scientist 1A of the CNPq. The work was funded by the CNPq sible final breakdown of the lipid molecule S1P, which is cleaved and the Fundac ¸ao de Pesquisa do Estado de Minas Gerais. to ethanolamine phosphate and trans-2-hexadecenal . Through G-protein-coupled receptor activation, it has been pro- Conflict of interest statement ven that S1P has important regulatory functions in normal physiology and disease processes, particularly involving the None declared. immune, central nervous and cardiovascular systems . Variants in upstream components of sphingolipid metabolism References result in the accumulation of excess glycosphingolipids and phosphosphingolipids and lead to inherited disorders known as 1. Wiggins RC. The spectrum of podocytopathies: a unifying sphingolipidoses . These conditions include Gaucher dis- view of glomerular diseases. Kidney Int 2007; 71: 1205–1214 ease, Niemann–Pick disease and Fabry disease, among others, 2. Lovric S, Ashraf S, Tan W, Hildebrandt F. Genetic testing in and they present highly variable clinicopathologic findings . steroid-resistant nephrotic syndrome: when and how? 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Clinical Kidney Journal – Oxford University Press
Published: Aug 1, 2018
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