Congenital Nephrotic Syndrome Of Finnish Type Research Articles

Congenital Nephrotic Syndrome: About A Case

Summary: Congenital nephrotic syndrome is a nephrotic syndrome present from birth or in the first three months of life, while infantile nephrotic syndrome is defined by a later onset but in the first year of life. Finnish-type congenital nephrotic syndrome and diffuse mesangial sclerosis represent the two main etiologies. Accurate diagnosis is based on clinical, histological and molecular biology criteria, and antenatal diagnosis is possible in some cases. We report the case of a female newborn, premature 35 WA + 9J, without particular pathological ATCDS admitted on D1 of life for a positive infectious assessment objectifying a bicytopenia made of thrombocytopenia and a neutropenia requested following an infectious anamnesis. positive in the mother, put on ATB, the evolution was marked by the appearance of edema of the two lower limbs on D6 of hospitalization taking the bucket in front generalized with puffiness of the face on D13 of hospitalization, a biological assessment was made and confirmed the nephrotic syndrome: hypoproteinemia at 20.3 g/l + hypoalbuminemia at 10.3 g/l + proteinuria for 24 hours at 3.3 g/24 hours proteinuria/creatinuria ratio 55. Associated symptomatic treatment nephroprotective treatment based on converting enzyme inhibitors was started with regular monitoring of renal function. In conclusion the congenital and infantile nephrotic syndromes are rare and generally have a poor prognosis whose evolution towards terminal renal insufficiency requires a program of dialysis and renal transplantationto the in the intensive Care Department A1 of the Hassan II University Hospital of Fez for the management of CT.

A novel mutation of congenital nephrotic syndrome in a Slovenian child eventually receiving a renal transplant

Congenital nephrotic syndrome (CNS) is a rare disease defined as heavy proteinuria, hypoalbuminemia, hyperlipidemia, and edema presenting in the first three months of life. It is most commonly caused by mutations in the NPHS1 gene associated with nephrotic syndrome type 1, also known as Finnish-type CNS, which is inherited in an autosomal recessive manner. Symptomatic treatment with intravenous albumins, vitamins, minerals, nutritional, and hormonal supplementation and treatment of complications are mandatory. Children refractory to the symptomatic treatment are recommended to undergo nephrectomy and renal replacement therapy, preferably renal transplantation. We report on a child with Finnish type CNS with a NPHS1 mutation, which is the first case confirmed by genetic study in Slovenia. We showed for the first time that homozygous mutation c.2928-3del in the NPHS1 gene caused exon 22 skipping, leading to a truncated protein and Fin-minor phenotype.

Finnish Type Congenital Nephrotic Syndrome With Exon Sequencing Confirmation in Taiwan: A Case Report

Congenital nephrotic syndrome Finnish type (CNF) is a rare and severe kidney disorder starting soon after birth, characterized by premature birth, a small size for gestational age, and an enlarged placenta. Early-onset nephrosis with heavy proteinuria, hyperlipidemia, hypercoagulopathy, and an immunocompromised status often causes poor growth and early mortality if not treated promptly. The current treatment strategy of parenteral albumin supplementation, a hyper-caloric and protein-abundant diet, and medications to prevent and treat complications has improved patient outcomes by making curative renal transplantation possible. This report describes a female newborn diagnosed with CNF incidentally before the onset of symptoms. To the best of our knowledge, she was the first CNF case with a diagnosis confirmed by genetic testing (whole-exon sequencing) in Taiwan.

Prenatal diagnosis of a fetus affected with Finnish type congenital nephrotic syndrome

To explore the genetic basis for a fetus suspected for congenital nephrotic syndrome of Finland (CNF). Genomic DNA was extracted from peripheral and umbilical cord blood samples derived from both parents and the fetus. Potential variants were detected by using next-generation sequencing. Suspected variants were confirmed by Sanger sequencing. The fetus was found to carry compound heterozygous variants c.1440+1G>A and c.925G>T of the NPHS1 gene, which were respectively inherited from its mother and father. Identification of the compound heterozygous NPHS1 variants has enabled diagnosis of CNF in the fetus and genetic counseling for the affected family.

Treatment and outcome of congenital nephrotic syndrome.

Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France. We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS. The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9-52)]. Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year. Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients.

Pituitary adenylate cyclase-activating polypeptide (PACAP) in zebrafish models of nephrotic syndrome.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an inhibitor of megakaryopoiesis and platelet function. Recently, PACAP deficiency was observed in children with nephrotic syndrome (NS), associated with increased platelet count and aggregability and increased risk of thrombosis. To further study PACAP deficiency in NS, we used transgenic Tg(cd41:EGFP) zebrafish with GFP-labeled thrombocytes. We generated two models for congenital NS, a morpholino injected model targeting nphs1 (nephrin), which is mutated in the Finnish-type congenital NS. The second model was induced by exposure to the nephrotoxic compound adriamycin. Nephrin RNA expression was quantified and zebrafish embryos were live-screened for proteinuria and pericardial edema as evidence of renal impairment. Protein levels of PACAP and its binding-protein ceruloplasmin were measured and GFP-labeled thrombocytes were quantified. We also evaluated the effects of PACAP morpholino injection and the rescue effects of PACAP-38 peptide in both congenital NS models. Nephrin downregulation and pericardial edema were observed in both nephrin morpholino injected and adriamycin exposed congenital NS models. However, PACAP deficiency was demonstrated only in the adriamycin exposed condition. Ceruloplasmin levels and the number of GFP-labeled thrombocytes remained unchanged in both models. PACAP morpholino injections worsened survival rates and the edema phenotype in both congenital NS models while injection with human PACAP-38 could only rescue the adriamycin exposed model. We hereby report, for the first time, PACAP deficiency in a NS zebrafish model as a consequence of adriamycin exposure. However, distinct from the human congenital NS, both zebrafish models retained normal levels of ceruloplasmin and thrombocytes. We further extend the renoprotective effects of the PACAP-38 peptide against adriamycin toxicity in zebrafish.

Diagnosis of Peritoneal-pleural Communication by Peritoneography With 99mTc-sulfur Colloid in a 3-year-old Girl With Congenital Nephrotic Syndrome of the Finnish Type

Around 5% of patients receiving renal replacement therapy in Spain are on peritoneal dialysis. Anatomical integrity of the peritoneum is essential since increased hydrostatic pressure due to peritoneal accumulation of dialysis fluid predisposes to abdominal or pelvic hernias or chest leakage via the embryonic pneumatoenteric recess.1 We report the case of a 3-year-old girl with a history of Finnish-type congenital nephrotic syndrome, receiving postnephrectomy peritoneal dialysis since the age of 2. Fourteen months after starting peritoneal dialysis, she was admitted to our hospital due to severe dyspnea, with massive right hydrothorax on chest X-ray. To rule out pleuroperitoneal leak, a peritoneal

Deficits in Sialylation Impair Podocyte Maturation

The role of sialylation in kidney biology is not fully understood. The synthesis of sialoglycoconjugates, which form the outermost structures of animal cells, requires CMP-sialic acid, which is a product of the nuclear enzyme CMAS. We used a knock-in strategy to create a mouse with point mutations in the canonical nuclear localization signal of CMAS, which relocated the enzyme to the cytoplasm of transfected cells without affecting its activity. Although insufficient to prevent nuclear entry in mice, the mutation led to a drastically reduced concentration of nuclear-expressed enzyme. Mice homozygous for the mutation died from kidney failure within 72 hours after birth. The Cmas(nls) mouse exhibited podocyte foot process effacement, absence of slit diaphragms, and massive proteinuria, recapitulating features of nephrin-knockout mice and of patients with Finnish-type congenital nephrotic syndrome. Although the Cmas(nls) mouse displayed normal sialylation in all organs including kidney, a critical shortage of CMP-sialic acid prevented sialylation of nephrin and podocalyxin in the maturing podocyte where it is required during the formation of foot processes. Accordingly, the sialylation defects progressed with time and paralleled the morphologic changes. In summary, sialylation is critical during the development of the glomerular filtration barrier and required for the proper function of nephrin. Whether altered sialylation impairs nephrin function in human disease requires further study.

The podocyte protein nephrin is required for cardiac vessel formation

Nephrin (NPHS1) has been described as an important structural protein of kidney podocytes. Mutations in this gene lead to the Finnish-type congenital nephrotic syndrome. More recently, a role of nephrin as a signalling molecule in kidney podocytes has been identified. Here, we show that nephrin not only has a function in kidney podocytes, but is also required for cardiovascular development. Nephrin is expressed in the epicardium and coronary vessels during human and mouse embryonic development. Nephrin knockout embryos showed abnormal epicardial cell morphology and, at later stages of development, a reduced number of coronary vessels due to increased apoptosis, and in addition, cardiac fibrosis. Connexin 43, which is required for coronary vessel formation, was downregulated in nephrin knockout embryos. Expression of the p75NTR neurotrophin receptor, a known mediator of apoptosis, was increased in mutants. Furthermore, co-immunoprecipitation studies demonstrated a direct interaction of nephrin with p75NTR. Primary nephrin-deficient cardiac cells showed a 5-fold higher rate of apoptosis in response to progenitor of nerve growth factor compared with wild-type cells, which could be rescued by RNAi against p75NTR. Taken together, our data demonstrate that nephrin directly interacts with p75NTR and reveal an important role for nephrin in murine cardiac development by permitting survival of cardiovascular progenitor cells.

Congenital Nephrotic Syndrome Masquerading as Respiratory Illness

Congenital nephrotic syndrome is rare and is often found incidentally while investigating other disorders. The diagnosis is made by typical clinical features and laboratory tests in infants < 3 months of age. It may be inherited, sporadic, acquired, or associated with a syndrome. We present the case of a former premature infant with respiratory distress at 3 months of age who was subsequently diagnosed with Finnish-type congenital nephrotic syndrome resulting from an unusual mode of inheritance.

Finnish type congenital nephrotic syndrome in a Sri Lankan neonate

The Journal is the primary organ of Continuing Paediatric Medical Education in Sri Lanka. The journal also has a website. Free full text access is available for all readers.The Sri Lanka Journal of Child Health is now indexed in SciVerse Scopus (Source Record ID 19900193609), Index Medicus for South-East Asia Region (IMSEAR), CABI (Centre for Agriculture and Bioscience International Global Health Database), DOAJ and is available in Google, as well as Google Scholar.The policies of the journal are modelled on the Committee on Publication Ethics (COPE) Guidelines on Principles of Transparency and Best Practice in Scholarly Publishing. Sri Lanka Journal of Child Health is recognised by the International Committee of Medical Journal Editors (ICMJE) as a publication following the ICMJE Recommendations.

Congenital Nephrotic Syndrome and Persistent Hypothyroidism After Bilateral Nephrectomy

Congenital nephrotic syndrome is commonly associated with hypothyroidism. Thyroid hormone supplementation is recommended as standard of care. The hypothyroidism is postulated to occur secondary to chronic massive proteinuria with loss of thyroid binding globulin, thyroid hormone and iodine. Previous reports have indicated that thyroxin may be discontinued following bilateral nephrectomy. We report our experience with one child with congenital nephrotic syndrome, Finnish type, and hypothyroidism who had a high requirement for thyroxin (100-150 μg/d) from infancy to 4 years of age. Hypothyroidism persisted despite bilateral nephrectomy and later following renal transplantation. However, his thyroxin requirement is now substantially lower (62.5 μg/d) at age 14 years. No goiter was detected clinically and antithyroid antibodies were negative. Thyroid ultrasound and 1231 scan revealed a thyroid gland in the anatomically normal location. 1231 uptake was elevated, 18% at 6 hours and 51% at 24 hours (normal values: 3-16% at 6 hours and 8- 25% at 24 hours). Perchlorate was unavailable for a perchlorate washout study. We speculate that this patient may have an intrinsic problem with thyroid hormone synthesis. It is unclear whether this is related or coincidental to the Finnish nephrotic syndrome. We recommend following thyroid functions closely if thyroxin is discontinued following bilateral nephrectomies in Finnish type congenital nephrotic syndrome.

A new case of Finnish-type congenital nephrotic syndrome, neuromuscular symptoms and early death.

Sir, The children affected by Finnish-type congenital nephrotic syndrome (FCNS) frequently show muscular hypotonia and neurological development retardation, which usually ameliorate after kidney transplantation [1,2,3,4]. However, Laakkonen H et al. recently described six FCNS patients with a severe dyskinetic cerebral palsy-like syndrome with dystonic features, athetosis and a hearing defect. Four of the patients died between 1 and 4 years of age in different circumstances; the others survived with severe neurological deficits. In spite of normal metabolic investigations, Laakkonen et al. hypothesize that the complex neurological picture was due to mitochondrial dysfunction [5]. We observed a child with FCNS and similar dyskinetic symptoms who died suddenly when he was 4.5 years. He was born at 34 weeks; elevated α-feto-protein was detected in maternal serum (1100 ng/ml) and amniotic fluid; the placenta was 1200 g with a placenta weight/newborn weight ratio of 0.44. Neonatal hyperbilirubinaemia, max 5.5 mg/dl (5.3 mg/dl non-conjugated and 0.2 mg/dl conjugated), was observed. At the age of 3 weeks, secondary hypothyroidism (T4 0.63 ng/dl and TSH 13.1 μU/ml; nv: T4 0.8–1.9 ng/dl, TSH 0.4–4 μU/ml) was diagnosed; thyroxine 37.5 μg/day normalized thyroid hormones (T4 1.2 ng/dl and TSH 3.4 μU/ml). Laboratory parameters also showed heavy proteinuria (>300 mg/Kg/day) and severe hypoalbuminaemia (0.78 g/dl). The clinical diagnosis of FCNS was later confirmed by molecular study for NPHS1 locus. At the age of 3 the patient developed ESRF and began peritoneal dialysis. When he was 4 years, in spite of a satisfactory cognitive and emotional development, the child showed severe neuromuscular deficit with focal hand dystonia and athetosis, inability to keep his head and trunk upright, or walk. He had no hearing defects. No metabolic investigations were performed. At the age of 4.4, after 6 months of treatment with growth hormone, the child weighed 14 kg (10°C) and was 96 cm tall (10°C). During a febrile illness, he manifested apnoea, followed by cardiac arrest, prolonged brain ischaemia and irreversible coma. An MRI performed in the first 24 h showed, besides brain atrophy, T2 hyperintensity on basal ganglia. Diffusion-weighted images showed an extensive signal alteration indicating water diffusion restriction in the lenticulostriate nuclei and the caudate nuclei head with low ADC values (4.1 ± 0.15 SD) in the posterior portion of the lenticulostriate nuclei. The anterior portions of lenticulostriate nuclei showed higher ADC values (7.3 ± 0.43 SD) in the same regions of hyperintensity on T2 weighted images (Figure ​(Figure1).1). Therefore the hyperintensity might be related to abnormalities of metabolic mechanisms existing before the hypoxic injury [6]. The child died after 2 months of coma. Fig. 1 MR imaging in the first 24 h after acute ipoxic–ischaemic brain damage. Axial apparent diffusion coefficient map shows a reduced ADC value (0.41) in posterior putamen and globus pallidus, and a high ADC value in anterior putamen and head of caudate ... Like the cases described by Laakkonen H et al., we can exclude prenatal or neonatal complications causing the neurological impairment in our patient. However, our case showed several different features, such as the more severe muscular hypotonia, adequate growth, growth hormone therapy and normal hearing. In spite of these differences, the MRI findings and the unexplained sudden event causing early death strongly suggest that our patient may have been suffering from the new clinical entity that Laakkonen et al. call NPHS1 with muscular dystonia and athetosis.

Basic science meets clinical medicine: identification of a CD2AP-deficient patient

Recent years have witnessed an explosion of research into the molecular basis of glomerular disease resulting in nephrotic- range urinary protein leak using both human genetics and animal models. Löwik et al. describe the first case report of an early-onset nephrotic syndrome presenting in conjunction with a homozygous CD2AP mutation. These data demonstrate the convergence between basic and clinical approaches and their potential to transform our understanding of the pathogenetic mechanisms underlying human glomerular disease.

A familial childhood-onset relapsing nephrotic syndrome

A familial childhood-onset relapsing nephrotic syndrome

Congenital and infantle nephrotic syndrome

Summary Congenital nephrotic syndrome can be present at birth or appears during the first 3 months of life, however, infantile nephrotic syndrome presents during the first year. Finnish-type congenital nephrotic syndrome is an autosomal recessive disease. Nephrotic syndrome present at birth, is severe and does not respond to therapy. Infectious and nutritional complications are frequent. Renal function deteriorates necessitating entry into a dialysis/transplantation program. Diffuse mesangial sclerosis is the second cause of congenital and infantile nephrotic syndrome. It may be isolated or part of Denys–Drash syndrome in association with male pseudohermaphroditism and Wilms' tumor. Nephrotic syndrome is resistant to therapy. Renal failure develops in early childhood. Other causes of congenital and infantile nephrotic syndrome include Pierson syndrome, Galloway syndrome, nephrotic syndrome with podocin mutations, congenital syphilis or toxoplasmosis and maternal alloimunisation to the podocyte protein neutral endopeptidase.

Role of podocyte slit diaphragm as a filtration barrier (Review Article)

Although the role of glomerular basement membrane has been emphasised as the barrier for retaining plasma proteins in the past three decades, some recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the barrier in the glomerular capillary wall. Nephrin and podocin were identified as gene products mutated in Finnish-type congenital nephrotic syndrome and autosomal recessive steroid-resistant nephrotic syndrome, respectively. Nephrin s located at the outer leaflet of plasma membranes of the slit diaphragm. Podocin is reported to have an interaction with nephrin. The anti-nephrin antibody is capable of inducing massive proteinuria, which indicates that nephrin is a key functional molecule in the slit diaphragm. The expression of nephrin and podocin was reduced in glomeruli of minimal change nephrotic syndrome, which suggested that the altered expression of these molecules contributes to the development of proteinuria also in acquired diseases. Some recent studies demonstrated that CD2-associated protein (CD2AP) is also a functional molecule in the slit diaphragm, and its expression is altered in membranous nephropathy. These observations suggested that alteration of the molecular arrangement in the slit diaphragm is involved in the development of proteinuria in several kinds of glomerular diseases.

Charge Selective Function in Childhood Glomerular Diseases

The charge selectivity (CS) function in human renal disease has not been unequivocally demonstrated to date. However, the clearance ratio of IgA to IgG may be theoretically useful in estimating CS in humans, since IgA and IgG have similar sizes and tertiary structures, but distinct isoelectric points (3.5-5.5 [IgA] and 4.5-9.0 [IgG]), and Stokes-Einstein radius: 61 A (IgA) and 49-60 A (IgG). Two-dimensional electrophoresis with the following immunoblotting revealed that the considerably anionic portion (isoelectric points [pI] <4.0) of IgA, visible in serum, was absent in the urine in steroid-sensitive nephrotic syndrome (SSNS) but present in the same during IgA nephropathy (IgAN) and membranoproliferative glomerulonephritis (MPGN). A latex assay revealed the CS index (CSI) was significantly low in patients with podocyte disease (group A), including SSNS, focal and segmental glomerulosclerosis (FSGS) and Finnish-type congenital nephrotic syndrome (FCNS), but high in those with Alport syndrome (AS), IgAN, Henoch-Schönlein purpura nephritis (HSPN), and MPGN (group B). The linear regression analysis of the IgA size selectivity index (IgA SSI; clearance ratio of IgA to transferrin) and SSI (clearance ratio of IgG to transferrin), which represents the clearance ratio of IgA to IgG referring to the transferrin clearance, revealed the influence of the charge more accurately. Indeed, the slope of the regression lines of IgA SSI (y) to SSI (x) were concluded to be y = 0.39x (group A) and y = 1.05x (group B), respectively. These results suggested that the charge selective barrier among podocyte diseases (group A) is preserved to some degree, but lost in cases of nephritis and AS (group B).

Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome

Congenital nephrotic syndrome (CNS) causes significant renal failure, and is classified into two types: (1) Finnish type; and (2) other, including diffuse mesangial sclerosis. Mutations of NPHS1 and NPHS2, which encode the slit diaphragm components nephrin and podocin, cause CNS and autosomal-recessive familial steroid-resistant nephrotic syndrome, respectively. Most patients with Finnish-type CNS in Europe and the United States have NPHS1 mutations. However, NPHS2 mutations have been detected in some cases. Mutations in ACTN4, encoding alpha-actinin-4, cause an autosomal-dominant focal segmental glomerulosclerosis. alpha-actinin-4 stabilizes the podocyte cytoskeleton structure, connecting with actin filaments. WT1 mutations, causing Wilm's tumor, have been demonstrated in some CNS patients with diffuse mesangial sclerosis. Systematic investigation of genes for CNS in Japan has never been performed. To clarify the role of mutations in these four genes, we used polymerase chain reaction (PCR) and direct sequencing to investigate all exons and exon-intron boundaries for these genes in 13 unrelated CNS patients from regional pediatric kidney disease centers in Japan. A novel homozygous nonsense mutation of NPHS1, E246X in exon 7, and a novel homozygous deletion mutation of NPHS1, 2156_2163del in exon 16 were detected in one patient each. A novel homozygous nonsense mutation of NPHS2, R196X in exon 5, was found in one patient, and the same heterozygous nonsense mutation was detected in another. No ACTN4 or WT1 mutations were detected. These studies demonstrate that mutation of NPHS1 is not a major cause of CNS in Japanese patients, and that mutation of NPHS2 can be responsible for CNS in this population.

Syndromes néphrotiques congénitaux et infantiles

Congenital nephrotic syndrome is present at birth or appears during the first three months of life and infantile nephrotic syndrome during the first year. Finnish type congenital nephrotic syndrome is an autosomal recessive disease. Nephrotic syndrome is present at birth, severe and does not respond to therapy. Infectious and nutritional complications are frequent. Renal function deteriorates necessitation a dialysis-transplantation program. Between age five and eight. The disease does not recurr after transplantation. Diffuse mesangial sclerosis is the second cause of congenital and infantile nephrotic syndrome. It may be isolated or part of a Denys-Drash syndrome (association of the nephropathy with male pseudohermaphroditism and Wilm's tumor). Nephrotic syndrom is resistant to therapy. Renal failure develops in early childhood. Therapy is aimed to prevent oedema, denutrition, infections and thrombosis. Proteinuria does not recurr after renal transplantation. Other causes are less frequent.