Kidney transplantation in a child with Pierson syndrome

Congenital nephrotic syndrome is commonly associated with mutations in genes that encode podocyte and slit diaphragm proteins or the structural and regulatory proteins of the GBM. These mutations lead to the formation of dysfunctional proteins, which account for the resistance of the renal manifestations to conventional treatment methods. Consequently, patients become renal replacement therapy dependent. Mutation of the LAMB2 gene is associated with Pierson syndrome, which is an autosomal recessive disorder characterized by congenital nephrotic syndrome and ocular abnormalities. In this report, a 2‐year‐old male patient who was diagnosed with Pierson syndrome is presented. He had bilateral microcoria and developmental delay in addition to nephrotic syndrome. His renal function deteriorated rapidly, and he underwent a deceased donor kidney transplantation. He showed dramatic improvement after kidney transplantation; in addition to having good renal function, he started to catch up to his peers in terms of growth. Pierson syndrome should be considered during the diagnostic investigations of children with renal manifestations and ocular abnormalities. Children with Pierson syndrome must be evaluated in terms of kidney transplantation as soon as they are diagnosed.     

Recent advances in congenital nephrotic syndrome

PURPOSE OF REVIEW: This review provides a concise update of the most recent literature related to the diagnosis and care of patients with congenital nephrotic syndrome. This topic is of particular interest in light of the rapidly growing body of literature regarding mutations of proteins such as nephrin and podocin that are expressed at or near the podocyte slit diaphragm. RECENT FINDINGS: The phenotypic variance of patients with congenital nephrotic syndrome with nephrin and podocin mutations resulting from triallelic mutations represents an important advance in our understanding of the effect of multiple genetic mutations on clinical disease expression. Clinically, the management of patients with unilateral nephrectomy, rather than the classic bilateral nephrectomy, represents an efficacious alternative management strategy and may impart better chances of graft survival by allowing later transplantation. Identification of a subset of patients with congenital nephrotic syndrome at increased risk of recurrence who also have antinephrin antibodies may enhance our understanding of recurrent disease in congenital nephrotic syndrome after transplantation. SUMMARY: Exciting recent findings in the genotypic/phenotypic correlations of patients with congenital nephrotic syndrome may not only modify our understanding of this disease but may also help to revolutionize our understanding of human genetics. Promising outcomes with unilateral nephrectomy in patients with congenital nephrotic syndrome have permitted transplantation to be delayed and may potentially decrease the risk of complications. New findings regarding recurrence of nephrotic syndrome in patients with congenital nephrotic syndrome after transplantation may lead to improved survival in future renal transplantations.     

First Japanese case of Pierson syndrome with mutations in LAMB2

Pierson syndrome (OMIM 609049) is typically characterized by congenital nephritic syndrome and peculiar ocular anomalies with microcoria. It is caused by mutations in LAMB2, which encodes laminin β2. Approximately 50 mutations of LAMB2 from approximately 40 unrelated families have been identified; however, most of them were from Western countries. Although three patients in Asia with mutations of LAMB2 have been reported, they were not typical cases. We report the first Japanese case of Pierson syndrome with proven causative LAMB2 mutations. She presented with congenital nephrotic syndrome and bilateral microcoria at birth, and developed end‐stage renal disease at 2 months of age. This is the first report of a typical case from Asia. LAMB2 analysis by direct sequencing revealed the compound heterozygous mutations c.3974_3975insA (p.N1325KfsX1331, maternal, novel) in exon 25 and c.4519C>T (p.Q1507X, paternal) in exon 27. The phenotype due to LAMB2 mutations appears to be similar between different ethnic groups.     

Nephrotic syndrome and aberrant expression of laminin isoforms in glomerular basement membranes for an infant with Herlitz junctional epidermolysis bullosa

Herlitz junctional epidermolysis bullosa (H-JEB) is a hereditary bullous disease caused by absent expression of laminin-5, a component of anchoring filaments within the dermal-epidermal basement membrane zone. Affected individuals usually die during the first 1 year of life. We studied an infant with H-JEB who presented with nephrotic syndrome, a previously unreported complication that may contribute to early death in this disease. DNA analysis revealed a compound heterozygote for mutations 2379delG and Q995X in the LAMB3 gene. The patient had massive albuminuria, attributable to failure of the glomerular filtration barrier, and high urinary N-acetylglucosaminidase levels, indicating renal tubular involvement. Electron-microscopic examination of the renal tissue revealed diffuse fusion of the foot processes, irregular swelling of the lamina rara interna, and disappearance of endothelial cell fenestrations. Immunohistopathologic analysis of the patient's renal tissue revealed compositional changes in laminin isoforms of the glomerular basement membrane and no detectable laminin-5 in the renal tubular basement membrane, which suggests that laminin-5 may play an important role in renal function. Our findings strongly suggest that H-JEB should be considered in the spectrum of congenital nephrotic syndromes. Combination therapy with meticulous skin care and treatment strategies established for congenital nephrotic syndromes may rescue patients with this disease.     

Congenital and infantile nephrotic syndrome in Thai infants

Congenital and infantile nephrotic syndrome reported from the Eastern world is rare and might be a different entity from that in the West. In a retrospective review of 10 nephrotic syndrome in Thai infants (5 girls and 5 boys), 7 were diagnosed with congenital nephrotic syndrome and 3 with infantile nephrotic syndrome. Two had congenital nephrotic syndrome secondary to congenital syphilis. All had edema, ascites, and failure to thrive. Of the 3 patients tested for thyroid function, all showed hypothyroidism. Two patients developed renal failure. Renal tissue was examined from 4 patients from 3 biopsies and 2 autopsies; only 1 patient showed tubular microcysts. Symptomatic therapy was performed concurrently with penicillin therapy in 2 patients having congenital syphilis. Prednisolone, cyclophosphamide, captopril, and enalapril were tried in some patients, with little effect. Five patients died from respiratory failure complicated by later infection, 1 patient died from renal failure, and 4 patients were lost to follow-up. Nephrotic syndrome in the first year of life in the Eastern world is rare. Prognosis of nephrotic syndrome in Thai infants at this time is still poor.     

初诊为原发性肾炎型肾病综合征患儿的病因构成分析——对国内儿童原发性肾病综合征临床分型的商榷

目的总结初诊为原发性肾炎型肾病综合征患儿的病因构成情况,探讨国内儿童原发性肾病综合征临床分型的价值。方法纳入2013年1月1日至2017年12月31日北京大学第一医院儿科收治的病初临床诊断为原发性肾炎型肾病综合征患儿,且经肾脏病理检查或基因突变分析明确最终诊断者,排除继发性、遗传性肾病综合征及伴有明显肉眼血尿者。原发性肾病综合征的临床分型参照中华医学会儿科学分会肾脏病学组标准。截取患儿入院时一般情况、入院时诊断和临床分型、肾脏穿刺活检病理检查结果、基因检测结果和最终诊断。结果 28例临床分型为原发性肾炎型肾病综合征的患儿进入本文分析,占同期收治的原发性肾病综合征的10.6%(28/265)。分型依据:25例(89.3%)为镜下血尿,2例为高血压(7.2%),1例为肾功能异常(3.6%)。28例均进行了肾穿刺活检,11例行基因检测,最终诊断:原发性肾炎型肾病综合征5例(17.9%),Ig A肾病10例(35.7%),Alport综合征8例(28.6%),遗传性肾病综合征3例(10.7%),急性感染后肾小球肾炎和纤维素性肾小球肾炎各1例(3.6%)。结论儿童原发性肾炎型肾病综合征临床分型诊断的主要依据为镜下血尿,通过肾脏病理检查和基因检测明确病因,以Ig A肾病、遗传性肾脏疾病等居多,因此,临床诊断儿童原发性肾炎型肾病综合征应该慎重。     

Congenital nephrotic syndrome

In strict sense, the term "congenital nephrotic syndrome" (CNS) refers to those cases of the nephrotic syndrome in which clinical symptoms, e.g. massive proteinuria, hypoalbuminemia and oedema are present at birth. However, the term is often extended to babies presenting with nephrotic syndrome before 3 months of age in whom proteinuria is likely to be present earlier, before the signs of the nephrotic syndrome become clinically manifest. The most common and probably the most severe type of CNS is the congenital nephrotic syndrome of the Finnish type (CNF), which is considered as the prototype of CNS. On the basis of this syndrome the clinical course, diagnosis and complex treatment strategy are described. A well-documented case of Denys-Drash syndrome - a rare type of congenital nephrotic syndrome is also presented.     

Congenital nephrotic syndrome associated with congenital toxoplasmosis

The authors report the case of a 1 month-old infant presenting with congenital toxoplasmosis associated with nephrotic syndrome and microscopic hematuria. Percutaneous renal biopsy showed a diffuse mild increase in mesangial cells and matrix, but immunofluorescence was negative. Electron microscopy revealed the presence of extensive fusion of foot processes. A review of the nephropathy of congenital toxoplasmosis is presented. Outcome seems to be favorable under steroid therapy. The pathophysiology of nephropathy is discussed, as well as the relationships or coincidence between congenital toxoplasmosis and nephrotic syndrome.     

Postural deformities in congenital nephrotic syndrome.

Six successive cases of congenital nephrotic syndrome are described. Each one showed flexion deformities of the knees and hips, widely open anterior and posterior fontanelles, and wide separation of the skull sutures. These abnormalities were present not only in cases in which the renal histology was of the microcystic Finnish type of congenital nephrotic syndrome, but also in those in which the histological picture was one of the variants associated with congenital nephrotic syndrome. It is suggested that such abnormalities are postural deformities, possibly produced by the large placenta.     

Nephrotic syndrome in children

Nephrotic syndrome is the commonest glomerular disease affecting children and is frequently encountered in general paediatrics. The most common subtype is minimal change nephrotic syndrome which typically occurs in preschool children and responds well to corticosteroids. Another subtype, congenital nephrotic syndrome, also presents in the neonatal period or in early infancy when it may be associated with genetic mutations. Such patients do not respond to immunosuppressant therapy. The study of congenital nephrotic syndromes has identified several causative genetic mutations and there have been significant recent advances in the understanding of disease mechanisms in nephrotic syndrome.Complications of prolonged nephrosis, seen in congenital, frequently relapsing, steroid dependent and particularly steroid resistant nephrotic syndromes can lead to significant morbidity. These include sepsis, thrombosis, hypothyroidism and hyperlipidaemia. It is important to identify and manage these complications. Children with nephrotic syndrome should complete the standard vaccination schedule and in addition should be vaccinated against varicella zoster. Live vaccines should be administered when children are in disease remission and on minimal immunosuppression. The management options for children with frequently relapsing or steroid resistant nephrotic syndrome include additional immunosuppression and several agents have been used in this context. These agents will often require additional therapeutic monitoring.     

Congenital glomerulosclerosis and nephrotic syndrome in two infants. Speculations and pathogenesis.

The incidental finding of hyalinized glomeruli in otherwise normal infant kidneys is referred to as congenital glomerulosclerosis. Two infants had extensive glomerulosclerosis manifested by nephrotic syndrome, severe oliguria, and progressive renal failure. Both patients were believed to have had intrauterine infections. These two cases have unequivocally identified congenital glomerulosclerosis as one of the causes of nephrotic syndrome in infancy. In addition, they suggest that extensive glomerulosclerosis in some cases may be a result of congenital infections.     

Congenital nephrotic syndrome with a novel NPHS1 mutation

Congenital nephrotic syndrome of the Finnish type (CNF) is a rare autosomal recessive disorder. The incidence of CNF is relatively high in Finland but considerably lower in other countries. We encountered a male newborn with CNF, associated with compound heterozygous mutations in nephrosis 1, congenital, Finnish type (NPHS1). The patient was admitted to hospital as a preterm infant. Physical and laboratory findings fulfilled the diagnostic criteria of nephrotic syndrome, and were compatible with a diagnosis of CNF, but there was no family history of the disease. On genetic analysis of NPHS1 a paternally derived heterozygous frame‐shift mutation caused by an 8 bp deletion, resulting in a stop codon in exon 16 (c.2156‐2163 delTGCACTGC causing p.L719DfsX4), and a novel, maternally derived nonsense mutation in exon 15 (c.1978G>T causing p.E660X) were identified. Early genetic diagnosis of CNF is important for proper clinical management and appropriate genetic counseling.     

Nephrotic syndrome in Saudi infants in the first year of life

Sixteen Saudi children with onset of nephrotic syndrome in infancy were seen at King Khalid University Hospital, Riyadh over a 5-year period. This figure represented 17% of the 92 cases of childhood nephrotic syndrome seen during the period. Onset of the nephrotic syndrome was less than or equal to 3 months of age in four patients. Ten of the patients developed renal failure. Eight patients died, seven of them by 1 year of age. Two patients given renal transplants have functioning grafts without recurrence of the disease. Renal biopsy in 12 patients showed congenital nephrotic syndrome of the Finnish type (4 cases), 2 each of congenital glomerulosclerosis, mesangioproliferative glomerulonephritis and minimal change disease, and 1 each of focal segmental glomerulosclerosis and tubular amyloidosis. Prognosis of infancy-onset nephrotic syndrome in Saudi children was poor. A significant prognostic factor appeared to be the age of onset of the disease rather than the histological lesion.     

Continuous enteral feeding in pediatric nephrology. Long-term results in children with congenital nephrotic syndrome, severe cystinosis and renal failure (author's transl)

This is the report of the results obtained with continuous enteral feeding in congenital nephrotic syndrome (3 cases), cystinosis (3 cases) and renal failure (3 cases). Ages of patients at the beginning of treatment ranged from 10 days to 3 years. Enteral nutrition was given for periods ranging from 4 to 37 months; mean energetic intake was 116% of the levels recommended according to developmental age and protein diets were 138%; 115% and 84% of the recommended amounts in nephrotic syndromes, cystinosis and renal failure, respectively. This treatment obtained the survival of most patients. In congenital nephrotic syndromes, growth improved clearly with acceleration of the curve and restoration of plasma albumin level. In cystinosis, a better fluid and electrolyte balance was obtained and growth curve sometimes improved in a spectacular fashion. Finally, in renal failure, effect on growth was favourable in 2 cases and nil in the third: these findings show that normalization of energetic intakes does not induce normal growth in children with uremia.     

Focal segmental glomerulosclerosis with and without nephrotic syndrome in children

The clinical presentation, initial laboratory and renal biopsy findings, and course of focal segmental glomerulosclerosis (FSGS) were studied retrospectively in 57 children in order to compare findings in those with and without nephrotic syndrome and to establish factors of prognostic significance. All patients had proteinuria. Eleven patients were otherwise asymptomatic, and nephrotic syndrome did not develop (group 1); 14 patients had asymptomatic proteinuria, but nephrotic syndrome subsequently developed (group 2); 32 patients had nephrotic syndrome (group 3). There were no differences between these three groups with regard to sex, age, initial renal function, incidence of hypertension and hematuria, and pathologic findings. At the latest follow-up, five group 1 patients, six in group 2, and 14 in group 3 had chronic renal failure; the incidence was similar for those with asymptomatic proteinuria and those with nephrotic syndrome. The location of the sclerosis within the glomerulus proved to have prognostic significance. All 12 patients with peripheral FSGS maintained normal renal function, whereas in 25 of the 44 with hilar FSGS chronic renal failure developed.     

DIAGNOSIS OF CONGENITAL NEPHROTIC SYNDROME: A CLINICAL AND A PATHOLOGIC CHALLENGE

The diagnosis of congenital nephrotic syndrome (NS) is a challenge both for clinicians and for pathologists. We observed three cases in a series of 50 children with NS nonresponsive to therapy, corresponding to one case each of minimal change disease, Finnish-type glomerulopathy, and diffuse mesangial sclerosis--two histopathologic studies were performed in each case. The age at presentation did not predict the diagnosis nor the prognosis: The NS presented at 7 months of age in the patient with diffuse mesangial sclerosis, but it was present at birth in the patient with minimal change disease. In these 2 patients the final diagnosis was made with the first renal biopsy. Conversely, in the patient with Finnish-type glomerulopathy, the diagnosis was only possible in the repeat biopsy, as the early pathologic changes were nonspecific. This study shows the essential role of the renal biopsy in determining the etiologic diagnosis and prognosis in patients with congenital nephrotic syndrome.     

Genetics of the nephrotic syndrome

There are a large number of glomerular diseases that may be responsible for a nephrotic syndrome, the most frequent in childhood being minimal change disease. In the past few years, the molecular genetic basis of several conditions that may cause a nephrotic syndrome have been identified. Denys-Drash syndrome and Frasier syndrome are related diseases caused by mutations in the WT1 gene. Familial forms of idiopathic nephrotic syndrome with focal and segmental glomerular sclerosis/hyalinosis have been identified with an autosomal dominant or recessive mode of inheritance and linkage analysis have allowed to localize several genes on chromosomes 1, 11 and 17. The gene responsible for the Finnish type congenital nephrotic syndrome has been identified. This gene, named NPHS1, codes for nephrin, which is located at the slit diaphragm of the glomerular podocytes and is thought to play an essential role in the normal glomerular filtration barrier.     

The association of nephrotic syndrome and renal vein thrombosis: a clinicopathological analysis of eight pediatric patients

Cases with a pathological diagnosis of renal venous thrombosis (RVT) associated with nephrotic syndrome (NS) were studied retrospectively for clinicopathological evaluation. The material consisted of 21 RVT cases which were diagnosed in 2000 consecutive pediatric necropsies, with an overall incidence of about one percent. Eight of the 21 RVT cases were associated with nephrotic syndrome (34%), and this group formed 0.4 percent of the total necropsies in our pediatric center. The glomerulopathies of these nephrotic patients consisted of three cases of Finnish-type congenital NS (FCNS), three cases of renal amyloidosis secondary to familial Mediterranean fever, and two cases of membranoproliferative glomerulonephritis (MPGN). The presence of sepsis associated with disseminated intravascular coagulation, and the morphological age of the thrombi suggested that the RVT was secondary to sepsis in the FCNS cases. In the MPGN and secondary renal amyloidosis cases, the long duration of both the nephrotic state and the administration of diuretics along with glucocorticoid treatment and also the newly formed thrombi without infarction are strong evidences, although not definite, that the RVT developed as a complication of the glomerulopathy. Even though there were no definite clinical criteria for the diagnosis of most of the RVT cases, we would like to emphasize the importance of flank pain, the rapid deterioration of renal functions in a stable nephrotic patient, as well as the hypercoagulable state in the consideration of the development of RVT which indicate the need for appropriate radiological studies for confirmation of this condition during life.     

Congenital nephrotic syndrome in a Nigerian infant

Although nephrotic syndrome is common among African children, the congenital forms of it are rare. This report describes the clinical presentation of a 6-week-old Nigerian infant who presented with marked pedal oedema, heavy proteinuria and serum hypoproteinaemia leading to the diagnosis of congenital nephrotic syndrome. This case is being reported to create awareness about this condition and to highlight diagnostic and therapeutic challenges.     

Nephrotic syndrome in indian children.

A clinicopathological study of 206 Indian children with nephrotic syndrome showed a primary renal cause in 195 (96%), of which 77% were boys. In 126 children (96 boys, 30 girls) onset of the disorder occurred before the age of 5 years. Renal biopsy showed minimal lesions in 150 patients (77%); in 85 of these biopsy was done 3 months to 16 years after onset of the nephrotic syndrome. Significant renal histological abnormalities in 45 cases were labelled as mesangiocapillary 8, mesangioproliferative 4, proliferative with extensive crescents 2, membranous 3, focal segmental glomerulosclerosis 9, focal global glomerulosclerosis 2, advanced nonspecific 8, and mild proliferative 9. Nephritic manifestations were mainly associated with significant renal lesions, which were more frequently encountered when the onset of disease was after the age of 5 years. Clearance of proteinuria with corticosteroid therapy was practically confined to patients with minimal or mild renal histological changes. Our findings suggest that the pattern of idiopathic nephrotic syndrome in Indian children is similar to that reported from Western countries.