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Congenital nephrot ic syndrome, Finnish type

Author: Professor Patr ick Niaudet1

Creation Date:October 2001Update: May 2004

1Member of the European editorial committee of Orphanet encyclopedia

Service de nphrologie pdiatrique, Hpital Necker - Enfants Malades, 149 Rue de Svres, 75743 ParisCedex 15, France. [email protected]

AbstractKeywordsDisease name and synonymsDefinitionIncidenceClinical descriptionHistologyTreatmentEtiologyAntenatal diagnosisReferencesAbstractThe congenital nephrotic syndrome of the Finnish type is a hereditary disease with autosomal recessiveinheritance. The gene frequency is approximately 1/200 in Finland.The disease is caused by mutations inthe gene for nephrin, which is a key component of the glomerual ultrafilter, the podocyte slit diaphragm.

The first symptom is fetal proteinuria, which leads to a more than 10-fold increase of the alpha-fetoproteinconcentration in amniotic fluid and a parallel but smaller rise in the maternal serum level. At birth, onenotes a large placenta, whose weight exceeds by 25% the birth weight of the often-premature child. Thenephrotic syndrome starts very early and is severe. Histologically, microcytic dilatations of the tubules areseen while glomeruli are only slightly modified. The nephrotic syndrome is resistant to corticosteroids andimmunosuppressants. Infectious and nutritional complications are common, due to the massive proteinloss. If the child survives, renal function deteriorates justifying initiation of dialysis/transplantation betweenthe ages of 5 and 8 years. The disease does not recur in the graft.

KeywordsCongenital nephrotic syndrome of the Finnish type, autosomal recessive disease, renal failure,corticoresistance.

Disease name and synonymsCongenital nephrotic syndrome of the Finnishtype (CNF)

DefinitionThe term congenital nephrotic syndrome refersto disease which is present at birth or within thefirst 3 months of life. Later onset, between threemonths and 1 year of age, is called infantilenephrotic syndrome. Most of these children havea genetic basis for the renal disease and a pooroutcome. The precise diagnosis of theglomerular lesion is based on clinical, laboratory

and histological criteria. The congenital nephroticsyndrome of Finnish type (CNF) is an autosomal

recessive disease responsible for severenephrotic syndrome with proteinuria beginning inutero.

IncidenceCNF is most common in Finland, with anincidence of 1.2 per 10,000 live births [1,2]. Ithas, however, been described in various ethnicgroups throughout the world [3,4].

Clinical descriptionMost infants with CNF are born prematurely (35-38 weeks), with a low birth weight for gestational

age. The placenta is enlarged, beingrepresenting than 25% of the total birth weight.

Niaudet, P. Congenital nephrotic syndrome of the Finnish type ; Orphanet encyclopedia, May 2004.http://www.orpha.net/data/patho/GB/uk-CNF.pdf 1
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Fetal distress is common and the cranial suturesare widely separated due to delayed ossification.Infants often have a small nose and low ears.Flexion deformities of the hips, knees andelbows are thought to be secondary to the largeplacenta.

Edema is present at birth or appears during thefirst week of life in half of the cases. Severenephrotic syndrome with marked ascites isalways present by 3 months. The proteinuria ishighly selective early during the course of thedisease and hematuria is uncommon, reflectingthe lack of inflammation in the glomeruli. Theurinary protein losses are accompanied byprofound hypoalbuminemia and severehypogammaglobulinemia due in part to loss offiltering selectivity as the disease progresses. Asa result of these changes, nutritional status andgrowth are poor, and affected infants are highly

susceptible to bacterial infections (peritonitis,respiratory infections) and to thromboemboliccomplications due to the severity of the nephroticsyndrome. Hypothyroidism due to urinary lossesof thyroxine-binding proteins is also common.The blood urea nitrogen and creatinineconcentrations are initially normal. Renalultrasonography shows enlarged,hyperechogenic kidneys without normalcorticomedullary differentiation.End-stage renal failure invariably occursbetween 3 and 8 years of age. Prolongedsurvival is possible with aggressive supportive

treatment, including dialysis and renaltransplantation.

HistologyLight microscopy studies of renal biopsyspecimens obtained early duting the course ofthe disease show mild mesangial hypercellularityand increased mesangial matrix in the glomeruli[3,5]. No immune deposits are detected byimmunofluorescence studies. Over time, themesangial matrix increases, accompanied byprogressive glomerulosclerosis.Tubulointerstitial changes are prominent in CNF.

Irregular microcystic dilatation of proximaltubules is the most striking feature; however, thischange is not specific and is not seen in allpatients [6]. Later, interstitial fibrosis, lymphocyteand plasma cell infiltrations, tubular atrophy, andperiglomerular fibrosis develop in parallel withsclerosis of the glomeruli.

TreatmentThe nephrotic syndrome in CNF is alwaysresistant to corticosteroids andimmunosuppressive drugs, since this is not animmune disease. Furthermore these drugs may

be harmful due to the already high susceptibilityto infection, as confirmed by a retrospectivestudy on 21 infants with CNF, who suffered of

(63 verified and 62 suspected) septic episodesover a mean follow-up period of 1 year [7].Standard conservative treatment includes dailyor every other day albumin infusion, gammaglobulin replacement, nutrition with a high-protein, low-salt diet, vitamin supplement and

thyroxine replacement, and prevention ofinfections and thrombotic complications.Nutrients are given by tube feeding or byparenteral alimentation.However, the rate of intercurrent complicationsremains high; growth and development areusually retarded. As a result, some patients mayrequire bilateral nephrectomy to preventcontinued massive protein losses even beforerenal failure develops. Dialysis is then performeduntil the patient reaches a weight of 8-9 kg, atwhich time, renal transplantation can beconsidered [8,9]. No recurrence of the nephrotic

syndrome has been observed aftertransplantation.A possible medical alternative to nephrectomyhas been described in two children. Thecombination of an angiotensin-convertingenzyme inhibitor and indomethacin therapy, bothof which should lower intraglomerular pressure,markedly reduced and led to strikingimprovement of nutritional status and growth[10].

EtiologyCNF is inherited as an autosomal recessive trait,

with both sexes being equally involved.Heterozygous individuals have no manifestationsof the disease.It has been advanced that proteinuria in CNFresults from an inherited error in the structure ofthe glomerular capillary filter. The abnormalgene has been localized to the long arm ofchromosome 19 in both Finnish and non-Finnishfamilies [11-13].The defective gene responsible for CNF, NPHS1was recently cloned [14]. The gene encodes fora transmembrane protein, named nephrin, whichis a member of the immunoglobulin family of cell-

adhesion molecules. Nephrin is specificallylocated at the slit diaphragm of the glomerularpodocytes; which could explain the absence ofslit diaphragms and foot processes in patientswith CNF who have a mutant nephrin protein[15,16].In the original report, four different mutations inthis gene were found to segregate with thedisorder in affected Finnish families [14]. Inanother study, 32 novel mutations in the nephringene were discovered in patients elsewhere inEurope and North America, but no abnormalitieswere found in seven affected individuals

(including the 5' flanking region) [17]. Thesepatients may have mutations elsewhere in thepromoter, intron areas, or a gene encoding

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another protein that interacts with nephrin [18].These results may indicate geneticheterogeneity in the disease.Mutations in the NPHS2 gene, encoding thepodocyte protein, podocin, have been shown tobe associated with steroid-resistant nephrotic

syndrome (SRN). Mutations in the NPHS1 gene,encoding the slit diaphragm protein, nephrin,have been shown to be associated withcongenital nephrotic syndrome of the Finnishtype (CNF). However, recent evidence showsthat NPHS2 alterations are sometimes found inCNF patients who lack NPHS1 mutations. Inaddition, patients with a unique phenotype havebeen identified with mutations in both NPHS1and NPHS2. These findings emphasise theimportance of screening for both NPHS1 andNPHS2 mutations in CNF, especially when noNPHS1 mutation is apparent. [22-24]

Antenatal diagnosisThe CNF becomes manifest during early fetallife, beginning at the gestational age of 15-16weeks. The initial symptom is fetal proteinuria,which leads to a more than a 10-fold increase ofthe alpha-fetoprotein (AFP) concentration in theamniotic fluid. A parallel, but less markedincrease in the maternal plasma AFP level isalso observed. These changes are not specific,but they permit the antenatal diagnosis of CNF inhigh-risk families in which termination of thepregnancy might be considered [19].

Measurement of maternal plasma AFP levels iscurrently the only method available for generalscreening. However, false-positive results dooccur, often leading to abortion of healthyfetuses. Preliminary studies suggest that geneticlinkage and haplotype analyses may diminishthe risk of false positive results in families withpreviously identified mutation(s) [20]. The fourmajor haplotypes, which cover 90% of theNPHS1 alleles in Finland, have been identified,resulting in a test with up to 95 % accuracy.Analysis of the NPHS1 gene is now the methodof choice for antenatal diagnosis in families with

an affected child whose mutation has beenidentified [21].

References1. Hallman, N, Norio, R, Rapola, J. Congenitalnephrotic syndrome. Nephron 1973; 11:101.2. Hallman, N, Hjelt, L. Congenital nephroticsyndrome. J Pediatr 1959; 55:152.3. Habib, R, Bois E. Htrognit dessyndromes nphrotiques dbut prcoce dunourrisson (Syndrome nphrotique "infantile").Helv Paediatr Acta 1973; 28:91.4. Sibley, RK, Mahan, J, Mauer, SM, Vernier,

RL. A clinicopathologic study of forty eightinfants with nephrotic syndrome. Kidney Int1985; 27:544.

5. Huttunen, RP, Rapola, J, Vilska, J, Hallman,N. Renal pathology of congenital nephroticsyndrome of Finnish type. A quantitative lightmicroscopic study on 50 patients. Int J PediatrNephrol 1980; 1:106. Rapola, J, Sariola, H, Ekblom, P. Pathology of

fetal congenital nephrosis: Immunohistochemicaland ultrastructural studies. Kidney Int 1984;25:701.7. Ljungberg, P, Holmberg, C, Jalanko, H.Infection in infants with congenital nephrosis ofthe Finnish type. Pediatr Nephrol 1997; 11:148.8. Mahan, JD, Mauer, SM, Sibley, RK, Vernier,RC. Congenital nephrotic syndrome: Theevolution of medical management and results ofrenal transplantation. J Pediatr 1984; 105:548.9. Holmberg, C, Jalanko, H, Koskimies, O, et al.Renal transplantation in small children withcongenital nephrotic syndrome of the Finnish

type. Transplant Proc 1991; 23:1378.10. Pomeranz, A, Korzets, Z, Wolach, B,Bernheim, J. Finnish congenital nephroticsyndrome (FCNS) managed successfully bycombined captopril/indomethacin therapy.Nephrol Dial Transplant 1993; 8:927.11. Jefferson, JA, Shanks, JH, Maxwell, AP, etal. Congenital nephrotic syndrome of the Finnishtype maps to chromosome 19q in Irish families(abstract). J Am Soc Nephrol 1995; 6:722.12. Kestil, M, et al. Congenital nephroticsyndrome of the Finnish type maps to the longarm of chromosome 19. Am J Hum Genet 1994;

54:757.14. Kestil, M, Lenkkeri, U, Mnnikk, M, et al.Positionally cloned gene for a novel glomerularprotein - nephrin - is mutated in congenitalnephrotic syndrome. Mol Cell 1998; 1:575.15. Ruotsalainen, V, Ljungberg, P, Wartiovaara,J, et al. Nephrin is specifically located at the slitdiaphragm of glomerular podocytes. Proc NatlAcad Sci U S A 1999; 96:7962.16. Tryggvason, K. Unraveling the mechanismsof glomerular ultrafiltration: Nephrin, a keycomponent of the slit diaphragm. J Am SocNephrol 1999; 10:2440.

17. Lenkkeri, U, Mannikko, M, McCready, P, etal. Structure of the gene for congenital nephroticsyndrome of the Finnish type (NPHS1) andcharacterization of mutations. Am J Hum Genet1999; 64:51.18. Shih, NY, Li J, Karpitskii, V, et al. Congenitalnephrotic syndrome in mice lacking CD2-associated protein. Science 1999; 286:312.19. Ryynnen, M, Seppl, M, Kuusela, P, et al.Antenatal screening for congenital nephrosis inFinland by maternal serum alpha-fetoprotein. BrJ Obstet Gynaecol 1983; 90:437.19. Kashtan, C, Mannikko, U, Lenkkeri, U, et al.

Mapping of the congenital nephrotic syndromelocus in North American families (abstract). J AmSoc Nephrol 1995; 6:723.


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20. Mannikko, M, Kestila, M, Lenkkeri, U, et al.Improved prenatal diagnosis of the congenitalnephrotic syndrome of the Finnish type based onDNA analysis. Kidney Int 1997; 51:868.21. Salomon R, Gubler, MC, Niaudet, P.Genetics of the nephrotic syndrome. Curr Opin

Pediatr 2000; 12: 129-34.22. Boute N, Gribouval O, Roselli S, et al.NPHS2, encoding the glomerular proteinpodocin, is mutated in autosomal recessivesteroid-resistant nephrotic syndrome. Nat Genet.2000 Apr;24(4):349-54. Erratum in: Nat Genet2000 May;25(1):12.

23- Koziell A, Grech V, Hussain S, et al.,Genotype/phenotype correlations of NPHS1 andNPHS2 mutations in nephrotic syndromeadvocate a functional inter-relationship inglomerular filtration. Hum Mol Genet. 200215;11:379-88.

24. Caridi G, Bertelli R, Di Duca M, et al.,Broadening the spectrum of diseases related topodocin mutations. J. Am. Soc. Nephrol. 2003;14:1278-86.


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