Revista Română de Medicină de Laborator Vol. 17, Nr. 4, Decembrie 2009

Congenital Nephrotic Syndrome of Finnish Type. A Report of Two Cases

Sindrom nefrotic congenital de tip finlandez – Prezentarea a două cazuri

Carmen Duicu1*, Eva Kiss1, Claudia Bănescu2, Virginia Bodescu1, Zsuzsanna Moreh1, Emöke Horvath3

1. 2nd Pediatric Department, University of Medicine and Pharmacy, Tîrgu Mureş2. Genetics Department, University of Medicine and Pharmacy, Tîrgu Mureş

3. Pathology Department, University of Medicine and Pharmacy, Tîrgu Mureş

Abstract

Congenital nephrotic syndrome of the Finnish type (CNSF) is a rare autosomal recessive disease withhigh infant mortality without aggressive treatment. CNSF is characterized by massive in utero proteinuria andnephrosis at birth. The majority of cases are caused by genetic defects in the components of the glomerular filtra-tion barrier, especially nephrin and podocin. Congenital nephrotic syndrome (CNS) may also be a part of a moregeneralized syndrome or caused by a perinatal infection. Immunosuppressive medication is not helpful in the ge-netic forms of CNS, and kidney transplantation is the only curative therapy. This paper describes the clinical fea-tures and outcome of the last 2 patients from 6 with CNSF who have been admitted to Pediatric Clinics from Târ-gu Mures in the last 15 years.

Keywords: congenital nephrotic syndrome, proteinuria

Rezumat

Sindromul nefrotic congenital tip finlandez este o boală rară, cu transmitere autozomal recesivă având omortalitate infantilă ridicată fară un tratament agresiv. Se caracterizează prin proteinurie masivă „in utero” şi sin-drom nefrotic prezent de la naştere. Majoritatea cazurilor sunt determinate de un defect genetic la nivelul compo-nentelor membranei bazale glomerulare, nefrina şi podocina. Sindromul nefrotic congenital poate fi partea unuisindrom generalizat sau cauzat de o infecŃie perinatală. Tratamentul imunosupresiv nu este eficient în formele gene-tice de sindrom nefrotic, transplantul renal constituind singura opŃiune terapeutică în aceste cazuri. În această lu-crare descriem ultimele 2 cazuri cu CNSF din cele 6 care au fost internate în clinicile de pediatrie din Târgu Mureşîn ultimii 15 ani.

Cuvinte cheie: sindrom nefrotic congenital, proteinurie

*Corresponding author: Carmen Duicu, University of Medicine and Pharmacy Târgu Mureş - 2nd Pediatric De-partment, 38 Gh. Marinescu Str, 540139 Tg. Mureş, RomâniaPhone: +40742092145, Email: duicucarmen@yahoo.com

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Introduction

CNSF is the most frequent of all typesof CNS. It was described for the first time in1959 by Hallman and Hjelt (1). CNSF is inher-ited as an autosomal recessive trait. The propor-tion of affected children in sibships is close to25% (2). CNSF is the commonest form of thedisease and occurs with an incidence of 1.2/ 10000 live births in Finland (3, 4). The disease isnot exclusive to Finland and has been describedthroughout the world.

CNSF is characterized by massive pro-teinuria, a large placenta (over 25% of thechild's birth weight) and nephrotic syndromefrom birth (3, 5). The definition is sometimesextended to children who develop these featureswithin the first 3 months of life (3, 6). The dif-ferential diagnosis includes Drash syndrome,which consists of the triad of Wilms’ tumor,male pseudohermaphroditism, and progressiverenal failure secondary to diffuse mesangialsclerosis; nail-patella syndrome; Lowe syn-drome. Congenital infection with TreponemaPallidum, Toxoplasma gondii, Cytomegalovirusor Human Immunodeficiency Virus can alsopresent with CNS (3, 6-8).

Diagnosis of CNSF in our cases wasbased on massive proteinuria, manifestation ofnephrotic syndrome soon after birth, exclusion ofother types of CNS and typical findings in renalhistology. These cases are reported to createawareness about this clinical entity in this part ofthe world especially among preterm infants.

Patients and clinical features

Since 1995, there have been 6 childrenwith congenital nephrotic syndrome diagnosedat Pediatric Departments from Târgu Mures.

We reviewed the medical records andpathologic specimens of the last two patients (1male- B.R. and 1 female- G.T.) in whom theonset consisted of edema, hypoalbuminemia,hyperlipidemia, and significant proteinuria

within the first month of life. Clinical features,family history, and laboratory data at the timeof presentation and during the evolution of thedisease were assessed in each child. Renal tis-sue from these patients, obtained by autopsy,was reviewed and light microscopy findingswere evaluated by the same pathologist. Themanagement of each infant was supervised by apediatric nephrologist, and included careful his-torical and laboratory evaluation at presentationand during hospital stays. There was no evid-ence of consanguinity or Finnish ancestry inany of these families. Infants with CNSF werediagnosed within the first 5 weeks of life.

Details of pregnancy were available inboth cases, with a normal evolution in both, andspontaneous labour. The gestational age was 38weeks in the first patient with a birth weight of3,3 kg, while in the 2nd patient the gestationalage was 33 weeks and the birth weight was 1,3kg. Placental weight was available in both casesand in each there was no evidence of placento-megaly. Mothers denied any history of renaldisease in their family.

Edema was the commonest presentingfeature. Both infants had similar clinical fea-tures: poor general state, pallor, hyporeactivity,generalized edema, bulky abdomen, hepatomeg-aly, hydrocele (B.R.), umbilical hernia, anteriorfontanella widely opened, dehiscent sutures, de-creased urine output, high blood pressure.

Proteinuria was higly selective (> 85%albumin) and heavy in both infants, up to 5 g/24hours. Renal function was impaired at presenta-tion. Respiratory tract infection was a commonproblem in both cases. None of our patients hadevidence of a congenitally acquired infection aftertesting for specific immunoglobulin antibodiesagainst Cytomegalovirus, Rubella, Herpes Sim-plex Virus, and Toxoplasma (Table 1).

In both cases echocardiography re-vealed an atrial septal defect; G.T. had also pat-ent ductus arteriosus. Abdominal ultrasono-graphy showed renomegaly, loss of cor-ticomedullary differentiation with increased

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parenchymal echogenity, without any evidenceof obstructive pathology.

Management in both cases included ahigh-energy and low-sodium diet; thiazide diur-etics were given daily to reduce edema, Albuminwas given as a 20% solution in a dose of 1-2g/kg day I.V. divided into one or two doses, to-gether with I.V. Furosemide (1 mg/kg). Captopril(0,5 mg/kg/day in two divided doses) was pre-scribed to both infants, but there was no declinein the degree of proteinuria or the need for albu-min transfusion. Additional treatment withSpironolactone was used in both infants. Bothpatients had arterial hypertension (blood pressure110-120/70 mmHg) (> 99th percentile), and bothof them died despite aggressive medical treat-ment because of bronchopneumonia and quickevolution to end-stage renal disease.

Autopsy findings:The other major systems were normal ex-

cept for the respiratory system which showed ed-ematous lungs. The kidneys were slightly edemat-ous. Cut surface of the kidneys was pale with somehemorrhagic spots at the cortico-medullary junc-tion. The cortex had normal thickness, the medullaand thepelvi-calyceal system were normal. Uretersand bladder were macroscopically normal.

Histology report of the kidneys: Renalbiopsies were examined for glomerular, tubular,interstitial, and blood vessel changes. The glomer-uli were assessed for cellularity, sclerosis, andperiglomerular fibrosis. The tubules were assessedfor the presence of atrophy, dilatation or micro-cyst formation. The interstitium was examined forfibrosis and inflammatory cell infiltrate. Light mi-croscopy revealed irregular pseudocystic dilata-tion of proximal tubules with proteic content, a

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Table 1. Laboratory investigation at presentation

B.R. G.T.Blood Count ValuesHemoglobin (g/dl)Leucocyte / mm3

Trombocyte / mm3

1427000189000

1717900170000

Erytrocyte sedimentation rate (ESR) (mm/h) 2 5Serum Chemistry ValueSerum creatinine (mg/dl)Blood urea (mg/dl)Total protein (mg/dl)Albumin (mg/dl)Gamma globulin (%)Cholesterol (mg/dl)Triglyceride (mg/dl)Na+ (mEq/l)K+ (mEq/l)HCO3

- (mmol/L)BE (mmol/L)

2,4494,44,322,073,92384011215,212

-18,3

0,880,93,52,54,22604241325,5--

Serology for TORCH Negativ NegativKaryotype 46, XY 46,XXUrine analysisProtein (mg/dl)Erytrocytes/ high power fieldpHSG

>5001005,5

1010

>3001505

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great number of glomeruli had a fetal appearance,mild proliferation of mesangial cells (Figure 1).Periodic Acid Schiff (PAS) stain suggested tubu-lar casts (Figure 2).

Discussions

Although CNSF occurs mostoften in Finland and Scandinavia,typical cases of CNSF have been re-ported all over the world (1:50000newborns in North America), includ-ing our country (5, 7, 9, 10). The in-cidence of CNSF in Romania is un-known as it is an exceptionally raredisease.

Although uncommon, CNSFcontinues to be a diagnostic and thera-peutic challenge for the pediatrician.

In 1998 Kestila et al identi-fied in the chromosomal region19q13.1 the gene on which differentmutations segregate with the disease(11). This gene NPHS1 (nephringene) encodes a protein called neph-rin which is expressed only in viscer-al epithelial cells of the glomeruliand was found to be defective inCNSF. This supports the hypothesisthat a mutation of the NPHS1 is re-sponsible for both typical and atypic-al CNSF in non-Finnish patients.NPHS1 encodes a podocyte-specifictype 1 membrane protein, nephrin,which belongs to the large immuno-globulin (Ig)-like superfamily. Theprotein has 1241 amino acidresidues, and extracellular part con-sisting of 8 Ig motifs followed by afibronectin type III domain, a shorttransmembrane region and a cyto-plasmic C-terminal part (5). Thenephrin is a cell adhesion moleculespecifically localized at the slit dia-phragm of the glomerular basementmembrane (7, 12). This emphasizesthe role of NPHS 1 in maintaining

proper glomerular filtration.In our cases there was no evidence of

consanguinity as is described in the study made

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Figure 1. Light microscopy reveales irregular pseudocysticdilatation of proximal tubules with proteic content, a great

number of glomeruli have a fetal appearance, mild proliferationof mesangial cells. 400X, Hematoxylin Eosin stain.

Figure 2. Light microscopy suggest tubular casts. 400X, PeriodicAcid Schiff (PAS) hematoxylin stain.

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by Hamed et al where most patients (80%) hadparents who were consanguineous (12).

We did not find placentomegaly, whichis the most important early sign of the diseaseas described in other papers (8, 9), in any of thecases (mean placental/fetal weight ratio 1/6).

The proteinuria was marked and highlyselective in both cases, as described in the liter-ature. According to Niuadet hematuria is un-common, fact that reflects the lack of inflam-mation in the glomeruli (3). In our study bothcases presented microscopic hematuria.

Fluid and electrolyte disturbance werepresent in both cases.

The urinary protein losses were accom-panied by profound hypoalbuminemia andsevere hypogamaglobulinemia.

Congenital heart disease has also beenrarely reported in few cases of CNS. Cardiac le-sions described in these children were pulmonarystenosis and subaortic stenosis (13, 14). However,atrial septal defect and patent ductus arterioasushave been reported in just one case (7).

Infectious and thromboembolic complic-ations are particularly dangerous (12, 15). Noneof our patients presented thromboembolic com-plications, but both cases developed recurrent res-piratory infections, prompting us to start aggress-ive therapy with 3rd generation cephalosporins.

Since CNSF is not an immune disease,it is resistant to corticosteroids and immunosup-pressive drugs, so we did not used these drugsin treating our patients. Furthermore, thesedrugs may be harmful due to already high sus-ceptibility to infection, as confirmed by a retro-spective study made by Ljungberg et al (16).

Aggressive treatment with albumin infu-sions, diuretics, antibiotics, supplemental thyroidpreparations and, sometimes, proteinuria-redu-cing drugs as Indomethacin and angiotensin-con-verting enzyme inhibitor (ACEI) improve theclinical evolution of the affected infants. Further-more early bilateral nephrectomy and renaltransplantation allow a longer life span (7). Thereduction in mortality secondary to CNSF is re-

lated to the introduction of aggressive interven-tional treatment in the past decade (20).

A possible medical alternative to neph-rectomy has been described in two children.The combination of an ACEI and Indomethacintherapy, both of them lowering intraglomerularpressure, markedly reduce proteinuria and ledto significant improvement of nutritional statusand growth (17).

Pomeranz et al (18) described two in-fants with CNS who responded to treatmentwith Captopril (5 mg/kg) and Indomethacin (4mg/kg) (18). Subsequently, Heaton et al havealso reported similar success (19). ACEI andprostaglandin inhibitors have been shown to re-duce proteinuria (18, 20). Prostaglandin inhibit-ors are most effective within 1-3 days, whileACEI show an optimal effect after 4-8 weeks oftreatment. A combination of these drugs wassuccessfully used by Pomeranz et al and Ko-vacevic et al in their studies to reduce protein-uria in children with CNS (18, 20).

In addition, contrary to the reportedlysuccessful clinical control of CNS by ACEI andnon-steroidal anti-inflammatory drugs(prostaglandin synthetase inhibitors) (17, 18, 20),we did not obtain any substantial response in ourpatients when these drugs were used alone(Captopril) similar with the results observed byHamed et al (12). In both cases hyperkalemiawas demonstrated at presentation in our depart-ment; that was the reason we used ACEI onlyand not a combination with indomethacin.

The goals of therapy during the firstmonths are to control edema and possibleuremia, prevent and treat complications such asinfections and thromboses, and provide optimalnutrition so that the child grows and developsas normally as possible. In most cases, kidneytransplantation is the only curative treatment (8,15). This progressive disease leads to death inthe first two years of life; the only curative ther-apy is bilateral nephrectomy followed by renaltransplantation. Renal transplantation after bi-lateral nephrectomy is a successful long-term

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treatment option. Nephrotic proteinuria may re-cur after transplantation as a result of alloim-munization against normal nephrin in the kid-ney graft, requiring increased immunosuppres-sion and plasma exchanges (6).

Kovacevic et al obtained good resultsin CNS patients using early treatment withCaptopril and indomethacin therapy in combin-ation with unilateral nephrectomy. With thistreatment the second nephrectomy, dialysis andtransplantation could be delayed until the 3rd

year of life (20).The typical histological findings of

Finnish congenital nephrosis kidneys are dilatedproximal tubules, mesangial hypercellularity, andglomerular fibrosis and sclerosis (4, 15), similarwith histology kidney reports of our cases.

Because of rapid progression to end-stage renal failure in our cases, we had to make adifferential diagnosis between CNSF and DMS(diffuse mesangial sclerosis). A review of the lit-erature shows that DMS has some features incommon with CNSF: early onset, familial occur-rence with autosomal recessive transmission andtubular ectasia on renal biopsy, but DMS is notassociated with premature birth, low birth weightor placental enlargement and has a characteristicpattern of involving the glomeruli (2).

CNSF is an extremely severe disease ofearly childhood and prenatal diagnosis shouldbe performed in families who previously had anaffected child.

Prenatal diagnosis of CNSF has previ-ously been based on the quantization of alpha-fetoprotein (AFP) in the amniotic fluid and ma-ternal serum during the second trimester, but anincreased AFP is not specific for the disease (7,15, 21). AFP values can be elevated also in oth-er fetal structural abnormalities, such as neuraltube defects and abdominal wall defects (6, 21).If the AFP concentration in amniotic fluid isvery high and the ultrasound examination doesnot reveal fetal anencephaly or other malforma-tions, CNSF is a probable diagnosis.

Prenatal diagnosis is a problem espe-

cially in families with no CNSF history. Im-proved prenatal diagnosis of CNSF, based onDNA analysis of chorionic villus tissue, is nowpossible in developed countries. Genetic ana-lysis is the method of choice for precise CNSFdiagnosis (6, 15, 21). The knowledge of eti-ology helps in assessing management and pro-gnosis, in follow-up for possible associatedsymptoms, and in genetic counseling of thefamily. Prenatal diagnosis in families with aknown risk for CNS should be based on genetictesting whenever possible (6).

Conclusion

The management of children withCNSF in the developing countries is differentfrom that in the developed countries because ofthe considerable cost of care, severe complica-tions and the poor outcome. The early diagnosisof CNSF is important for proper clinical man-agement of the patients, prognosis and geneticcounseling of the families.

In case of cardiovascular disease (cardi-ac heart defect) in a patient with CNS, differen-tial diagnosis must rule out a CNS secondary tointrauterine infection.

Complications of cardiac heart defectlike cardiac failure or infective endocarditismight affect the outcome, so associated anom-alies should be looked for in a child with CNSF.

If pregnancy occurs in families of ourpatients prenatal diagnosis should be done.

We can conclude that in all infants,even if apparently healthy, urinalysis must beperformed soon after birth, to evaluate the pres-ence of CNSF, especially those born from preg-nancies with placentomegalia and increasedmaternal serum AFP levels, when other causeshave been excluded.

Abbreviation list

ACEI = angiotensin-converting enzyme inhibitorBP = blood pressure

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CNS = congenital nephrotic syndromeCNSF = congenital nephrotic syndrome of Finnish-

typeDMS = diffuse mesangial sclerosisIV = intravenousNPHS1 = nephrin gene

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