Familial Nephrotic Syndrome
PATRICIA I. BADER, M.D.* JOHN GROVE, Ph.D.t Indianapolis, Indiana CARL W. TRYGSTAD, M.D. Torrance, California WALTER E. NANCE, M.D., Ph.D.
Indianapolis Indiana
From the Departments of Medical Genetics and Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, and the Di- vision of Nephrology, Harbor General Hospi- tal, Torrance, California. This work was sup- ported in part by the James Whitcomb Riley Memorial Foundation and a grant from the John A. Hartford Foundation, Inc. Requests for reprints should be addressed to Dr. Patri- cia I. Bader. Manuscript accepted April 19, 1973. * Present address: Coylor-Nickel Re- search Foundation, Bluffton, Indiana 46714. 7 Present address: Population Genetics Research Laboratory, University of Hawaii, Honolulu, Hawaii 96822.
Systematic pedigree information was obtained from 70 patients with idiopathic nephrotic syndrome; 16 patients were found to have familial nephrotic syndrome including 1 pair of affected monozygotic twins, 5 affected sibling pairs, 2 affected first cousins from a consanguineous family and 2 patients with spo- radic cases from consanguineous families. Patients with familial and sporadic forms of the disease were compared by applying both clinical and histopathologic criteria. No significant differences were found between these groups, but both had a preponderance of males. In contrast to previous reports, the clinical course in the af- fected monozygotic twins was quite different, providing evi- dence for the importance of environmental influences on the course of this disease. Furthermore, in affected relatives nei- ther the clinical course nor histopathologic classification was necessarily similar. The recurrence risk for siblings of patients with idiopathic nephrotic syndrome was 0.06. Several possible modes of inher- itance were considered. Segregation analysis permitted the ex- clusion of simple recessive inheritance. The invariable concor- dance for the occurrence of nephrotic syndrome in both mem- bers of monozygotic twinships as well as the sex ratio renders a mixed model, with a small proportion of high risk recessive cases, equally unlikely. The available data are most consistent with a polygenic model which assumes a continuous distribu- tion of disease liability with a discreet threshold effect.
In 1951, Fanconi described what he considered to be a dis- tinct form of “familial” nephrotic syndrome of childhood char- acterized by (1) occurrence of the disease in multiple siblings and (2) onset after infancy [1,2]. Other investigators [3,4] sug- gested that “familial” nephrotic syndrome could be distin- guished from congenital nephrotic syndrome, a rare autosomal recessive disease, by the patient’s age at onset, and from spo- radic nephrotic syndrome by its increased severity, poorer re- sponse to therapy and worse prognosis. In a comprehensive review of familial nephrotic syndrome, Norio [5] found 11 pairs of concordant twins (both affected); 16 affected sibling pairs and 11 nephrotic patients with close relatives who were nephrotic. To explain the high incidence of concordance in monozygotic twins and Ihe relatively low in- cidence of affected siblings, Norio concluded that familial ne- phrotic syndrome results from the interaction of abnormal genes carried at several separate genetic loci. Siblings would seldom inherit the same set of required genes, but the identical twin of an affected proband would invariably carry the same geno- type. Additional familial cases were subsequently reported by
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Vernier et al. [6] and Barnett et al. [7]. In 1971, Roy and Pitcock [8] reported a twelfth pair of af- fected monozygotic twins and suggested that when monozygotic twins are affected, the clinical courses and biopsies are similar. This study concerns the clinical findings, renal histopathology and response to therapy of 16 pa- tients with familial nephrotic syndrome in compar- ison with 54 patients with sporadic idiopathic ne- phrotic syndrome. The patient material includes a set of manozygotic twins who had different clinical courses and markedly different pathologic findings on renal biopsy. MATERIAL AND METHODS Seventy consecutive patients with apparent idio- pathic nephrotic syndrome who were referred to the Pediatric Renal Clinic at Indiana University Medical Center from July 1968 through December 1971 were studied. The diagnosis was based upon the presence of the foltowing: edema, pronounced proteinuria, hypo- proteinemia and hyperlipidemia. The patients ranged in age from 28 months to 20 years; 45 were male and 25 female. The clinical evaluation of each patient in- cluded the history, physical examination and laborato- ry tests confirming the diagnosis of nephrotic syn- drome and quantitating renal dysfunction. Patients with systemic diseases associated with glomeruione- phritis and nephrotic syndrome were excluded from the study by criteria outlined elsewhere [9]. A systematic three generation pedigree was ob- tained for each proband, usually from the mother. This type of information is not routinely obtained from pa- tients wi.th the nephrotic syndrome and may explain the high incidence of familial
c ses in our
series. When there appeared to be a family history of the ne- phrotic syndrome, a more detailed pedigree was ob- tained, and the parents, siblings and affected relatives were examined whenever possible. Evaluation includ- ed physical examination, urinalysis and blood counts. Blood samples were also obtained for genotyping, and the phenylthiocarbamide tasting status [lo] was deter- mined for genetic linkage analysis. Dermatoglyphic studies were performed to assist in determining the zygosity of patients who were twins [ll].
The pedigree data
in both familial and isolated cases were subject- ed to segregation analysis [12] to estimate the recur- rence risk for the nephrotic syndrome and to investi- gate its inheritance. Each ipatient with the nephrotic syndrome was clas- sified by clinical severity into one of the following four groups: (1) Steroid-responsive: Patients with the ne- phrotic syndrome who had one to two episodes of edema which was easily controlled by corticosteroid therapy and who currently are not taking any medica- tions. (2) Steroid-dependent: Patients who had numer- ous recurrences of the nephrotic syndrome which were easily controlled with intermittent corticosteroid therapy, but who may have a relapse when corticoste- roid thelrapy
is
withdrawn. (3)
Steroid-resistant, alka-
FAMILIAL NEPHROTIC SYNDROME-l3ADER ET AL,
TABLE
I
Analysis of the Total Population and the Popu- lation with Nonfamilial and Familial Disease with Respect to Sex Incidence, Clinical Grade, Biopsy Classification .__ _ ~~ ~~~ ~~ ~~_.._. ~~~
Total INon- Popu- familial Familial lation Disease Disease Sex incidence Male Female Clinical grade 45 33 12 25 21 4 Steroid-responsive Steroid-dependent Steroid-resistant, alkalating agent-responsive Resistant
Biopsy Classification
4 2 2 26 23 3 31 22 9 9 7 2
Minimal change Major glomerular changes ______ -____. 25 16 9 11 8 3 lating agent-responsive: Patients with numerous recur- rences of the nephrotic syndrome, unresponsive to corticosteroid therapy (often with repeated exacerba- tions even during corticosteroid therapy) but respon- sive to therapy with intravenous nitrogen mustard or oral cyclophosphamide. (4) Resistant: fJatients with the nephrotic syndrome who had progressive disease, evidence of renal failure and did not respond to thera- py with either corticosteroids, nitrogen mltstard or cy- clophosphamide. Classification was made on the basis of a careful review of the clinical records. Percutaneous renal biopsies were periormed in 36 patients [13]. These specimens can be c:lassified into two categories: (1) Those in which all glomeruli were intact, showing at most diffuse minor changes (prolif- erative or inflammatory) on light microscopy (minimal change) [14]; and (2) those in which there were sig- nificant numbers of glomeruli with major structural al- terations similar to those seen in progressive disease processes. These changes range from epithelial prolif- eration to complete glomerular sclerosis (major glo- merular change). RESULTS
Total Patient Population.
The total patient popula- tion included 70 patients, 16 of whom were con- sidered to have familial nephrotic syndrome (Table I). There were 45 males and 25 females, who ranged in age from 28 months
‘to
20
years. The mean age of onset for males (4.38 years) did not differ significantly from that of females (5.52 years). The median age of onset was 3.5 years. The clinical record showed the following: 4 pa- tients steroid-responsive, 26 patients steroid-de- pendent, 31 patients steroid-resistant, alkalating agent-responsive, and 9 patients resistant. Thirty- six patients were studied by renal biopsies. Five of these had two renal biopsies and are classified
January 1974 The American Journtil of Medicine Volume 56 35
 
FAMILIAL NEPHROTIC SYNDROME 6ADER ET AL.
as
IA IR 2A 2B 3A 3B 4A 4B 5A 5D 8A 9A
Figure 1
Pedigrees of patients with familial nephrotic syndrome with clinical grade and histologic classification of renal biopsy specimen when available.
here by the findings on their second biopsy; 25 patients had minimal glomerular changes, and patients had major glomerular changes.
Patients with “Nonfamilial” Nephrotic Syndrome.
Fifty-four patients had no history of affected sib- lings and were not products of consanguineous marriages (Table I); 33 were male, 21 were fe- male. Two patients were steroid-responsive; 23 were steroid-dependent; 22 patients were steroid- resistant and alkalating agent-responsive; and 7 patients were resistant to all medication. This was normally distributed as tested by chi square. The biopsy data can be summarized as follows: 16 pa- tients had minor glomerular changes, and 8 pa- tients had major glomerular changes.
Patients with “Familial” Nephrotic Syndrome.
Sixteen patients had siblings with the nephrotic syndrome or are products of consanguineous matings (Table I); 12 were male and 4 female. Clinical grading was as follows: steroid-respon- sive, 2 patients; steroid-dependent, 3 patients; steroid-resistant, alkalating agent-responsive, 9 patients; and resistant, 2 patients. There was a normal distribution of clinical grades as tested by chi square. The biopsy data can be summarized as follows: 9 patients had minor glomerular changes, and 3 patients had major glomerular changes. positive family history; the details of the case histories of these patients are summarized in Ap- pendix I. In families 1 through 6 sibships were found with two affected children. Family 5 con- tained a set of monozygotic twins, both of whom had the nephrotic syndrome. In family 7, two af- fected first cousins were found who were both off- spring of consanguineous marriages. Two addi- tional (families 8 and 9) cases were considered “familial” because of documented parental con- sanguinity. Parental consanguinity is frequently an indication of autosomal recessive inheritance, and the occurrence of nephrotic syndrome in these families could result from homozygosity for one or more recessive genes. Among patients with affected relatives, consanguinity was found in 2 of 8 families whereas among those with sporad- ic forms of the disease, consanguinity was pres- ent in only 2 of 56 families.
Histologic Findings and Clinical Course in Patients with Familial Nephrotic Syndrome.
Family 1 in- cluded an affected brother and sister. The clinical severity was similar (resistant). The female sib was affected longer, and on renal biopsy progres- sive structural changes were noted; her younger brother showed only minimal changes. Figures 2 and 3 illustrate the histologic differences between the two sibs. In an attempt to search for evidence of clinical In family 2, the two affected males had clinical- heterogeneity, an analysis of variance was em- ly similar disease (steroid-resistant, alkalating ployed to compare the variance in age of onset agent-responsive). Both are now asymptomatic, between families with the variance in age of onset and neither has had a renal biopsy. among family members. The variance among Family 3 contains two clinically similar males families was greater ( F1 = 5.75, p < 0.05). (steroid-dependent). Renal biopsy, performed in Each family can also be internally summarized. one member of the pair, revealed minimal Figure 1 illustrates pedigrees of families with a changes. Both are asymptomatic.
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FAMILIAL NEPHROTIC SYNDROME-BADER ET AL.
Figure 2. Patient 1A. Some glomeruli in this biopsy specimen were entirely normal. Others as illustrated showed glomervlosclerosis
with
surrounding areas of interstitial fibrosis. Some glomervli also displayed prominent periglomervlar fibrosis and others had small foci of mononuclear inflammatory cells surrounding them. In a few glomer- uli there were sclerotic areas which appeared to be segmentally located toward the vascular pole. The remainder of these glomervli were essentially normal. Hematoxylin and eosin stain; srcinal magnification X 150 reduced by 23 per cent. Figure 3. Patient 18. This specimen shows 2 glomeruli with minimal changes. Both displayed slight proliferation but were considered to be minimal change. The tubules were dilated and contained vacuoles in the proximal tubule epithelial cells.
Hematoxy-
lin and eosin stain; srcinal magnification X 750. reduced by 23 per cent. Figure 4. Patient 4A. Twelve glomeruli were present in this biopsy specimen. Two showed complete glomervlosclerosis as illustrated in the
figure,
2 showed slight in-. creases in periodic acid-Schiff-staining material in the mesangial areas and 8 were completely normal. There were also scattered areas of interstitial fibrosis without evi.- dent mononuclear cell infiltrates. Vacvolizafion of fhe fvbvlar epifhelivm was promi- nent. Periodic acid-Schiff stain; original magnification X 150 reduced by 23 per
cent.
Figure 5.
Pafienf 48. All the glomervli in this biopsy specimen showed only minimal changes. There was minimal tubular atrophy and interstitial fibrosis. Hematoxylin and eosin stain; srcinal magnification X 150 reduced by 23 per cent.
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