Background
Idiopathic nephrotic syndrome (INS) in children is caused by various entities that differ in their histopathological forms and their clinical course [
1]. Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most common causes of INS representing 80% and 20% of the cases respectively [
1]. The clinical outcome of INS is determined by the responsiveness to treatment by steroids. Most steroid-sensitive INS (SSINS) are due to MCD, while steroid-resistant INS (SRINS) are mostly represented by FSGS.
Although INS is well known as a sporadic disease, familial occurrences with autosomal dominant or recessive mode of inheritance have been described especially in FSGS forms [
2]. Several genes have been associated with or shown to be causative for some specific forms of INS, mostly steroid-resistant, including
NPHS1,
NPHS2, PLCE1, WT1,
ACTN4,
TRPC6, CD2AP, APOL1 or
INF2[
3]. However, reports of familial MCD are scarce and no causal gene has been identified yet. Here, we describe five cases of steroid sensitive MCD in two non-consanguineous families and perform a review of the literature. The objective of our report is to encourage physicians to identify and characterize genetic causes of MCD. This may help to understand more precisely the pathophysiological mechanisms of INS and provide a first step toward the identification of the underlying genetic cause.
Conclusion
In the past years, many familial FSGS cases have been reported and genetic studies have identified mutations in several genes coding for proteins of the slit diaphragm complex and the podocyte which leads to autosomal recessive (
NPHS1, NPHS2) or autosomal dominant (ACTN4, CD2AP, TRPC6 genes) steroid-resistant FSGS [
1,
4‐
6]. Identification of genes related to FSGS has contributed significantly to a better understanding of the molecular paths involved in SRINS and is an important determinant for the course of the disease. For instance, relapses in renal transplant recipient carrying FSGS genes mutations are rare as compared to FSGS kidney transplant recipients without any gene mutation [
3]. But while important genetic clues have been identified for familial steroid-resistant INS and FSGS, reports of genes causative for familial steroid sensitive INS and MCD are still lacking. This might be due to the low prevalence of the disease and to the few numbers of cases described so far. Here, we report two novel families with 5 cases of MCD. We encourage clinicians to report their cases in order to collect enough families to conduct genetic studies.
Literature review (using PubMed Advanced Search Builder, date: 1960–1980 with the following key words: familial nephrotic syndrome, and the date: 1980–2011 using the following key words: familial minimal change disease, familial nephrotic syndrome) of familial cases of SSINS revealed several reported cases within siblings (Table
1) and only sixteen families with SSINS affecting two generations (Table
2). Several interesting features taken from these reports may help in managing these cases. In their report of fifteen families with childhood-onset SSINS, Fuchshuber et al. [
7] reported that the clinical course of the familial forms was equivalent to sporadic SSINS cases. A strong heritability of the age of onset of the disease was suggested. In this first large report of familial SSINS, linkage with the candidate gene NPHS2 was excluded and the authors concluded the existence of a distinct gene locus for familial SSINS. Landau et al. [
8] reported on several extensive Bedouin families affected by SSINS with similar clinical course - in terms of age of onset, male predominance and spontaneous cure at puberty -compared to those in sporadic cases. By linkage analysis, the authors showed a complete absence of linkage with the usual candidate genes loci implicated in nephrotic syndrome or other glomerulopathies and they advised for more specific genome-wide screening with a denser marker set. In three families with SSINS, Ruf et al. [
9] were able to pinpoint a locus on chromosome 2p12-p13.2, and also demonstrated clear evidence for genetic locus heterogeneity upon examination of ten additional families with SSINS. The rare cases of familial SSINS reported in the literature confirm that the disease course is similar to sporadic cases of SSINS, but clearly distinct from familial FSGS nephrotic syndrome.
Table 1
Reported siblings with SSINS
| 1971 | Identical twins | Biopsy performed in 2 cases |
| 1973 | 18 cases in 9 families | Biopsy performed in 12 cases |
| 1973 | 12 cases from 24 centers in Europe | Biopsy performed in 12 cases |
| 1974 | 1 affected sibling pairs | Biopsy performed in 1 case |
| 1989 | 2 cases in a family | Data not available |
| 1989 | 3 cases in a family | Biopsy performed in 3 cases |
| 2001 | 32 cases in 15 families | Biopsy performed in 12 cases |
| 2003 | 7 cases in 3 families | Biopsy performed in 2 cases |
| 2007 | 6 cases in 2 related families | No biopsy performed |
| 2008 | 2 cases in a family | Biopsy performed in one case |
| 2009 | 2 cases in a family | No biopsy performed |
Table 2
Reported familial cases with SSINS in two generations
| 1973 | A father and his daughter | Biopsy of the daughter only |
| 1974 | 2 affected first cousins from a consanguineous family | Biopsy performed in both cases |
| 1989 | A father and his son | |
Two families with 2 affected first cousins | Data not available |
| 1989 | 3 cases in a family and a cousin | Biopsy performed in all 3 cases |
| 2007 | - 2 families with parent/child affected | Biopsy performed in one case of the 14 affected Bedouin consanguineous family members |
- 2 Bedouin consanguineous family with 14 affected members |
- 5 non-related Bedouin families with 10 affected members |
| 2009 | A father and a daughter | No biopsy performed |
Cases of familial SSINS spread over two generations have rarely been described (see list in Table
2). Outcome, in terms of renal function and blood pressure, is usually favorable [
7] compared to familial FSGS [
18‐
20].
As the majority of familial cases of SSINS reported in the literature is limited to one generation of siblings (Table
1), the first genetic inheritance pattern suggested was autosomal recessive or a possible germinal mosaicism. However, description of familial SSINS cases in two generations (Table
2) with transmission from father to children broadens the disease inheritance possibilities to autosomal dominant transmission model with variable penetrance. Altogether, analysis of the data issued from the literature does not allow definitive conclusions about the inheritance pattern of familial MCD and is permissive for different possible transmission hypothesis, including autosomal recessive, autosomal dominant with variable penetrance or genetic heterogeneity. In addition, a more complex inheritance pattern associated with oligogenic predisposition and possible environmental effects is also possible. More reports of familial MCD are needed in order to understand the disease transmission pattern.
In this report, case 1 presented with typical INS at age six and the follow-up was marked by a single relapse occurring three months after the interruption of the steroids. Renal biopsy was not performed in that case due to rapid favorable outcome. The second case presented with INS at the age of 3 with an initial favorable disease course, later complicated by frequent relapses. A renal biopsy confirmed the diagnosis of MCD. The child eventually showed a favorable evolution after the introduction of MMF. Case 3, a first cousin once removed, presented with a classical INS at age 6 and the renal biopsy showed typical MCD. Despite treatment with corticosteroids, frequent relapses were observed and treated with cyclophosphamide, cyclosporine, and finally, MMF. These 3 cases had normal renal function (estimated GFR using the revised Schwartz formula were 96, 97 and 99 ml/min 1.73 m2 respectively) and blood pressure. Pedigree of this family is compatible with an autosomal dominant inheritance with variable penetrance, but other forms of heritability are possible. A de novo mutation in this family of two affected siblings and their cousin seems less probable though. In the second reported family, renal outcome was also favorable and the pedigree is compatible with an autosomal dominant inheritance. Overall, all familial cases of MCD reported here had a clinical presentation in terms of age of onset, symptoms during the initial phase, renal morphology and outcome close to other familial cases described in the literature.
We are aware of this report’s few limitations. First, it is descriptive and does not propose precise genetic or molecular mechanisms that could explain familial MCD. However, this publication is meant to encourage further reports of similar rare cases that, once collected, may allow wider genetic analysis. Second, recent reports have suggested a role of CD80 induction in the occurrence of
sporadic MCD [
21]. We did not dose soluble CD80 in the urine of the patients presented here and therefore could not conclude about the possible value of this biomarker and this proposed pathophysiological mechanism for
familial MCD.
In summary, here we describe five cases issued from two families with steroid sensitive INS occurring in two generations. The clinical course of these cases was similar to sporadic INS regarding the age of onset, clinical presentation and the presence of minor infection prior to the onset of recurrences, response to treatment and disease outcome. This confirms the few previous observations of familial MCD reported in the literature. The aim of this paper is to emphasize the importance of identifying these families in order to allow further genetic analysis, determine mode of inheritance and understand the mechanisms of INS appearance.
Competing interest
No part of this manuscript has been previously published. The authors declare they have no conflict of interest related to this manuscript.
Authors’ contributions
HC, FC, EG, AJC treated and followed the patients. SR provided the histopathological analysis. FF provided genetic counsels. OB and HC prepared the manuscript. All authors read and approved the final manuscript.