INTRODUCTION
Steroid-resistant nephrotic syndrome (SRNS) is caused by a defective expression of podocyte-specific proteins resulting from genetic defects in ∼30% of cases [1].
Identification of such genetic cause in children is of utmost importance for genetic counselling, to avoid ineffective and potentially harmful therapies [2] and to start early suitable treatment in rare instances such as ubiquinone Coenzyme Q10 (COQ10) deficiency and hopefully in the near future—to offer-specific variant-based therapies, to predict the recurrence risk after transplantation and to select potential intra-familial kidney donors.
STRATEGY LEADING TO GENETIC TESTING
A comprehensive genetic screening comprising all SRNS-related genes is recommended (gene panel or whole exome sequencing) in:
Children with congenital or syndromic nephrotic syndrome (NS)
Children who do not respond to an initial 4-week course of steroids after exclusion of differential diagnoses by kidney histology [2].
Monogenic variants in >50 genes have been identified as the aetiology of SRNS in ∼30% of children with SRNS and 50% in consanguineous families [1] (Figure 1).
No genetic cause has been definitely identified in children with steroid/immunosuppressant sensitive NS to date including in familial forms [3].
Diagnostic flowchart of steroid-resistant nephrotic syndrome in children the contours of the squares and arrows appear irregular on the figure.
CONGENITAL NS
Congenital NS (CNS) is defined by NS starting in utero or before the age of 3 months.
Enlarged fetal nuchal translucency, enlarged hyperechoic kidneys, increased amniotic fluid alpha-foetoprotein, fetal oedema, oligohydramnios and large placenta weighting >25% of newborn weight are suggestive (although non-specific) of CNS.
Rarely caused by congenital infections or alloimmune maternal disease, it is mostly due to podocyte genetic defects (60–70%).
Bi-allelic NPHS1 variants account for 78% of cases with identified variant [4]. Kidney lesions are typically but not exclusively mesangial hypercellularity, hyperlobulated capillary tufts and microcystic dilation of proximal and distal tubules with diffuse podocyte foot process effacement.
Other genetic causes include mainly NPHS2, WT1, PLCE1 or LAMB2 variants [1].
Clinical examination should be performed to identify possible associated extrarenal manifestations: genital examination, dysmorphic signs and skeletal abnormalities, ophthalmological and neurologic examination, hearing test [5].
Kidney biopsy is not routinely indicated but may be considered in absence of identified causative variant. It can reveal diffuse mesangial sclerosis (DMS) in case of WT1, PLCE1 or (rarely) LAMB2 variants.
Treatment is supportive to prevent CNS complications (hypovolaemia, thromboses, infections, failure to thrive, etc.) until End-Stage Kidney Disease (ESKD).
Most children progress to ESKD from early infancy to adulthood.
Few patients with truncated NPHS1 variants can develop de novo autoimmune-mediated NS due to anti-nephrin antibody deposition in the kidney graft .
NON-SYNDROMIC SRNS
The frequency of a monogenic cause of SRNS decreases with increasing age [1]:
4–12 months: 50%
13 months to 6 years: 25%
7–12 years: 18%
13–17 years: 11%
Autosomal recessive (AR) causes are more frequent and tend to occur earlier than autosomal dominant (AD):
Main causes are NPHS2 variants followed by NPHS1 or PLCE1 variants.
NPHS2 variants are more likely to cause early-onset SRNS [6] except for the p.R229Q variant, which is pathogenic only when trans-associated with specific pathogenic variants in exons 7 and 8 and leads to late-onset NS in adolescents and young adults [7].
AD forms are rare in children and start later than AR ones, except for WT1-related NS (see below). They have incomplete penetrance and variable expressivity. TRPC6 variants are responsible for 5–10% of NS with AD inheritance [8]. Most patients develop proteinuria in the second or third decade, but more and more children with de novo variant develop proteinuria/NS during childhood.
Treatment is symptomatic and consists of renin–angiotensin–aldosterone system blockers, cautious use of diuretics, prevention of NS complications (vaccination, vitamin D, thyroid hormone substitution, etc.), conservative management of CKD then renal replacement therapy.
SYNDROMIC SRNS
WT1-related syndromes
WT1-related NS has a peak of onset at 4–12 months [1, 9], then a regular distribution among adolescents and young adults. WT1 variants are found in 2–5% of children with hereditary SRNS [1]. Almost all pathogenic variants are de novo, but some with AD inheritance were reported [10, 11]. Distinct WT1 variants may cause isolated or syndromic NS depending on the variant and karyotype [12]. All patients with WT1 pathogenic variants should undergo renal ultrasound every 3 months until 7 years to detect Wilms’ tumour [13].
Denys–Drash syndrome due to exon 8 or 9 variants: CNS or infantile SRNS with DMS, male pseudohermaphrodism (46XY sexual development disorder with sex inversion) and susceptibility to Wilms’ tumour.
Frasier syndrome due to a specific intron 9 splice-site variant: SRNS with focal segmental glomerulosclerosis (FSGS) lesions, male pseudohermaphrodism and susceptibility to gonadoblastoma.
Heredity is AD, with variable penetrance and expressivity.
Mitochondriopathies
Variants in nuclear genes encoding mitochondrial proteins involved in coenzyme-Q10 biosynthesis account for ∼3% of genetic SRNS cases [1]: COQ2, PDSS2, COQ6 and COQ8B (previously ADCK4), the latter being the most commonly mutated gene.
COQ8B variants accounting for 0.7–7% of hereditary SRNS may be isolated or associated with neurological and behavioural perturbances [14]. Patients progress to ESKD during adolescence.
Pathogenic variants in other genes can cause Leigh’s syndrome (PDSS2), sensorineural deafness (COQ6) and cardiomyopathy, seizures, encephalopathy or nystagmus (COQ2) from the neonatal period through adolescence [1].
Coenzyme-Q10 supplementation may be effective in reducing proteinuria [14].
Pathogenic variants in mitochondrial gene MT-TL1 are responsible for Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like (MELAS) that can be associated to NS with maternal inheritance and variable expressivity.
Galloway–Mowat syndrome (GAMOS)
Patients develop progressive proteinuria or NS during the first few months of life, with DMS or FSGS on kidney biopsy, associated with microcephaly and neurological features.
Pathogenic variants in nine genes are responsible for >100 reported cases of Galloway–Mowat syndrome (Figure 1) [15–17].
Nail-patella syndrome [18]
Caused by LMX1B variants of AD inheritance.
Associates: dysplasia of the patellae, nails and elbows; iliac horns; glaucoma with renal involvement (proteinuria ± renal failure; focal or diffuse irregular thickening of the GBM) in 30–40% of cases.
Schimke syndrome [19]
Caused by SMARCAL1 variants with AR inheritance.
Associates short stature, spondyloepiphyseal dysplasia, defective cellular immunity and progressive ESKD.
Fifty per cent of patients develop arteriopathy with cerebral infarction.
Cognitive development is generally normal.
Pierson syndrome [20]
Caused by AR LAMB2 variants.
Associates ophthalmologic malformations (microcoria, retinal abnormalities) and DMS.
Isolated NS can also be caused by variants in genes usually associated with syndromic forms of NS such as WT1, INF2, LMX1B, COQ genes and MT-TL1.
CONFLICT OF INTEREST STATEMENT
None declared.
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