Case 2 -
Imperial College London
Kensington, London, United Kingdom
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The patient was a female referred at age 7 for the investigation of asymptomatic proteinuria initially
diagnosed following a history of abdominal pain. She was one of 4 children and all her siblings were
well. The only family history of note was that her mother had persistent microscopic haematuria. The
patient had no urinary symptoms and she had a normal renal ultrasound. On examination her height was
between the 75th and 90th centile and her weight on the 75th centile for
her age. Blood pressure was 106/64 mmHg. Urinalysis showed 3+ proteinuria and 3+ haematuria but no red
blood cells or casts were seen on urine microsocopy. Urine protein was 2.5g/24 h. Her urinary
proteinuria persisted and so she was admitted for a renal biopsy. Her laboratory results at that time
were as follows:
- Hb 13.6 g/dL
- WBC 6 x 109 per litre
- C3, C4 normal
- Creatinine 56 micromol/l (0.49 mg/dL)
- GFR 96 ml/min/1.6 m2
- Albumin 35 g/l
- ANCA negative
- IgG 8.2 g/l, IgA 1.8 g/l, IgM 0.7 g/l (all normal)
Case 2 - Slide 1
Case 2 - Slide 2
Case 2 - Slide 3
Case 2 - Slide 4
Renal biopsy #1. Representative light microscopy and EM is shown in
Powerpoint slides. Immunoperoxidase staining showed segmental mesangial IgM+, C1q+
She was started on enalapril. Her proteinuria persisted and at age 10 was 2.2 g/24h and so the dose
of enalapril was increased. At age 11 her GFR had decreased to 74 ml/min/1.6 m2 and Renal biopsy #2 was performed
At age 13 her weight was 51.9 kg and height 163.5cm. BP 106/78 mmHg. GFR 52 ml/min/1.6
m2. Her family were very anxious that her GFR had continued to decline and concerned about
the effect of her renal failure on her general health. Her mother commented that her periods had not yet
started and wondered if this was due to the renal impairment and whether a special diet was needed.
Renal biopsy #3 was performed.
Renal Biopsy Interpretation
Biopsy #1: The biopsy contained 49 glomeruli most of which were normal.
Five had prominent areas of increased matrix and increased cellularity and in 2 there were adhesions to
Bowman's space. There were several small foci of tubular atrophy and there were collections of foam
cells in the interstitium. Immunoperoxidase staining on paraffin sections showed some segmental
mesangial IgM+ and C1q+. On electron microscopy the glomerular basement membrane appeared slightly thin
in many areas. In other places there was some thickening but no basket weave pattern was seen. There
were some focal electron dense 'deposits' in mesangial areas. Podocytes showed segmental foot process
The biopsy was interpreted as 'not diagnostic'. It was suggested that there were some features
raising the possibility of hereditary nephropathy but that there was also possibly a focal immune complex
Biopsy #2: The biopsy contained 20 glomeruli of which 3 showed global
sclerosis. Two showed tuft collapse and periglomerular fibrosis and the rest showed mild mesangial
hypercellularity. Six showed segmental areas of sclerosis with hypercellularity in the sclerotic areas.
Tubular atrophy was estimated at 10% and again foam cells were seen in the interstitium.
Immunoperoxidase staining of paraffin sections showed mesangial IgA+, IgM++, C1q++. On electron
microscopy there were some large areas of electron density in the mesangium and occasional
The biopsy was interpreted as most likely IgA nephropathy with segmental scarring. There was said to
be no evidence to suggest hereditary nephropathy
Biopsy #3: The biopsy contained 22 glomeruli of which 9 showed global
sclerosis. The others showed variable changes with some showing a slight increase in mesangial cells and
matrix while others showed a more marked increase. Four had segmental areas of sclerosis with adhesions
to Bowman's capsule. There was about 20% tubular atrophy. There were widespread collections of foam
cells. Immunoperoxidase staining on paraffin sections showed mesangial IgM++/+++ and C3+. On electron
microscopy the capillary basement membrane appeared thin in areas while in other areas there was
thickening with possible lamellation. There was variable mesangial matrix increase. In more scarred
glomerular segments there was accumulation of electron dense material within basement membranes and
The biopsy was interpreted as showing focal and segmental glomerulosclerosis suggestive of some form
of hereditary nephropathy
As noted above her mother had been very concerned that she had not reached puberty and therefore she
was assessed by an endocrinologist. She was noted to have no breast development and only scanty pubic
hair. Blood was sent for measurement of FSH and LH. FSH was >200U/L (normal 3.0-11.0) and LH was 141
(3.0-12.0) consistent with ovarian failure. Her karyotype was 46,XY. On ultrasound she had a small
uterus and small ovaries were identifiable. Subsequently WT1 gene analysis showed a mutation consistent
with Frasier syndrome.
This is a case of a patient with persistent non-nephrotic proteinuria and progressive focal and
segmental glomerulosclerosis. The EM appearances were difficult to interpret and included thin and thick
areas of the basement membrane, mesangial expansion and areas of electron density in the mesangium and
glomerular basement membrane. In the second biopsy, but not in the other two, there was some scanty IgA
which led at that time to a diagnosis of IgA nephropathy. However, on both the first and third biopsies
the suggestion had been raised that there might be a genetic cause.
Genetic causes of FSGS include those shown below
- NPHS1 mutations - nephron
- NPHS2 mutation - podocin
- NPHS3 mutation - phospholipase C epsilon-1
- LAMB2 mutation - laminin β2
- Localized to 11q21-22
- ACTN4 mutations - α-actinin-4
- TRPC6 mutations
- WT1 mutations
- Diffuse mesangial sclerosis
- Denys-Drash syndrome
- Frasier syndrome
Mitochondrial DNA mutations.
WT1 is a zinc finger transcription factor that plays a major role in kidney and gonad development and
the maintenance of podocyte function .
There are 3 well-defined syndromes associated with WT1
Diffuse mesangial sclerosis (DMS) and Denys-Drash syndrome
show similar glomerular pathology with progressive accumulation of mesangial matrix and progression to
renal failure in the first few years of life.
Frasier syndrome comprises male pseudohermaphroditism (XY chromosomes, female external genitalia and
progressive nephropathy and ovarian gonadoblastoma
is composed of 10 exons. Alternative splicing generates four isoforms that are expressed in
stable and definite proportions during development and throughout life: the fifth exon may or may not be
present and an alternative splice site in exon 9 allows the addition of three amino acids (KTS) between
the third and fourth zinc fingers. Frasier syndrome is caused by mutations in the WT1 donor splice site of intron 9 leading to defective splicing of WT1
. This leads to a reduction in the KTS+ transcript compared with controls.
In contrast to the glomerular lesions of Denys-Drash syndrome and DMS the characteristic glomerular
change is FSGS. However, it is clear that there is overlap with some patients with the typical intron 9
mutations having morphological changes of DMS . In addition some
patients may present with FSGS but without the typical features of Frasier syndrome
classification is prognostically important and patients with Frasier syndrome generally have slowly
progressive FSGS, a low incidence of Wilms' tumour and a higher risk of gonadal tumours.
Most reports of the glomerular changes in Frasier syndrome describe a non-specific FSGS but there are
several cases with in which variable thinning and thickening of the basement membrane has been described
and in the report by Ito  these changes were said to resemble those of Alport's syndrome.
- Morrison AA et al. New insights into the function of the Wilms' tumor suppressor gene WT1 in podocytes. Am J Physiol Renal Physiol 295:F12-F17, 2008
- Niaudet P and Gubler M-C. WT1 and glomerular diseases. Pediatr Nephrol 21:1653-1660, 2006
- Frasier SD et al. Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins. J Pediatr 64:740-745, 1964
- McTaggart SJ et al. Clinical spectrum of Denys-Drash and Frasier syndrome. Pediatr Nephrol 16:335-339, 2001
- Barbaux S. Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nature Genetics 17:467-470, 1997
- Denamur E. et al. WT1 splice-site mutations are rarely associated with primary steroid-resistent focal and segmental glomerulosclerosis. Kidney Int 57:1868-1872, 2000
- Aucella F et al. WT1mutations in nephrotic syndrome revisited. High prevalence in young girls,associations and renal phenotypes. Pediatr Nephrol 21:1393-1398, 2006
- Ito S et al. Alport syndrome-like basement membrane changes in Frasier syndrome: an electron microscopy study. Am J Kidney Dis. 41:1110-1115, 2003