We describe the novel association in a girl of nephrotic syndrome due to focal segmental glomerulosclerosis, bilateral sensorineural deafness, basal ganglia calcification, bilateral retinopathy similar to that seen in Coats’ disease, with de novo duplication of a subtelomeric region of chromosome 4q35. The chromosomal duplication was identified during investigation of a possible association with features of fascio-scapulo-humeral dystrophy (FSHD). This duplication has not previously been reported with FSGS and adds to the expanding number of genetic associations with steroid-resistant nephrotic syndrome

A Ottaviani

Allan G. Howatson

B Hinkes

Ben C. Reynolds

David A. Hughes

F Goutieres

JC Greef De

JE Phillips

John Tolmie

K Baker

L Snider

M Pollak

M Zenker

MA Gierson

MM Lowik

Richard J. L. F. Lemmers

RJ Lemmers

RR Allingham

S Prakash

TE Keats

VD D’Agati

YJ Crow

English

PubMed

Crossref

We describe the novel association in a girl of nephrotic syndrome due to focal segmental glomerulosclerosis, bilateral sensorineural deafness, basal ganglia calcification, bilateral retinopathy similar to that seen in Coats' disease, with de novo duplication of a subtelomeric region of chromosome 4q35. The chromosomal duplication was identified during investigation of a possible association with features of fascio-scapulo-humeral dystrophy (FSHD). This duplication has not previously been reported with FSGS and adds to the expanding number of genetic associations with steroid-resistant nephrotic syndrome.Mechanisms of disease, diagnostics and therap

Reynolds, B.C.

Lemmers, R.J.L.F.

Tolmie, J.

Howatson, A.G.

Hughes, D.A.

Leiden University Scholary Publications

Focal segmental glomerulosclerosis, Coats'-like retinopathy, sensorineural deafness and chromosome 4 duplication: a new association

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Focal segmental glomerulosclerosis, Coats’-like retinopathy, sensorineural deafness and chromosome 4 duplication: a new association

BRIEF REPORT
Focal segmental glomerulosclerosis, Coats’-like retinopathy,
sensorineural deafness and chromosome 4 duplication:
a new association
Ben C. Reynolds & Richard J. L. F. Lemmers &
John Tolmie & Allan G. Howatson & David A. Hughes
Received: 23 November 2009 /Revised: 11 January 2010 /Accepted: 12 January 2010 /Published online: 27 February 2010
# The Author(s) 2010. This article is published with open access at Springerlink.com
Abstract We describe the novel association in a girl of
nephrotic syndrome due to focal segmental glomerulo-
sclerosis, bilateral sensorineural deafness, basal ganglia
calcification, bilateral retinopathy similar to that seen in
Coats’ disease, with de novo duplication of a subtelomeric
region of chromosome 4q35. The chromosomal duplication
was identified during investigation of a possible association
with features of fascio-scapulo-humeral dystrophy (FSHD).
This duplication has not previously been reported with FSGS
and adds to the expanding number of genetic associations
with steroid-resistant nephrotic syndrome.
Keywords Nephrotic syndrome . Genetic inheritance .
Glomerulonephritis
Introduction
We describe a 5-½-year-old girl with a prior background of
sensorineural deafness, Coat’s-like retinopathy, basal
ganglia calcification and reflex myoclonus who developed
renal impairment secondary to advanced glomerulosclerosis.
We identified a duplication of a subtelomeric region of
chromosome 4q35 including the D4Z4 repeat array of which
contractions are associated with the muscular dystrophy
FSHD. We discuss the known genetic implications of
D4Z4 and briefly review the genetic basis for nephrotic
syndrome. We highlight how D4Z4 duplication could
theoretically be associated with nephrotic syndrome, and
further discuss the extra-renal manifestations and their
associations.
Case report
A 5½-year-old girl with a complex medical background was
referred with a 12-month history of intermittent peri-orbital
and subsequently pretibial oedema. She was hypertensive at
130/80 mmHg (95th centile 111/73) with significant micro-
scopic haematuria and heavy proteinuria (protein:creatinine
ratio 1.876 g/mmol creatinine, normal <0.020). Plasma
biochemistry suggested chronic renal impairment with urea
10.6 mmol/l, creatinine 111 μmol/l, calcium 1.76 mmol/l,
phosphate 1.99 mmol/l, albumin 12 g/l, parathormone
25.2 pmol/l. Urinary catecholamines, plasma renin and
aldosterone were normal. Anti-neutrophil cytoplasmic anti-
body (ANCA) and anti-nuclear factor antibody (ANA) were
negative. Complement studies showed normal C3, mildly
elevated C4 (0.44 g/l, normal 0.12–0.4 g/l). There was also
hypertriglyceridaemia (21.65 mmol/l, normal 0.4–1.5 mmol/
B. C. Reynolds (*) :D. A. Hughes
Renal Unit, Royal Hospital for Sick Children,
38 Dalnair Street,
Glasgow G3 8SJ, UK
e-mail: pinkdoc@doctors.org.uk
R. J. L. F. Lemmers
Department of Human Genetics,
Leiden University Medical Centre,
Leiden, The Netherlands
J. Tolmie
Department of Clinical Genetics,
Ferguson Smith Centre, Royal Hospital for Sick Children,
Glasgow, UK
A. G. Howatson
Department of Paediatric Pathology,
Royal Hospital for Sick Children,
Glasgow, UK
Pediatr Nephrol (2010) 25:1551–1554
DOI 10.1007/s00467-010-1474-5
l). Renal ultrasound showed mildly echogenic large kidneys
(right 9.2 cm, left 9 cm, both just above 95th centile) [1].
Percutaneous renal biopsy demonstrated obsolescent
sclerosed glomeruli and glomeruli showing variable
degrees of segmental sclerosis, increasing mesangial
matrix and capillary loop thickening. No normal glomeruli
were present. Hyaline droplets and hyalinosis were
visualised in capillary loops. There was tubular atrophy
with foci of interstitial chronic inflammatory cell infiltrate.
Arterial vessels were normal. Immunofluorescence showed
segmental IgM and capillary loop C3 deposition. Electron
microscopy, restricted to sclerosed glomeruli demonstrated
electron dense material in both capillary loops and
mesangium. Appearances were in keeping with advanced
focal and segmental glomerulosclerosis (FSGS) of the “not
otherwise specified” pattern (Fig. 1).
A 4-week trial of prednisolone (60 mg/m2/day) for her
nephrotic syndrome was unsuccessful in reducing her
proteinuria. Angiotensin-converting-enzyme inhibition
(ACEI) was introduced in the form of enalapril (2.5 mg)
to improve blood pressure control and reduce proteinuria.
Nephrotic proteinuria persisted and her function deteriorated
so this was removed after several months. Renal function
rapidly deteriorated over a course of 7 months so she was
commenced on nocturnal automated peritoneal dialysis.
Blood pressure is controlled on amlodipine alone. She is
currently undergoing transplantation preparation.
The patient originally presented to paediatric services
at 8 months of age with left leukocoria and retinal
detachment. A pattern of extensive subretinal exudate,
dilated tortuous vessels and telangiectasia was consistent
with Coats’ disease except that the patient was female.
She was also identified as having bilateral profound
sensorineural deafness. Magnetic resonance imaging
(MRI) of the brain was normal. Computed tomography
(CT) assessment for cochlear implantation identified basal
ganglia calcification. The cochleae appeared normal.
The patient was also known to the Neurology service with
reflex myoclonic jerks triggered by touch only, and three
previous tonic–clonic seizures associated with fever. She did
not require any anti-epileptic medication. Developmentally,
she was identified as delayed, primarily in speech and social
functioning, attributed partly to her sensorineural deafness.
Cochlear implantation markedly improved this, and she
currently attends mainstream education.
The association between Coats’-like retinopathy and
sensorineural deafness had been described in fascio-scapulo-
humeral dystrophy (FSHD). This prompted genetic analysis
despite the absence of muscle weakness and a normal muscle
biopsy. Initial standard genetic testing for FSHD by linear gel
electrophoresis, Southern blotting and hybridisation with
probe p13E-11 suggested a de novo contraction of the D4Z4
repeat array at the subtelomere of chromosome 4q, which is
well described in FSHD [2]. Subsequently, more detailed
genetic analysis of the D4Z4 region was performed by
pulsed-field gel electrophoresis and the use of several
hybridisation probes (p13E11, D4Z4, A and B) and also by
a newly identified simple sequence length polymorphism
(SSLP), 3.5 kb proximal to D4Z4. Hybridisation probes A
and B recognise the region immediately distal to D4Z4 on
chromosomes 4q and 10q. Previously, multiple subtelomeric
chromosome 4q and 10q variants have been identified,
mainly based on the SSLP marker proximal to D4Z4 and
probes A and B distal to D4Z4. Interestingly, only one of the
4qA variants, namely 4A161 seems to be permissive to
FSHD by D4Z4 contractions, while similar contractions on
chromosomes 4qB and 10q do not result in FSHD. Detailed
genetic analysis showed that both parents carry one non-
permissive 4qB chromosome and one permissive 4A161
chromosome, both with a normal sized D4Z4 repeat array.
The patient inherited the 4qB chromosome from her father
and the 4A161 chromosome from her mother, but in addition
an extra 15-kb fragment is visible upon hybridisation with
p13E-11 and D4Z4. This additional short D4Z4 repeat array,
did not hybridise to probe A or B, but the SSLP analysis
showed that it is derived from the permissive maternal
4A161 chromosome. More extensive Southern blot analysis
of NotI-digested DNA fragments confirmed the D4Z4
duplication along with a subtelomeric fragment of at least
100 kb proximal to D4Z4 [3]. Further investigations,
including karyotype and podocin 1 mutation, were normal.
Discussion
We have described a novel association of Coats’-like
retinopathy, sensorineural deafness, basal ganglia calcifi-
cation, and steroid-resistant nephrotic syndrome with
Fig. 1 Haematoxylin and eosin stain demonstrating glomerulosclerosis
and mesangial thickening
1552 Pediatr Nephrol (2010) 25:1551–1554
histological appearances of FSGS. We have identified
duplication of the D4Z4 repeat on chromosome 4q35,
which may account for some, or all, of these features.
Contraction of the D4Z4 repeat is associated with
FSHD and is often used as a confirmatory genetic test
[2]. The D4Z4 array is located in the subtelomeric area of
chromosome 4q and chromosome 10q, and consists of a
number of highly conserved repeat units that are 3.3 kb in
size. Normal individuals have 10–100 copies, whereas the
presence of 1–10 copies is highly associated with FSHD,
though only on a specific haplotype of chromosome 4qA
[2]. Similar D4Z4 repeat contractions on chromosome 4qB
and 10q are non-pathogenic. Intriguingly, the absence of
copies on chromosome 4 (as in monosomy for 4q) has no
FSHD correlate. The D4Z4 repeat unit encodes for a
double homeobox protein DUX4, a transcription activator
with a role in cellular apoptosis [4]. It has been suggested
that stable DUX4 transcription can only emerge from the
most distal D4Z4 unit. Recently, it has been shown that
several sense and antisense transcripts emerge from FSHD
and control myoblast, and therefore the role of these
transcripts in FSHD remains unclear.
Various hypotheses exist as to how contraction of the
array causes disease, including dysregulation of the
normal transcription mechanisms. One such hypothesis
involves signalling via CTCF (CCCTC-binding factor)
and A-type lamins [5]. CTCF is a highly conserved
protein with multiple regulatory roles, including within
chromatin modelling [6]. CTCF binding at D4Z4 appears
enriched in the FSHD disease model [4], though again the
mechanism and effects are uncertain. Much current
research focus within nephrotic syndrome centres around
the podocyte actin cytoskeleton, and this may provide
another cellular target for research. The constellation of
symptoms including retinopathy, deafness, nephrosis, and
cerebral calcification may also suggest a defect within
cilial physiology. The recognition of the pathological
importance of ciliopathies is an expanding field [7]. The
existence of a genetic duplication in an area highlighted as
important in chromatin regulation could be theorised to
lead to cilial dysfunction.
In our case, the association among FSHD, retinopathy
and sensorineural deafness [8] triggered the genetic
analysis, despite the lack of muscle weakness. The more
detailed analysis demonstrated duplication rather than
contraction of D4Z4. The duplicated short D4Z4 repeat
array shows all characteristics of a locus that would
otherwise cause FSHD. There are no previous reports of
renal disease associated with either FSHD or Coats’-like
retinopathy (S. van der Maarel (2010), personal commu-
nication). Duplication of D4Z4 has not previously been
associated with clinical symptomatology. Duplication
within chromosome 4q35 has been identified in heredi-
tary benign intraepithelial dyskeratosis by Allingham et
al. [9], but no other associations are reported. No clinical
correlation between our patient and that described by
Allingham et al. is apparent.
Genetic aetiologies are increasingly recognised in
steroid-resistant nephrotic syndrome [10]. Congenital
nephrotic syndrome of the Finnish type and mutations in
nephrin (NPHS1) have been well characterised. The role
of podocin (NPHS2) mutations is well recognised in its
association with FSGS-related nephrotic syndrome [11].
Several mutations within NPHS2 have now been consis-
tently identified. Mutation within the WT1 gene is
identified in both Frasier and Denys–Drash syndromes.
Other genes with established roles in steroid-resistant
nephrotic syndrome include LAMB2, PLCE1, ACTN4,
CD2AP and TRPC6 [10]. The increasing recognition of
these genes, and the proteins encoded, are elucidating the
molecular pathophysiology of FSGS. The advances here
have been reviewed recently [10, 12].
None of the candidate genes or structural components of
the podocyte is known to localise to 4q35. The pathogenesis
of the nephrotic syndrome in our patient is therefore
impossible to predict. Unfortunately, the original biopsy
demonstrated advanced sclerosed glomeruli preventing
definite clarification of the initial histology. This case may
highlight another area of interrogation for mutational
analysis in children presenting with steroid-resistant FSGS,
and offers a further site for investigation in nephrotic
syndrome models. It is plausible that characterisation of
these gene products may further elucidate the pathological
process within nephrotic syndrome.
The extra-renal manifestations also fail to fit a single
association. The presence of basal ganglia calcification
has been reported with Coats’-like retinopathy in a
number of families [13, 14]. Although other features have
been recognised in combination, none has included renal
disease. The intracranial calcification was identified in our
patient, as part of pre-operative assessment for artificial
cochlear implantation. It is plausible that there may be
other patients with “normal” MR imaging, intracranial
calcification and FSGS. Other patients previously de-
scribed with intracerebral calcification and Coats’-like
retinopathy [14] have also been tested for the duplication,
but this has not been identified.
Eye abnormalities are associated with LAMB2 mutations
in Pierson syndrome [15], though these are distinctly
different from our case. Retinal changes are also seen in
Tetraspanin-22 mutation, whilst TSPAN7 is associated with
developmental delay, and TSPAN24 with glomerulosclerosis
and deafness [12]. It could be theorised that the genetic
defect in our patient affects multiple transpanin function,
leading to this combination of features. Correlation between
FSGS and sensorineural deafness is seen in several
Pediatr Nephrol (2010) 25:1551–1554 1553
conditions, and may be related to a shared structural anomaly
[16]. This correlation has been further highlighted in
mutations affecting mitochondrial genes. The multisystemic
involvement of seemingly disparate organs could suggest
mitochondrial involvement, though the ocular changes in this
case are again notably different. Mitochondrial mutations
leading to nephrotic syndromes have now been described by
several authorities [17]. No prior associations between
cortical reflex myoclonus and FSGS have been reported.
Conclusion
We have described a previously unreported association
between duplication of D4Z4 region on chromosome 4q35
and several clinical features, including the development of
steroid-resistant nephrotic syndrome with histological
appearances of FSGS. This may indicate a further area of
interest in the increasing list of genetic factors influencing
the development of FSGS.
Acknowledgements Professor Silvere Van der Maarel, Department of
Human Genetics, Leiden University Medical Centre, The Netherlands.
Barbara Young, Consultant Pathologist, Western Infirmary
Glasgow, UK.
Sameer Zuberi, Consultant Paediatric Neurologist, Royal Hospital
for Sick Children, Glasgow, UK.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
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A duplication in chromosome 4q35 is associated with hereditary benign intraepithelial dyskeratosis.

Atlas of radiologic measurements, 7th edn.

Coats’ plus: a progressive familial syndrome of bilateral Coats’ disease, characteristic cerebral calcification, leukoencepehalopathy, slow pre- and post-natal linear growth and defects of bone marrow and integument.

CTCF: master weaver of the genome.

D4F104S1 deletion in facioscapulohumeral dystrophy: phenotype, size and detection.

Epigenetic mechanisms of facioscapulohumeral muscular dystrophy.

Extensive brain calcification in two children with bilateral Coats’ disease.

Facioscapulohumeral dystrophy with cochlear hearing loss and tortuosity of retinal vessels.

Inherited podocytopathies: FSGS and nephrotic syndrome from a genetic viewpoint.

Making sense of cilia in disease: the human ciliopathies.

Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review.

Reis A

RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of fascioscapulohumeral dystrophy.

Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome.

The D4Z4 macrosatellite repeat acts as a CTCF and A-type lamins-dependent insulator in fascio-scapular-humeral dystrophy.

The spectrum of focal segmental glomerulosclerosis: new insights.

Vats A

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Focal segmental glomerulosclerosis, Coats’-like retinopathy, sensorineural deafness and chromosome 4 duplication: a new association

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