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Paediatric Renal Genetic Clinics
Adrian S. Woolf
University of Manchester
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Children’s Hospital and University of Manchester, UK
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The Nobel Prize in Physics 2010Andre Geim and Konstantin Novoselov
University of Manchester, UK
Discovered graphene…a new class of material…….2D atomic crystals
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Clinical Importance of Malformations of the Human Kidney and Urinary Tract
● CHILDREN: Of the 800 children in the UK with renal
failure severe enough to need treatment with dialysis
and kidney transplantation, 40% have renal
malformations.
● ADULTS: Several thousands of UK adults who have
severe renal failure were born with abnormal kidneys.
● FETUSES: Renal tract malformations are among the
commonest anomalies detected upon fetal screening in
mid-gestation.
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CLINICAL IMPORTANCE OF KIDNEY MALFORMATIONS
Three main histological varieties of
kidney malformations:
Hypoplasia (too few nephrons)
Dysplasia (undifferentiated kidney
sometimes with cysts)
Agenesis (absent kidney)
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Worsening excretory function → →
Spectrum of Human Kidney Malformations
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The Beginning of the Kidney:Ureteric Bud (UB)
Penetrates Renal Mesenchyme (RM)
RM
UB
Pitera JE et al Hum Mol Genet 17:3953-3964, 2008
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Back in 1991, Genetics of Human Kidney Development Seemed Rather Simple….
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TWO PAEDIATRIC RENAL GENETICS CLINICS
Between 2006 and 2009, I ran a clinic at Great Ormond Street Hospital, London with a focus
on ‘Genetics of Renal Tract Malformations' … A clinical genetics expert, Prof Raoul Hennekam
sat in with me and advised me. Since moving to Manchester in 2010, I have run a similar clinic with Dr Bronwyn Kerr
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RENAL TRACT MALFORMATION/GENETICS CLINIC
• The idea was see whether we can help with genetic diagnosis and/or counselling in families with either:
• a child with a renal tract malformation and another organ involved, developmental delay, external dysmorphic features etc)
or• a child with a renal tract malformation and one
or more siblings or a parent with a renal tract malformation
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CLINICAL REASONS TO MAKE GENETIC
DIAGNOSES OF RENAL TRACT MALFORMATIONS
● Finding mutations of developmental genes provides
families with reasons why disease occurred.
● Genetic diagnosis may suggest useful future health
screens and also external factors which can be modified
to enhance health.
● Better classification will optimise clinical follow-up
and allow better outcome studies.
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SUMMARY OF CLINIC 2006-2009● Established as a clinical service rather than a
research clinic.
● A few relevant gene tests (especially HNF1B)
available on UK Genetic Testing Network and
comparative genomic hybridization by microarray
available at GOSH from 2008.
● 91 referrals (most from Paediatric Nephrologists
and Urologists), from 68 families.
● 27 children could be assigned to a recognised genetic
syndrome and/or were found to have a mutation
considered to be the cause of the renal malformation.
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MULTICYSTIC DYSPLASTIC KIDNEY (MCDK)
Contralateral kidney
Often large (‘hypertrophy’)
Unilateral MCDK
Cysts → Atretic ureter →
Normal urinary bladder
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FAMILY ONE
• JP – female now a teenager.• Antenatal diagnosis of right multicystic dysplastic
kidney: this involuted (spontaneously disappeared) after birth.
• Left solitary functioning kidney was ‘normal size’ (should be larger than normal) and was echobright on ultrasound scan.
• Between 9 and 12 years old, increasing weight centiles with normal fasting glucose and but raised insulin levels.
• Developed overt diabetes mellitus (non ketotoic) with blood sugar of 30 mM.
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MULTICYSTIC DYSPLASTIC KIDNEY - RADIOLOGY
Shukunami K et al J Obstet Gynaecol24:458-459, 2004
Ultrasound scan32 weeks gestation
Postnatal renal isotope scan
‘Normal’ MCDK kidney (no uptake)
↑ ↑
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INVOLUTION OF MULTICYSTIC DYSPLASTIC KIDNEYS
Neonatal ultrasound………..and two years later
● These massive structures usually ‘involute’ over weeks/months, prenatally or postnatally, often becoming undetectable by US
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FAMILY ONE
● She has a heterozygous mutation of the
hepatocyte nuclear factor 1B (HNF1B)
transcription factor gene
● Predicted to result in aberrant splicing
● Parents have normal kidney US scans
●Mother has normal HNF1B; father not
yet tested.
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RENAL CYSTS AND DIABETES SYNDROME (RCAD)
● RCAD is a relatively newly-recognised syndrome which was defined at the start of the 2000’s● Autosomal dominant or sporadic● Diabetes mellitus (MODY5) and uterus malformations● Renal disease resulting from abnormal development (but not classic ‘diabetic nephropathy’)● Renal cysts (histology showing cystic dysplasia and/or glomerulocystic type of polycystic kidney disease)● Hepatocyte Nuclear Factor 1Btranscription factor mutations (chromosome 17cen-q21.3)
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HNF1BGENE EXPRESSED IN HUMAN EMBRYONIC KIDNEY
Kolatsi-Joannou M et al, J Am Soc Nephrol 12:2175-2180, 2001
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HNF1B MUTATIONS CAN BE ASSOCIATED WITH DIABETES MELLITUS AND
PANCREAS HYPOPLASIA
Body of pancreas Head of pancreas
Haldorsen IS et al Diabet Med 25:782-787, 2008
NormalIndividual
HNF1Bmutation
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HNF1BMUTATIONS• Great Ormond Street Nephrology Unit
• Since we started looking in 2001, up to 2007 we found 21 families with mutations of HNF1B
• Renal phenotypes are rather varied and include MCDK, solitary functioning kidney,
cystic dysplastic kidneys, pelviureteric junction obstruction and the glomerulocystic variety of polycystic kidneys
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HNF1B Mutations not only Cause Renal Malformations but also Lead to
Abnormal Kidney Physiology after Birth
● Blood magnesium levels in children with renalmalformations
● Those with HNF1B mutations can have low blood magnesium levels
● HNF1B transactivates FXYD2, a gene implicated in magnesium handling in the distal convoluted tubule
Adalat S et al
J Am Soc Nephrol 20:1123-1131, 2009
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FAMILY TWO• CK – male 5 years old• Presented with icthyosis and undescended
testicles• Found to have a hypoplastic left kidney and
normal sized right kidney• Two of his mother’s brothers also had
icthyosis• One of them had a solitary functioning
kidney and went into end-stage renal failure
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FAMILY TWO• Index case and his two uncles have X-linked
Kallmann syndrome. Recessive condition, so female carriers are well
• The gene is expressed in the ureteric bud and collecting ducts, and also in the front of the brain
• Patients have anosmia, hypogonadotrophic hypogonadism and often have unilateral renal agenesis
• In the index case, the icthyosis is caused by a continguous gene deletion of the Steroid Sulphatase gene
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EXPRESSION OF ANOSMIN-1
Glomerular basement membrane
Ureteric bud epithelia
Hardelin JP et al Dev Dyn 215:26-44, 1999
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FAMILY THREE• LS – one year old
• Normal antenatal renal scan
• Respiratory distress
• Found to have raised creatinine and
bilateral hypoplastic kidneys
• Visual impairment with abnormal visual
evoked potentials
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Dutton GN Eye 18:1038-1048, 2004
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OPTIC NERVE COLBOMA
Dutton GN Eye 18:1038-1048, 2004
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FAMILY THREE• Index case has heterozgous mutation of
the Paired Box 2 (PAX2) gene
• Renal coloboma syndrome
• Commonest renal lesions are hypoplasia; VUR and MCDK also reported
• Father of the index case has ‘slightly anomalous optic disc up’
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BREAKTHROUGH IN 1995
Sanyanusin P et al Nature Genetics 9:358-364, 1995
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RENAL COLOBOMA SYNDROME
Sanyanusin P et al Nature Genetics 9:358-364, 1995Eccles MR and Schimmenti LA Clin Genet 56:1-9, 1999
● Autosomal dominant inheritance● Highly variable presentation even in the same family● Optic nerve colobomas● Kidney hypoplasia or dysplasia● ? Secondary glomerular lesions● Ureter malformations
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PAX2 TRANSCRIPTION FACTOR
Human fetal ureter Human fetal kidney
Winyard PJ et al J Clin Invest 98:451-459, 1996
PAX2 is expressed in the developing eye and renal tract. It prevents death of undifferentiated cells
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FAMILY FOUR• ES – female 2 years old
• Presented with ‘hidden eyes’ (cyryptophthalmos), laryngeal web, fused fingers and toes, abnormal genitalia and malformed hindgut.
• Has a solitary, pelvic kidney
• Previous sibling – terminated and had bilateral renal agnenesis
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FRASER SYNDROME
● Autosomal recessive
● Slavotinek and Tifft (J Med Genet
2005) reviewed 117 cases……..
Major criteria: cryptophthalmos,
syndactyly, abnormal genitalia,
and a sibling with Fraser syndrome
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RENAL FEATURES OF FRASER SYNDROME
● Slavotinek and Tifft (J Med Genet 2005)
review of 117 cases…….
27% had ‘bilateral renal agenesis’
19% had ‘unilateral renal agenesis’
14% had renal ‘cystic dysplasia’
14% had renal ‘hypoplasia’
20% had absent or small urinary bladder
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FRAS1 PROTEIN AND HOMOZYOUS MUTATIONS
(MacGregor L et al Nature Genet 34:203-208, 2003)
Human Blebbed mouse
FRAS1 codes for a 4007 amino acid protein
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IN FRASER SYNDROME THE URETERIC BUD (UB) FAILS TO
PENETRATE RENAL MESENCHYME (RM)
RM
UB
Pitera JE et al Hum Mol Genet 17:3953-3964, 2008
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FAMILY FIVE• AF – female index case now seven years old
• Potter sequence (oligohydramnios and
bilateral renal malformation) in two previous
siblings.
• Oligohydramnios at 33 weeks gestation.
• Subsequently she had a diagnosis of bilateral
renal hypoplasia/dysplasia
• Aged 3 years, her renal function was about
1/5th of normal.
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THREE GENERATIONS AFFECTED BY KIDNEY
HYPOPLASIA AND DYSPLASIA
Kerecuk L et al Nephrol Dial Transplant 22:259-263, 2007
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THREE GENERATIONS AFFECTED BY KIDNEY MALFORMATIONS:
MIS-CLASSIFICATION OF TWO ADULTS
Kerecuk L et al Nephrol Dial Transplant 22:259-263, 2007
► ◄
► ◄
“Focal segmental glomerulosclerosis”
“Minimal change nephrotic syndrome”
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FAMILY FIVE• Looks like an autosomal dominant
disorder
• Very variable expression of kidney disease with fetal, childhood and adult presentations
• No syndromic clinical features
• Normal analyses of PAX2, HNF1 and EYA1 genes
• ? A new renal malformation gene ?
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FINAL THOUGHTS AND QUESTIONS• Genetic testing may cost several hundred Euros
but……• Finding a mutation provides a family with an answer to
their often long-sought question “why was my child born with a kidney malformation?”
but…..• Should we perform genetic and/or renal ultrasound
screening of parents, siblings and the ‘next generation’.• Nephrologists need to link-up with clinical geneticists
for help with counselling • Why can the severity of renal malformation vary
considerably within one family? (‘modifying’ genes)