Paediatric Renal Genetic Clinics

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Paediatric Renal Genetic Clinics

• Adrian S. Woolf
• University of Manchester

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Childrens Hospital and University of
Manchester, UK
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The Nobel Prize in Physics 2010Andre Geim and
Konstantin NovoselovUniversity 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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Spectrum of Human Kidney Malformations

Worsening excretory
function ? ?
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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 173953-3964, 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)
Unilateral MCDK Cysts ?
Atretic ureter ?
Contralateral kidney Often large
(hypertrophy)
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
Ultrasound scan 32 weeks gestation
Postnatal renal isotope scan
? ?
Shukunami K et al J Obstet Gynaecol 24458-459,
2004
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 2000s
• ? 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 1B transcription
• factor mutations (chromosome 17cen-q21.3)

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HNF1B GENE EXPRESSED IN HUMAN EMBRYONIC KIDNEY
Kolatsi-Joannou M et al, J Am Soc Nephrol
122175-2180, 2001
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HNF1B MUTATIONS CAN BE ASSOCIATED WITH DIABETES
MELLITUS AND PANCREAS HYPOPLASIA
Normal Individual HNF1B mutation
Body of pancreas Head of
pancreas Haldorsen IS et al Diabet Med
25782-787, 2008
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HNF1B MUTATIONS

• 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
renal malformations ? 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 201123-1131,
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 mothers 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 21526-44, 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 181038-1048, 2004
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OPTIC NERVE COLBOMA
Dutton GN Eye 181038-1048, 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 9358-364, 1995
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RENAL COLOBOMA SYNDROME
? Autosomal dominant inheritance ? Highly
variable presentation even in the same
family ? Optic nerve colobomas ? Kidney
hypoplasia or dysplasia ? ? Secondary glomerular
lesions ? Ureter malformations
Sanyanusin P et al Nature Genetics 9358-364,
1995 Eccles MR and Schimmenti LA Clin Genet
561-9, 1999
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PAX2 TRANSCRIPTION FACTOR
PAX2 is expressed in the developing eye and renal
tract. It prevents death of undifferentiated
cells
Human fetal ureter Human
fetal kidney Winyard PJ et al J Clin Invest
98451-459, 1996
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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

Human Blebbed mouse
FRAS1 codes for a 4007 amino acid protein
(MacGregor L et al Nature Genet 34203-208, 2003)
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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 173953-3964, 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
22259-263, 2007
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THREE GENERATIONS AFFECTED BY KIDNEY
MALFORMATIONSMIS-CLASSIFICATION OF TWO ADULTS
Focal segmental glomerulosclerosis
? ?
Minimal change nephrotic syndrome
? ?
Kerecuk L et al Nephrol Dial Transplant
22259-263, 2007
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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, HNF1b 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)