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Paediatric Renal Genetic Clinics. Adrian S. Woolf University of Manchester. Children ’ s Hospital and University of Manchester, UK. The Nobel Prize in Physics 2010 Andre Geim and Konstantin Novoselov University of Manchester, UK. Discovered graphene… a new class of material…

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paediatric renal genetic clinics

Paediatric Renal Genetic Clinics

Adrian S. Woolf

University of Manchester

the nobel prize in physics 2010 andre geim and konstantin novoselov university of manchester uk
The Nobel Prize in Physics 2010Andre Geim and Konstantin NovoselovUniversity of Manchester, UK

Discovered graphene…

a new class of material…

….2D atomic crystals

clinical importance of malformations of the human kidney and urinary tract
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.

clinical importance of kidney malformations
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)

slide6

Spectrum of Human Kidney Malformations

Worsening excretory function → →

slide7

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

two paediatric renal genetics clinics
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

renal tract malformation genetics clinic
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
slide11
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.

summary of clinic 2006 2009
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.

multicystic dysplastic kidney mcdk
MULTICYSTIC DYSPLASTIC KIDNEY (MCDK)

Unilateral

MCDK

Cysts →

Atretic ureter →

Contralateral kidney

Often large

(‘hypertrophy’)

Normal urinary bladder

family one
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.
multicystic dysplastic kidney radiology
MULTICYSTIC DYSPLASTIC KIDNEY - RADIOLOGY

Ultrasound scan

32 weeks gestation

Postnatal renal isotope scan

↑ ↑

Shukunami K et al

J Obstet Gynaecol

24:458-459, 2004

‘Normal’ MCDK

kidney (no uptake)

slide17

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

family one1
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.

renal cysts and diabetes syndrome rcad
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)

hnf1b gene expressed in human embryonic kidney
HNF1BGENE EXPRESSED IN HUMAN EMBRYONIC KIDNEY

Kolatsi-Joannou M et al,J Am Soc Nephrol 12:2175-2180, 2001

hnf1b mutations can be associated with diabetes mellitus and pancreas hypoplasia
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 25:782-787, 2008

hnf1b mutations
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

slide23
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 20:1123-1131, 2009

family two
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
family two1
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
expression of anosmin 1
EXPRESSION OF ANOSMIN-1

Glomerular basement membrane

Ureteric bud epithelia

Hardelin JP et al Dev Dyn 215:26-44, 1999

family three
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

optic nerve colboma
OPTIC NERVE COLBOMA

Dutton GN Eye 18:1038-1048, 2004

family three1
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’
breakthrough in 1995
BREAKTHROUGH IN 1995

Sanyanusin P et alNature Genetics 9:358-364, 1995

renal coloboma syndrome
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 alNature Genetics 9:358-364, 1995

Eccles MR and Schimmenti LA Clin Genet 56:1-9, 1999

pax2 transcription factor
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 alJ Clin Invest 98:451-459, 1996

family four
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
fraser syndrome
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

renal features of fraser syndrome
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

fras1 protein and homozyous mutations
FRAS1 PROTEIN AND HOMOZYOUS MUTATIONS

Human Blebbed mouse

FRAS1 codes for a 4007 amino acid protein

(MacGregor L et al Nature Genet 34:203-208, 2003)

in fraser syndrome the ureteric bud ub fails to penetrate renal mesenchyme rm
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

family five
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.

three generations affected by kidney hypoplasia and dysplasia
THREE GENERATIONS AFFECTED BY KIDNEY HYPOPLASIA AND DYSPLASIA

Kerecuk L et al Nephrol Dial Transplant 22:259-263, 2007

three generations affected by kidney malformations mis classification of two adults
THREE GENERATIONS AFFECTED BY KIDNEY MALFORMATIONS:MIS-CLASSIFICATION OF TWO ADULTS

“Focal segmental glomerulosclerosis”

► ◄

“Minimal change nephrotic syndrome”

► ◄

Kerecuk L et al Nephrol Dial Transplant 22:259-263, 2007

family five1
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, HNF1band EYA1 genes
  • ? A new renal malformation gene ?
final thoughts and questions
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)