Genitourinary abnormalities in EB

1
Genitourinary abnormalities in EB
Jemima Mellerio St Johns Institute of
Dermatology Great Ormond Street Hospital London
UK
2
GU abnormalities in EB

• Little in literature
• Mainly one-off case reports
• Data from NEBR
• Little practical guidance on monitoring or
  management

3
GU abnormalities in EB

• Which GU problems arise?
• Which types of EB get which problems?
• What is the scale of GU problems?
• Cases from Great Ormond Street
• Can we formulate some protocols for screening and
  management?

4
Which GU problems arise?
Kidneys
Renal parenchyma
Ureters
Collecting system
Bladder
Urethra
5
Which GU problems arise?

• 4 main patterns seen
• Acute or chronic glomerulonephritis
• Renal amyloidosis
• IgA nephropathy
• Obstructive uropathy

6
Acute or chronic glomerulonephritis

• Secondary to streptococcal or other infection
• Presentation
• Probably need to treat infection to enable
  resolution

7
Acute or chronic glomerulonephritis

• Despite treatment may lead to

8
Acute or chronic glomerulonephritis

• Described in RDEB and JEB
• Most skin fragility therefore more likely
  assoiciated skin infection

9
Renal amyloidosis

• Amyloid secondary to chronic antigen stimulation
  and inflammation
• Elevated serum amyloid A protein
• Presentation of nephrotic syndrome

10
Renal amyloidosis

• No specific treatment and may lead to

11
Renal amyloidosis

• Described only in RDEB
• Presumably could occur in any severe
  (longstanding) form of EB

12
IgA nephropathy

• Cause not fully understood
• Possibly from chronic mucosal infection
• Presentation

13
IgA nephropathy

• No specific treatment and may lead to

14
IgA nephropathy

• Described only in RDEB
• Presumably could occur in any severe
  (longstanding) form of EB

15
Obstructive uropathy

• Predominantly at vesico-ureteric junction and
  urethra
• Presentation

16
Obstructive uropathy

• If untreated leads to

17
Obstructive uropathy

• Strictures of urethra, including meatus, in RDEB,
  JEB and Kindler syndrome
• VUJ obstruction in JEB especially EB with pyloric
  atresia

18
EB with pyloric atresia

• Usually fatal in infancy
• Survivors may have profound morbidity from GU
  tract disease
• Bladder wall thickening, blistering and fibrosis
• VUJ obstruction
• Congenital focal segmental gloemrulosclerosis
  described

19
Which GU problems arise?

• Exacerbating factors in EB
• Dehydration (reduced oral intake, increased fluid
  loss from skin or gut)
• Chronic skin colonisation and infections
• Surgical intervention
• Constipation

20
The scale of GU problems in EB

• Difficult to ascertain in great detail
• Largest series from National EB Registry in US

21
Frequency of clinical complications ()
From Fine et al. 1999
22
Risk of death from renal failure in EB

• Notable cumulative risk of death for severe RDEB
  increasing from age 15 years (second only to SCC)
• Plateaus at 12 by age 35 years
• Risk for other types lt2 in total

Fine et al. 2004
23
Case 1
24
Case 1

• 11 year old boy with non-Herlitz JEB (LAMB3
  mutations)
• Born with coronal hypospadias
• Repaired 1999 (age 4 y)
• 2000 difficulty voiding
• Urethral dilatations Mar and Oct 2001
• Still pain tip of penis on voiding and poor
  stream

25
Case 1

• Dec 2001 EUA and ventral meatotomy
• 2002 suprapubic catheter - unable to clamp due to
  pain
• 2004 urethral dilatation
• 2005 meatotomy
• Apr 2006 midpenile urethrostomy showed adhesions
  in posterior urethra

26
Case 1

• Sep 2006 urethrostomy - inflammation and stenoses
• Self-dilatation at home with ultrapotent topical
  steroids
• ? where next
• Appendix Mitrofanoff?
• Fertility issues

27
Case 2
28
Case 2

• 13 year old boy with non-Herlitz JEB (laminin
  5-deficient)
• Dysuria and penile blisters 2002 (age 9 y) -
  normal urodynamic studies
• Sep 2005 renal USS
• 2 echogenic foci Rt kidney
• calculus distal Lt ureter
• mild Lt ureteric dilatation

29
Case 2

• Nov 2005 acute urinary retention for 30 h
• Bladder to umbilicus
• Constipation treated with enema
• Still no urine - suprapubic catheter
• USS normal
• KUB normal

30
Case 2

• Clamp and release suprapubic catheter - no PU for
  48 h
• Antegrade cystogram no stricture
• Started to PU on clamping
• 4 days after admission calculus appeared at
  meatus
• Removed with minor meatotomy
• Tests showed idiopathic hypercalciuria

31
Case 2

• Had poor oral intake and no gastrostomy
• Did not PU at school and only 1-2x per day at
  home
• Constipation (on opiates)
• Subsequent gastrostomy and adequate fluid and
  nutritional input
• BP, urinalysis and KUB normal

32
Case 3
33
Case 3

• 15 year old boy with severe RDEB
• Jan 2005 (age 13 y) macroscopic haematuria and
  trace protein
• Jun 2005 acute renal failure 2o to acute tubular
  necrosis with hypernatraemic dehydration
• Na 171, urea 40.2, creat 239
• Hypertensive - amlodipine

34
Case 3

• ? Post-infectious raised ASOT and DNAase
• ? Due to reduced fluid intake
• Renal US small Rt kidney, nil focal
• Renal function recovered to baseline level with
  rehydration

35
Case 3

• 2006 ongoing haematuria /- proteinuria
• Increased gastrostomy and oral fluids (3L per
  day)
• Hypertension well-controlled
• Renal USS normal
• Refused IV access for DMSA
• Holding off renal biopsy at present

36
Case 3

• Dehydration a significant contributing factor
• Still in diapers
• Was restricting fluid intake so no need to PU at
  school
• Allowing diaper change only once a day
• Now using bottle to PU but diaper for BO

37
Case 4
38
Case 4

• 8 year old boy with EB with pyloric atresia
  (mild)
• 2001 (age 3 y) diarrhoea and vomiting on trip to
  Pakistan
• Developed protein-losing enteropathy
• Settled with parenteral nutrition and prednisolone

39
Case 4

• 2002 further episode of protein-losing
  enteropathy after campylobacter infection
• Settled with prednisolone and azithromycin
• 2002-3 younger brother also with EB-PA died due
  to severe gut involvement

40
Case 4

• Mar 2005 protein on urinalysis
• Aug 2005 penile pain on urinating, frequency, no
  UTI
• USS 2cm thick polypoid thickening of bladder
• Cystoscopy haemorrhagic, polypoid oedematous
  lesion in dome of bladder, rest of bladder
  haemorrhagic

41
Case 4

• Bladder biopsy fragmented epithelium with
  inflammatory cells. No tumour
• Started on prednisolone 30mg od for 1 week with
  improved symptoms
• When steroids weaned, symptoms and haematuria
  recurred

42
Case 4

• Nov 2005 started Elmiron in addition to
  prednisolone
• Currently continues Elmiron and pred 2.5mg od
• USS normal kidneys, bladder wall thickening
• DMSA normal
• 2006 further episode PLE requiring methyl
  prednisolone and IVIG

43
Case 4

• Elmiron (pentosan polysulphate sodium)
  heparin-like molecule
• Indication interstitial cystitis
• Anticoagulant and fibrinolytic effects
• Mechanism in IC unknown may line bladder wall,
  may have an effect on cytokines

44
Case 5
45
Case 5

• 15 year old boy with EB with pyloric atresia
  (mild) with ITGB4 mutations
• 1993 (age 2.5 y) macroscopic haematuria and
  dysuria
• Cystoscopy normal urethra, haemorrhagic
  cystitis, urothelial debris
• Suprapubic catheter inserted

46
Case 5

• Extreme pain on clamping SP catheter
• 1995 (age 5 y) vesico-ureteric reflux
• UTIs
• hydronephrosis
• bladder outflow obstruction
• dribbling
• pain on voiding
• SP catheter still in

47
Case 5

• 2000 (age 9 y) hypertension
• proteinuria
• bilateral VU reflux
• bilateral renal calculi
• pyelonephritis
• scarring Rt kidney
• SP catheter still on free drainage due to pain
  when clamped

48
Case 5

• 2002 (age 11 y) small Rt kidney
• Lt kidney 2 calculi
• Cystoscopy attempted but not possible due to
  stricture proximal to meatus
• Percutaneous removal of calculi
• SP catheter still in

49
Case 5

• 2003 (age 12 y) Rt nephrectomy, ileocystoplasty
  and appendix Mitrofanoff
• Subsequently self-catheterises Mitrofanoff
• Coping well at present

50
Case 6
51
Case 6

• 10 year old girl with severe RDEB
• Long-standing constipation
• Poor weight gain (lt 0.4th centile)
• Gastrostomy for medication only
• Anaemic
• Compliance issues

52
Case 6

• Early 2006 several UTIs, started on trimethoprim
• USS hydronephrosis
• Subsequently urinary retention
• USS marked renal and ureteric dilatation
• Very distended bladder and post-micturition
  volume 300 ml

53
Case 6

• MAG3 scan stasis of urine bilaterally in dilated
  pelvicalyceal systems, no VU reflux
• Intermittent catheterisation by mother
• Constipation treated
• Gastrostomy used for feeds

54
Case 6

• Bowels open most days (PEG-based laxative)
• Eating better, weight increasing
• Missing less school
• In diapers but will try to toilet train
• Occasional catheterisation with no residual
• Repeat USS due soon

55
(No Transcript)
56
Screening for GU disease in EB
6 monthly
Annually
If abnormal
If scar or discrepancy
57
Screening for GU disease in EB
If abnormal
58
Screening for GU disease in EB
? Obstruction
? Vesico-ureteric reflux
59
Management of GU disease in EB

• General principles
• Avoid instrumentation and surgery if possible
• Urethral catheters tolerated short-term
• Supra-pubic catheters well-tolerated longer term
• Avoid constipation and dehydration
• Encourage toilet training at normal age

60
References

• Berger TG et al. Junctional epidermolysis
  bullosa, pyloric atresia and genitourinary
  disease. Pediatr Dermatol 1986 3 130-4.
• Donatucci CF et al. Management of urinary tract
  in children with epidermolysis bullosa. Urology
  1992 40 137-42.
• Fine JD. Epidemiology of urogenital problems in
  EB. In Clinical Management of Children and
  Adults with Epidermolysis Bullosa, DebRA UK,
  2003.
• Fine JD et al. Inherited epidermolysis bullosa
  and the risk of death from renal disease
  experience of the National Epidermolysis Bullosa
  Registry. Am J Kidney Dis 2004 44 651-60.
• Mann JF et al. The spectrum of renal involvement
  in epidermolysis bullosa dystrophica hereditaria
  report of two cases. Am J Kidney Dis 1988 11
  437-41.