IIIrd IPPA Update Course
in
Paediatric Pathology
Venice September 2010
Slide seminar
CASE 26
R.M. NASH
SS26 – clinical history:
Late termination (29+ weeks) because of multiple
dilated loops of bowel and very poor fetal movement
in utero. Fetus appeared “sick”; also polyhydramnios
Complex family history including cardiovascular
anomalies in sibling and in cousin.
Fetal medicine specialist and clinical geneticist
queried “multiple intestinal atresias” due to
underlying vascular abnormality/accident.
o/e: Fairly large male fetus, 1802g, 97th centile; mildly
dilated, non-obstructed patent bowel with thin, brown
liquid contents; normal bladder and urinary tract.
21
weeks
• Fetus at 28
weeks
• Marked
polyhydramnios
• Multiple loops of
dilated bowel
• Poor fetal
movement
28 weeks
this case
FP
FP – older sibling (male)
• Antenatal diagnosis of cardiac abnormality (Fallot’s
tetralogy) but appeared to “resolve”.
• Aberrant left subclavian artery arising from arterial duct,
leading to acute ischaemic left arm when ductus closed.
• VSD
• Mild PS
• Severe “iatrogenic” hyponatremia in neonatal period
• Nystagmus, amblyopia and strabismus
• Developmental delay (mod to severe)
• “Absence” seizures
• MRI- large ventricles, lack of white matter bulk, no
ischaemia
FP – older sibling (male)
• Antenatal diagnosis of cardiac abnormality (Fallot’s
tetralogy) but appeared to “resolve”.
• Aberrant left subclavian artery arising from arterial duct,
leading to acute ischaemic left arm when ductus closed.
• VSD
• Mild PS
• Severe “iatrogenic” hyponatremia in neonatal period.
• Nystagmus, amblyopia and strabismus
• Developmental delay (mod to severe)
• “Absence” seizures
• MRI- large ventricles, lack of white matter bulk, no
ischaemia
FP – older sibling (male)
• Antenatal diagnosis of cardiac abnormality (Fallot’s
tetralogy) but appeared to “resolve”.
• Aberrant left subclavian artery arising from arterial duct,
leading to acute ischaemic left arm when ductus closed.
• VSD
• Mild PS
• Severe “iatrogenic” hyponatremia in neonatal period.
• Nystagmus, amblyopia and strabismus
• Developmental delay (mod to severe)
• “Absence” seizures
• MRI- large ventricles, lack of white matter bulk, no
ischaemia
FP – older sibling (male)
• Antenatal diagnosis of cardiac abnormality (Fallot’s tetralogy)
but appeared to “resolve”.
• Aberrant left subclavian artery arising from arterial duct,
leading to acute ischaemic left arm when ductus closed.
• VSD
• Mild PS
• Severe “iatrogenic” hyponatremia in neonatal period.
• Nystagmus, amblyopia and strabismus
• Developmental delay (mod to severe)
• “Absence” seizures
• MRI - large ventricles, lack of white matter bulk, no ischaemia
Transposition of
AL the great arteries
AL
• Maternal first cousin
• Coarctation of aorta and VSD
• Neonatal CVA:
– R carotid artery coarctation
– right temporafrontal infarct and left focal seizures
– profuse collateralisation and ectasia of the left IC circulation
• Small Sternal Cleft
• Facial haemangiomas (3) - now resolved
• Learning and behavioural difficulties
??PHACES - (Posterior fossa malformations, Hemangiomas, Arterial
anomalies, Coarctation of the aorta and other cardiac defects,
and Eye abnormalities; may also have sternal clefting)
Baby of N.P. P09 - 376
21
weeks
• Fetus at 28
weeks
• Marked
polyhydramnios
• Multiple loops of
dilated bowel
• Poor fetal
movement
28 weeks
Intestinal atresia
multiple intestinal atresia
SUMMARY OF FINDINGS
• macerated male baby, weight 1802g, >97th centile (29+ wks)
• brownish, dried material on skin surface, especially creases
• markedly dilated, non-obstructed patent bowel containing thin
brown liquid contents (not thick meconium).
• abnormal foramen ovale – partial closure with aneurysmal
dilatation (? – or normal variant)
• not hydropic; umbilical cord slightly oedematous.
• no other anatomical abnormalities; not dysmorphic.
Potential causes of intrauterine
pan-intestinal dilatation:
• Atresia/anatomical abnormality – especially
if low, e.g. ano-rectal malformation
• Other cause for physical obstruction,
e.g. meconium ileus.
• Hirschsprung’s disease.
• Congenital intestinal pseudo-obstruction.
Causes of congenital intestinal
pseudo-obstruction [CIPO]
• Intestinal neuropathy/myopathy
• MMIHS (megacystis microcolon intestinal
hypoperistalsis syndrome)
• Paralytic ileus – maternal drugs?
• Transient fetal bowel ischaemia
• Congenital chloride diarrhoea
Causes of congenital intestinal
pseudo-obstruction [CIPO]
• Intestinal neuropathy/myopathy
• MMIHS (megacystis microcolon intestinal
hypoperistalsis syndrome)
• Paralytic ileus – maternal drugs?
• Transient fetal bowel ischaemia
• Congenital chloride diarrhoea
Features of congenital chloride
diarrhoea
• Rare (Finland and Middle East – Kuwait).
• Polyhydramnios
• CIPO – dilated bowel
• Liquor stained by thin “meconium”
• Lifetime watery diarrhoea.
• Hypochloraemic metabolic alkalosis; also Na↓, K+↓
• Treatable if pickedup – oral salt substitution.
• (other features during later life – renal, IBD,
subfertility in males).
• Mutations (>30) in SLC26A3 – three are common
Mutations in SLC26A3 [= DRA]
• Several missense mutations have been
found between exons 5 and 15 of the
SLC26A3 gene, and have been reported
to cause CLD.
ref: Mäkelä et al. Human Mutation 2002
Dec; 20(6):425 – 38.
RESULTS IN THIS FAMILY:
• Fetus: two heterozygous sequence variants of
the SLC26A3 gene found:
c. 408G>A (p.M1361) in exon 5
c.1136G>C(p.G379A) in exon 10.
• Father: one heterozygous sequence variant of
the SLC26A3 gene found:
c. 408G>A (p.M1361) in exon 5
• Mother: one heterozygous sequence variant of
the SLC26A3 gene found:
c.1136G>C(p.G379A) in exon 10.
“no carriers of these variants have been detected in a set of
hundreds of patients and controls studied in our laboratory.”
RESULTS IN THIS FAMILY:
• Fetus: two heterozygous sequence variants of
the SLC26A3 gene found:
c. 408G>A (p.M1361) in exon 5
c.1136G>C(p.G379A) in exon 10.
• Father: one heterozygous sequence variant of
the SLC26A3 gene found:
c. 408G>A (p.M1361) in exon 5
• Mother: one heterozygous sequence variant of
the SLC26A3 gene found:
c.1136G>C(p.G379A) in exon 10.
“no carriers of these variants have been detected in a set of
hundreds of patients and controls studied in our laboratory.”
Management of CLD
• Life-long oral salt substitution
• Management of acute dehydration and hypokalaemia
during gastroenteritis or other infection
• Recognition and management of other manifestations of
the disease, such as intestinal inflammation, renal
impariment and male subfertility.
MESSAGE:
If uniform, global dilatation of loops of bowel +
polyhydramnios – think of congenital CLD.
References:
• Antenatal U/U diagnosis of dilated fetal bowel due to
congenital chloride diarrhoea.
Rowlands S et al.Aust NZ Ostet Gynaecol 1996; 36: 366-8.
• Prenatal bowel dilatation: Congenital chloride diarrhoea
Husu S et al.Arch Dis Child Neonate Ed 2001; 85:F65.
• Prenatal diagnosis of intestinal pseudo-obstruction.
Shen O et al. Ultrasound Obstet Gynecol 2007; 29:220-231.
• SLC26A3 and congenital chloride diarrhoea.
Höglund P. Novartis Found Symp.2006; 273:74-86,disc.86-90
Acknowledgements:
Satu Wedenoja Sahar Mansour
Dept of Medical Genetics Dept of Clinical Genetics
Univ of Helsinki, Finland St George’s Univ.London