1. PATHOLOGY OF
CONGENITAL
MALFORMATIONS
Professor EEU Akang,
MBBS FMCPath FWACP,
Department of Pathology,
University College Hospital,
Ibadan

2. OUTLINE
DEFINITIONS- Malformation, Disruption,
Deformation, Sequence, Syndrome, Association
AETIOLOGY AND PATHOGENESIS
SELECTED CHROMOSOMAL DISORDERS
SELECTED ORGAN MALFORMATIONS

3. CONGENITAL
MALFORMATIONS- Definition
Morphological defects present at
birth. May sometimes manifest in later
adult life
 Due to an intrinsically abnormal
developmental process
 May either be inherited or acquired
 3% of neonates have a major anomaly
 Up to 20% of (post)neonatal deaths


4. CONGENITAL MALFORMATIONSDifferential diagnosis-1
DISRUPTIONSecondary destruction of
normally developed tissue by
extrinsic factors
Will not recur
e.g. amniotic bands

5. 1 in 2000 live births
DISRUPTION- Amniotic band
2 THEORIES
1. Partial rupture of
amniotic sac forms
amniotic strands that
encircle and trap part of the
foetus
2. Intrinsic defect of blood
circulation
Characterised by
constriction of digits, arms
and legs
Accompanied by
lymphoedema
Auto amputation may occur

6. CONGENITAL MALFORMATIONSDifferential diagnosis- 2

DEFORMATION- Localised/generalised
compression of foetus by extrinsic
forces
such as 1st pregnancy, small uterus,
bicornuate uterus, leiomyoma,
oligohydramnios, multiple pregnancy,
abnormal presentation
e.g. talipes

7. Pathomechanism of malformations, disruptions
and deformations (Queiβer-Luft and Spranger, 2006)

8. DEFORMATIONTalipes equinovarus
Club foot may be
classified as
1. structural (hereditarye.g. Edward’s syndrome,
Ehlers-Danlos syndrome)
2. Postural (intrauterine
compression)
Against the classical,
widely accepted teaching
of postural club foot, this
anomaly also occurs in
the absence of restriction
of the intrauterine space

9. CONGENITAL MALFORMATIONSTerminology
SEQUENCEPattern of cascade anomalies
(malformations, disruptions or
deformations) due to a single
localised abnormality in
organogenesis
e.g. Oligohydramnios (Potter)
sequence

10. OLIGOHYDRAMNIOS SEQUENCE

11. OLIGOHYDRAMNIOS SEQUENCEPotter facies, talipes and lung hypoplasia

12. PLACENTA IN
OLIGOHYDRAMNIOSAmnion nodosum
a localized
accumulation of
amorphous
material (vernix
caseosa) with
embedded
desquamated
foetal skin cells to
produce small
nodules

13. CONGENITAL MALFORMATIONSTerminology
SYNDROMEConstellation of congenital
anomalies that are pathologically
related and not due to a single
localised initiating defect. May be
caused by single agent (virus,
alcohol, etc.)- e.g. Congenital
Rubella syndrome

14. CONGENITAL RUBELLA
SYNDROME

15. ASSOCIATION
A group of anomalies that occur more frequently
together than would be expected by chance alone
but that do not have a predictable pattern of
recognition and/or a suspected unified
underlying aetiology.
Examples include
• VACTERL (Vertebral, Anal, Cardiac, TE fistula,
Renal, Limb defects) and
• MURCS (Mullerian duct aplasia, Renal aplasia,
Cervical Somite dysplasia

16. AGENESIS
AGENESISComplete
absence of
an organ
and its
primordium

17. APLASIA
APLASIAAbsence of
an organ due
to failure of
development
of its
primordium

18. HYPOPLASIA
HYPOPLASIAIncomplete
development
of an organ
with
decreased
numbers of
cells

19. ATRESIA
Failure of luminal development in a hollow
organ- e.g. oesophageal atresia

20. CONGENITAL MALFORMATIONSOther Terms
HYPOTROPHYAbnormally
small cells
HYPERTROPHYAbnormally
large cells

21. CONGENITAL
MALFORMATIONS- Aetiology
Idiopathic Multifactorial Cytogenetic (Chromosomal) Monogenic (Mendelian) Maternal diseases Transplacental infections
 Drugs and chemicals Irradiation
40-60%
20-25%
10-15%
2-10%
6-8%
2-3%
1%
1%

22. Risk factors for major malformations
Queiβer-Luft and Spranger, 2006

23. MULTIFACTORIAL CAUSES
20-25% of malformations
 Interaction between several disease
genes and multiple environmental
factors
 Subject to geographic and temporal
variation
 Congenital dislocation of the hip, neural
tube defects

24. HEREDITARY CAUSES
12-25% of malformations
 Chromosomal aberrations
(Trisomy 21, 18, 13, Klinefelter,
Turner)
 Monogenic disorders
(Autosomal recessive/dominant,
X-linked recessive/dominant)

25. ENVIRONMENTAL CAUSES
10-13% of malformations
 Maternal disease (DM, PKU,
endocrine)
 Infections (TORCHES/HIV)
 Drugs/chemicals (alcohol,
antifolates, androgens, phenytoin,
thalidomide, warfarin, 13-cisretinoic acid)
 Irradiation

26. PATHOGENESIS OF
MALFORMATIONS
Timing determines nature/severity
of malformation (3-9 weeks)
 Insults affect migration,
proliferation, cellular interactions,
cell-matrix associations, apoptosis
 Homeobox genes, Paired box
genes, cytokines, growth factors,
adhesion molecules, hormones,
mechanical forces


28. KARYOTYPING
1. Incubate cell suspension with
phytohaemagglutinin
2. Add colchicine (arrests cell division in
metaphase)
3. Stain (i. Giemsa (G), ii. Reverse (R), iii.
Centric (C), iv. Quinacrine (Q), v. Silver
nucleolar organiser region (AgNOR)
4. Photograph and arrange chromosomes
(A1-3; B4-5; C6-12; D13-15; E16-18;
F19-20; G21-22; X/Y)

29. TRISOMY 21- Down syndromeKaryotype

30. TRISOMY 21- Phenotype

31. TRISOMY 21- Mongoloid facies

32. TRISOMY 18- Edward syndromeKaryotype

33. TRISOMY 18- Phenotype

34. TRISOMY 18- Facies

35. TRISOMY 13- Patau syndromeKaryotype

36. TRISOMY 13- Phenotype

37. TRISOMY 13- Facies

38. TURNER SYNDROMEKaryotype

39. TURNER SYNDROMEPhenotype

40. TURNER SYNDROMEWebbed neck

41. Ventricular septal defect

42. Atrial septal defect

43. Patent ductus arteriosus

44. Renal cystic dysplasia

45. Adult polycystic disease
Autosomal dominant
PKD1 (polycystin 1) and
PKD2 (polycystin 2)
Hepatic cysts, pancreatic
cysts, berry aneurysms,
colon diverticula

46. Infantile polycystic disease
Autosomal recessive
PKHD1 (fibrcocystin)
Pancreatic cysts, hepatic
biliary dysgenesis and
fibrosis

47. CNS MALFORMATIONS





NEURULATION- wk 3 (anencephaly, spina bifida)
TELENCEPHALISATION- wk 5-6
(arrhinencephaly, holoprosencephaly)
PROLIFERATION- 2-4 mos (micrencephaly)
MIGRATION- 3-5 mos (lissencephaly (MillerDieker syndrome), pachygyria, polymicrogyria,
heterotopia)
MATURATION- 3rd trim.-post natal
(megalencephaly, Arnold-Chiari, Dandy-Walker)

48. ANENCEPHALY

49. MYELOMENINGOCELE

50. HOLOPROSENCEPHALY

53. ARNOLD-CHIARI MALFORMATION
Hydrocephalus
Cerebellar tonsil
herniation
Z-shaped kinking
of brainstem
Spina bifida

54. Congenital cytomegalovirus
infection

55. HYDROPS FETALIS
Iso-immunisation

Turner syndrome

Parvovirus infection

Twin-twin transfusion

syndrome

56. Summary
• An overview of processes that can result in
acquired or inherited structural malformations
manifesting at the time of birth or in some cases
later in life has been presented
• Malformations arise from insults occurring
during the critical period of organogenesis and
may range from minor to severe, life threatening
conditions
• Many cases are preventable by the avoidance of
teratogenic exposure, immunisation and genetic
56
counselling in selected cases

57. THANKS
FOR
LISTENING!