PATHOLOGY OF CONGENITAL

MALFORMATIONS

Professor EEU Akang,MBBS FMCPath FWACP, Department of Pathology,

University College Hospital, Ibadan

OUTLINE

DEFINITIONS- Malformation, Disruption,

Deformation, Sequence, Syndrome, Association

AETIOLOGY AND PATHOGENESIS

SELECTED CHROMOSOMAL DISORDERS

SELECTED ORGAN MALFORMATIONS

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

CONGENITAL MALFORMATIONS-Differential diagnosis-1

DISRUPTION-Secondary destruction of normally developed tissue by extrinsic factors

Will not recure.g. amniotic bands

DISRUPTION- Amniotic band1 in 2000 live births

2 THEORIES1. Partial rupture of amniotic sac forms amniotic strands that encircle and trap part of the foetus2. Intrinsic defect of blood circulation

Characterised by constriction of digits, arms and legsAccompanied by lymphoedemaAuto amputation may occur

CONGENITAL MALFORMATIONS-Differential diagnosis- 2

DEFORMATION- Localised/generalised compression of foetus by extrinsic forcessuch as 1st pregnancy, small uterus,

bicornuate uterus, leiomyoma, oligohydramnios, multiple pregnancy, abnormal presentation

e.g. talipes

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

DEFORMATION-Talipes equinovarus

Club foot may be classified as 1. structural (hereditary- e.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

CONGENITAL MALFORMATIONS-Terminology

SEQUENCE-Pattern of cascade anomalies (malformations, disruptions or deformations) due to a single localised abnormality in organogenesis

e.g. Oligohydramnios (Potter) sequence

OLIGOHYDRAMNIOS SEQUENCE

OLIGOHYDRAMNIOS SEQUENCE-Potter facies, talipes and lung hypoplasia

PLACENTA IN OLIGOHYDRAMNIOS-

Amnion nodosuma localized accumulation of amorphous material (vernix caseosa) with embedded desquamated foetal skin cells to produce small nodules

CONGENITAL MALFORMATIONS-Terminology

SYNDROME-Constellation 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

CONGENITAL RUBELLA SYNDROME

ASSOCIATIONA 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

AGENESIS

AGENESIS-Complete

absence of an organ and its primordium

APLASIA

APLASIA-Absence of an organ due to failure of development of its primordium

HYPOPLASIA

HYPOPLASIA-Incomplete development of an organ with decreased numbers of cells

ATRESIAFailure of luminal development in a hollow organ- e.g. oesophageal atresia

CONGENITAL MALFORMATIONS-Other Terms

HYPOTROPHY-Abnormally small cells

HYPERTROPHY-Abnormally large cells

CONGENITAL MALFORMATIONS- Aetiology

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

Risk factors for major malformationsQueiβer-Luft and Spranger, 2006

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

HEREDITARY CAUSES

12-25% of malformations Chromosomal aberrations

(Trisomy 21, 18, 13, Klinefelter, Turner)

Monogenic disorders(Autosomal recessive/dominant, X-linked recessive/dominant)

ENVIRONMENTAL CAUSES

10-13% of malformations Maternal disease (DM, PKU,

endocrine) Infections (TORCHES/HIV) Drugs/chemicals (alcohol,

antifolates, androgens, phenytoin, thalidomide, warfarin, 13-cis-retinoic acid)

Irradiation

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

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)

TRISOMY 21- Down syndrome-Karyotype

TRISOMY 21- Phenotype

TRISOMY 21- Mongoloid facies

TRISOMY 18- Edward syndrome-Karyotype

TRISOMY 18- Phenotype

TRISOMY 18- Facies

TRISOMY 13- Patau syndrome-Karyotype

TRISOMY 13- Phenotype

TRISOMY 13- Facies

TURNER SYNDROME-Karyotype

TURNER SYNDROME-Phenotype

TURNER SYNDROME-Webbed neck

Ventricular septal defect

Atrial septal defect

Patent ductus arteriosus

Renal cystic dysplasia

Adult polycystic disease

Autosomal dominantPKD1 (polycystin 1) and PKD2 (polycystin 2)Hepatic cysts, pancreatic cysts, berry aneurysms, colon diverticula

Infantile polycystic disease

Autosomal recessivePKHD1 (fibrcocystin)

Pancreatic cysts, hepatic biliary dysgenesis and fibrosis

CNS MALFORMATIONS

NEURULATION- wk 3 (anencephaly, spina bifida) TELENCEPHALISATION- wk 5-6

(arrhinencephaly, holoprosencephaly)

PROLIFERATION- 2-4 mos (micrencephaly) MIGRATION- 3-5 mos (lissencephaly (Miller-

Dieker syndrome), pachygyria, polymicrogyria, heterotopia)

MATURATION- 3rd trim.-post natal (megalencephaly, Arnold-Chiari, Dandy-Walker)

ANENCEPHALY

MYELOMENINGOCELE

HOLOPROSENCEPHALY

ARNOLD-CHIARI MALFORMATION

Hydrocephalus

Spina bifidaZ-shaped kinkingof brainstem

Cerebellar tonsilherniation

Congenital cytomegalovirus infection

HYDROPS FETALIS

Iso-immunisation

Turner syndrome

Parvovirus infection

Twin-twin transfusion

syndrome

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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 counselling in selected cases

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