malformations
TRANSCRIPT
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PATHOLOGY OF CONGENITAL
MALFORMATIONS
Professor EEU Akang,MBBS FMCPath FWACP, Department of Pathology,
University College Hospital, Ibadan
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OUTLINE
DEFINITIONS- Malformation, Disruption,
Deformation, Sequence, Syndrome, Association
AETIOLOGY AND PATHOGENESIS
SELECTED CHROMOSOMAL DISORDERS
SELECTED ORGAN MALFORMATIONS
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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
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CONGENITAL MALFORMATIONS-Differential diagnosis-1
DISRUPTION-Secondary destruction of normally developed tissue by extrinsic factors
Will not recure.g. amniotic bands
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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
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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
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Pathomechanism of malformations, disruptions and deformations (Queiβer-Luft and Spranger, 2006)
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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
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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
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OLIGOHYDRAMNIOS SEQUENCE
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OLIGOHYDRAMNIOS SEQUENCE-Potter facies, talipes and lung hypoplasia
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PLACENTA IN OLIGOHYDRAMNIOS-
Amnion nodosuma localized accumulation of amorphous material (vernix caseosa) with embedded desquamated foetal skin cells to produce small nodules
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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
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CONGENITAL RUBELLA SYNDROME
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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
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AGENESIS
AGENESIS-Complete
absence of an organ and its primordium
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APLASIA
APLASIA-Absence of an organ due to failure of development of its primordium
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HYPOPLASIA
HYPOPLASIA-Incomplete development of an organ with decreased numbers of cells
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ATRESIAFailure of luminal development in a hollow organ- e.g. oesophageal atresia
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CONGENITAL MALFORMATIONS-Other Terms
HYPOTROPHY-Abnormally small cells
HYPERTROPHY-Abnormally large cells
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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%
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Risk factors for major malformationsQueiβer-Luft and Spranger, 2006
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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
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HEREDITARY CAUSES
12-25% of malformations Chromosomal aberrations
(Trisomy 21, 18, 13, Klinefelter, Turner)
Monogenic disorders(Autosomal recessive/dominant, X-linked recessive/dominant)
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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
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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
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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)
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TRISOMY 21- Down syndrome-Karyotype
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TRISOMY 21- Phenotype
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TRISOMY 21- Mongoloid facies
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TRISOMY 18- Edward syndrome-Karyotype
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TRISOMY 18- Phenotype
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TRISOMY 18- Facies
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TRISOMY 13- Patau syndrome-Karyotype
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TRISOMY 13- Phenotype
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TRISOMY 13- Facies
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TURNER SYNDROME-Karyotype
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TURNER SYNDROME-Phenotype
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TURNER SYNDROME-Webbed neck
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Ventricular septal defect
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Atrial septal defect
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Patent ductus arteriosus
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Renal cystic dysplasia
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Adult polycystic disease
Autosomal dominantPKD1 (polycystin 1) and PKD2 (polycystin 2)Hepatic cysts, pancreatic cysts, berry aneurysms, colon diverticula
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Infantile polycystic disease
Autosomal recessivePKHD1 (fibrcocystin)
Pancreatic cysts, hepatic biliary dysgenesis and fibrosis
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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)
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ANENCEPHALY
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MYELOMENINGOCELE
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HOLOPROSENCEPHALY
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ARNOLD-CHIARI MALFORMATION
Hydrocephalus
Spina bifidaZ-shaped kinkingof brainstem
Cerebellar tonsilherniation
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Congenital cytomegalovirus infection
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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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