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Disorders of

Differentiation

By
Prof. J.T. Anim
Department of Pathology
Definitions
 Growth:- increase in size and mass from
synthesis of tissue components
• Multiplicative: - increase in numbers (mitoses)
• Auxetic: - increase in size of individual cells
• Accretionary: - increase in intercellular
components eg. bone
Definitions
 Differentiation
• Development of overt specialised morphology and or
function which distinguishes from parent cell
 Morphogenesis
• Development of structural shape and form of organs
etc. from primitive cell masses during embryogenesis
(co-ordination of growth and differentiation as well as
programmed cell death – apoptosis)
 Cell turnover
• Balance between cell proliferation and cell death
(proliferation > cell death in foetus; decreases in adult)
Disorders of Differentiation and
Morphogenesis
 Congenital: - chromosomal (3-5%); non-chromosomal
(2%)
• Whole chromosomes
• Autosomal: Trisomy 21 (Down), 18 (Edward), 13 (Patau)
• Sex chromosomes: Klinefelter (47XXY), Turner (45X0)
• Parts of chromosomes
• Cri-du-chat syndrome (46XX, 5p- or 46XY, 5p)
• Single gene alterations
• 80-85% familial; 15-20% new mutations
Abnormalities of Organogenesis
 Agenesis:- Failure of development of an organ or structure
• Failure to develop ureteric bud (blastema) – Renal agenesis
• Thymic agenesis – Di George syndrome
• Defect in neural tube - anencephaly
 Atresia: - Failure of development of lumen in a normally tubular epithelial atructure

Esophageal atresia with or without tracheo-espohageal fistula; biliary atresia,
urethral atresia
 Hypoplasia: - Failure of development of normal size of organ
• May affect only part of the organ eg. kidney
 Maldifferentiation: - Failure of normal differentiation of an organ – often
retains primitive atructures
• Kidney (renal dysplasia) – abnormal metanephric differentiation
 Ectopia and heterotopia: - Small areas of mature tissue from one organ
which are present within another tissue
• Gastric or pancreatic tissue in Meckel’s diverticulum; Endometriosis in
peritoneum
Abnormalities of Organogenesis
• Embryo division abnormalities: Incomplete separation
(siamese twins)
• Failure of cell and organ migration – undescended testis,
Hirschsprung’s disease, situs inversus
• Failure of fusion (dysraphia) – spina bifida, cleft palate
• Failure of separation – webbed digits (syndactyly)
• Failure of involution – thyroglossal cyst
• Failure of organ to move from site of development
(dystopia) eg. pelvic kidney, undescended testis
(cryptorchidism)
Acquired Disorders of
Differentiation and Growth
 Metaplasia (transdifferentiation)
• Reversible transformation of one type of terminally
differentiated cell into another fully differentiated cell type
• Squamous metaplasia in bronchi or urinary bladder
• Gastric cardiac epithelium in esophagus – reflux esophagitis
• Mesenchymal tissue eg. bone in soft tissue
 Dysplasia (atypical hyperplasia)
• A premalignant condition characterised by increased cell
growth, presence of cellular atypia and altered
differentiation
 Neoplasia (new growth)
• Abnormal tissue mass showing excessive growth that is
uncoordinated with that of normal tissue and persists after
removal of inducing stimulus
Control of Differentiation
 Genetic control
• Genes are switched on and off to control synthesis of
gene products
• Transcription – controlling formation of RNA
• Transport – controlling export of mRNA from nucleus to
ribosomes in cytoplasm
• Translation – controlling formation of gene products
• Degradation – controlling destabilisation of some
mRNAs in cytoplasm
• Control of protein activity (sequestration/inactivation)
Control of Differentiation

Master control gene


influence

Control gene
influence

Transcription
Some switched on and off
Control of Differentiation
 Cell determination – the determined cell must:
• have differences which are heritable from one cell
generation to another
• be committed and commit their progeny to specialised
development
• change its internal character, not merely its
environment
 Cells may be determined but not differentiated
eg. stem cells of bone marrow, basal cells of
skin.
Control of Differentiation
 Organs contain multiple distinct populations of
cells which originate separately, but later
interact
 Differentiation in one cell may be controlled by
another – induction
• Mesoderm + ectoderm → neural tube
• Mesoderm + ectoderm → skin and appendages
• Ureteric bud (mesonephric) induces metanephric
blastema → kidney
 Inductive phenomena may also occur in cell
migration