Disorders of growth, differentiation and morphogenesis Flashcards Preview

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Flashcards in Disorders of growth, differentiation and morphogenesis Deck (45):
1

Types of growth

Types of growth in a tissue are:

• multiplicative involving an increase in numbers of cells (or nuclei and associated cytoplasm
in syncytia) by mitotic cell divisions; this
type of growth is present in all tissues during embryogenesis;

• auxetic resulting from increased size of individual cells, as seen in growing skeletal muscle;

• accretionary, an increase in intercellular tissue components, as in bone and cartilage; and

• combined patterns of multiplicative, auxetic and accretionary growth, as seen in embryological development, where there are differing directions and rates of growth at different sites of the developing embryo, in association with changing patterns of cellular differentiation.

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Differentiation

(see diagram)

Differentiation is the process whereby a cell develops an overt specialised function or morphology which distinguishes it from its parent cell. Thus, differentiation is the process by which genes are expressed selectively and gene products act to produce a cell with a specialised function. After fertilisation of the human ovum, and up to the eight-cell stage of development, all of the embryonic cells are apparently identical.

Thereafter, cells undergo several stages of differentiation in their passage to fully differentiated cells, for example, the ciliated epithelial cells lining the respiratory passages of the nose and trachea.

Although the changes at each stage of differentiation may be minor, differentiation can be said to have occurred only if there has been overt change in cell morphology (e.g. development of a skin epithelial cell from an ectodermal cell), or an alteration in the specialised function of a cell (e.g. the synthesis of a hormone).

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Regeneration

Mammalian cells fall into three classes according to their regenerative ability:
• labile
• stable
• permanent

Labile cells proliferate continuously in postnatal life; they have a short-lifespan and a rapid ‘turnover’ time. Their high regenerative potential means that lost cells are rapidly replaced by division of stem cells. However, the high cell turnover renders these cells highly susceptible to the toxic effects of radiation or drugs (such as anticancer drugs) which interfere with cell division.

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Labile cells

Examples of labile cells include:
• haemopoietic cells of the bone marrow, and lymphoid cells
• epithelial cells of the skin, mouth, pharynx, oesophagus, the gut, exocrine gland ducts, the cervix and vagina (squamous epithelium), endometrium, urinary tract (transitional epithelium), etc.

The high regenerative potential of the skin is exploited in the treatment of patients with skin loss due to severe burns. The surgeon removes a layer of the split skin which includes the dividing basal cells from the unburned donor site, and fixes it firmly to the burned graft site where the epithelium has been lost.

Dividing basal stem cells in the graft, and dividing stem cells from residual basal and adnexal structures (such as the cells from the neck of pilosebaceous units) from the donor sites, ensure that squamous epithelium at both sites regenerates. This enables rapid healing to take place in a large burned area, when natural regeneration of new epithelium from the edge of the burn would otherwise be prolonged.

Skin epithelium from a donor site can now be grown in the laboratory by tissue/organ culture for eventual grafting onto burned areas, and this is important for patients with extensive burns.

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Stable cells

(Sometimes called ‘conditional renewal cells’) Stables cells divide very infrequently under normal conditions, but stem cells are stimulated to divide rapidly when such cells are lost. This group includes cells of the liver, endocrine glands, bone, fibrous tissue and the renal tubules. Thus the liver is able to regenerate to its normal weight even after large partial resections for neoplastic disease.

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Permanent cells

Permanent cells normally divide only during fetal life, but their active stem cells do not persist long into postnatal life, and they cannot be replaced when lost. Cells in this category include neurons, retinal photoreceptors and neurons in the eye, cardiac muscle cells and skeletal muscle cells (although skeletal muscle cells do have a very limited capacity for regeneration).

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Cell cycle

(See diagram)

Successive phases of progression of a cell through its cycle of replication are defined with reference to DNA synthesis and cellular division. Unlike the synthesis of most cellular constituents, which occurs throughout the interphase period between cell divisions, DNA synthesis occurs only during a limited period of the interphase: this is the S phase of the cell cycle.

A further distinct phase of the cycle is the cell division stage or M phase comprising nuclear division (mitosis) and cytoplasmic division (cytokinesis).

Following the M phase, the cell enters the first gap (G1) phase and, via the S phase, the second gap (G2) phase before entering the M phase again.

Some cells (e.g. some of the stable cells) may ‘escape’ from the G1 phase of the cell cycle by temporarily entering a G0 ‘resting’ phase: others ‘escape’ perman- ently to G0 by a process of terminal differentiation, with loss of potential for further division and death at the end of the lifetime of the cell: this occurs in permanent cells, such as neurons.

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Pharmacological interruption of the cell cycle diagram

Pharmacological interruption of the cell cycle diagram

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Apoptosis

Apoptosis can be triggered by factors outside the cell or it can be an autonomous event (‘programmed cell death’). In embryological development, there are three categories of autonomous apoptosis:

• morphogenetic
• histogenic
• phylogenetic

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Morphogenetic apoptosis

This is involved in alteration of tissue form. Examples include:
• interdigital cell death responsible for separating the fingers
• cell death leading to the removal of redundant epithelium following fusion of the palatine processes during development of the roof of the mouth;
• cell death in the dorsal part of the neural tube during closure, required to achieve continuity of the epithelium, the two sides of the neural tube and the associated mesoderm
• cell death in the involuting urachus, required to remove redundant tissue between the bladder and umbilicus.

Failure of morphogenetic apoptosis in these four sites is a factor in the development of syndactyly (webbed fingers), cleft palate, spina bifida, and bladder diverticulum (pouch) or fistula (open con- nection) from the bladder to the umbilical skin.

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Histogenic apoptosis

This occurs in the differentiation of tissues and organs, as seen, for example, in the hormonally controlled differentiation of the accessory reproductive structures from the Müllerian and Wolffian ducts.

In the male, for instance, anti-Müllerian hormone produced by the Sertoli cells of the fetal testis causes regression of the Müllerian ducts (which in females form the fallopian tubes, uterus and upper vagina) by the process of apoptosis.

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Phylogenetic apoptosis

Phylogenetic apoptosis This is involved in removing vestigial structures from the embryo; structures such as the pronephros, a remnant from a much lower evolu- tionary level, are removed by the process of apoptosis.

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Skin healing

The healing of a skin wound is a complex process involving the removal of necrotic debris from the wound and repair of the defect by hyperplasia of capillaries, myofibroblasts and epithelial cells.

When tissue injury occurs, there is haemorrhage into the defect from damaged blood vessels; this is controlled by normal haemostatic mechanisms, during which platelets aggregate and thrombus forms to plug the defect in the vessel wall. Because of interactions between the coagulation and complement systems, inflammatory cells are attracted to the site of injury by chemotactic complement fractions. In addition, platelets release two potent growth factors – platelet-derived growth factor (PDGF) and transforming growth factor beta (TGFà)

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Skin healing II

Platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF beta) – which are powerfully chemotactic for inflammatory cells, including macrophages; these migrate into the wound to remove necrotic tissue and fibrin.

In the epidermis, PDGF acts synergistically with epidermal growth factor (EGF) and the somatomed- ins (IGF-1 and IGF-2) to promote the progression of basal epithelial cells through the cycle of cell proliferation.

PDGF acts as a ‘competence factor’ to move cells from their ‘resting’ phase in G0 to G1. EGF and IGFs then act sequentially in cell progres- sion from the G1 phase to that of DNA synthesis. Thereafter, the cell is independent of growth factors.

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Skin healing III

In the epidermis, EGF is derived from epidermal cells (autocrine and paracrine mechanisms), and is also present in high concentrations in saliva when the wound is licked. IGF-1 and IGF-2 originate from the circulation (endocrine mechanisms) and from the proliferating cell and adjacent epidermal and dermal cells (autocrine and paracrine mechanisms).

(Note that once a specialised adnexal structure such as a pilosebaceous unit has been destroyed, new units cannot regenerate from the basal layer of the epidermis. Hairs will, therefore, not grow in areas where deep burns have destroyed adnexal tissues, even if split skin grafting is successful. Similarly, in ‘scarring alopecia’, hair loss is permanent once hair follicles have been destroyed.)

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Skin healing IV

In the dermis, myofibroblasts proliferate in response to PDGF (and TGFà); collagen and fibronectin secretion is stimulated by TGFà, and fibronectin then aids migration of epithelial and dermal cells.

Capillary budding and proliferation are stimulated by angiogenic factors such as vascular endothelial growth factor (VEGF: see above). The capillaries ease the access of inflammatory cells and fibroblasts, par- ticularly into large areas of necrotic tissue.

Hormones (e.g. insulin and thyroid hormones) and nutrients (e.g. glucose and amino acids) are also required. Lack of nutrients or vitamins, the presence of inhibitory factors such as corticosteroids or infec- tion, or a locally poor circulation with low tissue oxy- gen concentrations, may all materially delay wound healing; these factors are very important in clinical practice.

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Ulcers and erosions I

An ulcer is a full-thickness defect in a surface epithelium or mucosa, which may also extend into subepithelial or submucosal tissue. An erosion is a partial-thickness defect in a surface epithelium or mucosa.

Both ulcers and erosions occur when adverse tissue circumstances (‘ulcerating factors’, such as hypoxia, factors such as gastric acid forming the local physico-chemical environment, or infection) cause local death of cells which cannot be replaced by regenerative cell proliferation, leading to net loss of epithelial or mucosal tissue. The presence of one or more of these ‘ulcerating factors’, therefore, overpowers the local ‘survival factors’, such as the regenerative potential and oxygenation of the tissue, and an ulcer or erosion develops.

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Ulcers and erosions II
(See diagram)

Once the ‘ulcerating factor or factors’ are removed, however, the residual ‘survival and healing factors’, or healing capacity of the tissue predominates, and cell proliferation exceeds cell loss, producing net tis- sue growth to fill the ulcer cavity. In deep ulcers , angiogenic growth factors (produced by macro- phages in the necrotic ulcer crater) stimulate growth and migration of capillaries into the base of the ulcer (producing vascular ‘granulation tissue’, seen as finely granular red tissue in the ulcer base).

Myofibroblasts also migrate into the ulcer crater, where they prolif- erate and secrete collagen and matrix proteins, filling the ulcer crater. Once this has happened, the epithe- lial cells at the edge of the ulcer migrate over the new scar tissue: eventually the ulcer crater is filled, and the epithelium totally covers the former ulcer. Eventually, subepithelial scar tissue contracts (caused by myofi- broblast contraction), and myofibroblasts differentiate into mature fibroblasts.

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Ulcers and erosions III

If ‘ulcerating factors’ persist, or if there are recur- rent cycles of ulceration – healing – ulceration, an ulcer may become ‘chronic’, with a large deep crater and very extensive scar formation, perhaps leading to marked deformity of the tissue (for example, an ‘hour glass’ deformity with possible stenosis in a stomach with a large chronic gastric ulcer).

At the epithelial edge of large chronic ulcers, per- sistent attempts to regenerate occasionally lead to the development of a malignant neoplasm (carcinoma).

If an ulcer fails to heal after ‘ulcerating factors’ have been removed, this may indicate that there is an underlying neoplasm. Many malignant neoplasms, which arise in (or invade) epithelial or mucosal tissues, ulcerate as they outgrow their blood supply or invade local blood vessels. A classical example is basal cell carcinoma
of the skin (a ‘rodent’ ulcer), but other examples include breast adenocarcinoma ulcerating overlying skin, and large ulcerated bowel adenocarcinomas.
Note that epithelial proliferation and regeneration alone are required to heal an erosion, once the causative factor has been removed.

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Peritoneum and healing I
(See 2 diagrams)

The practice of abdominal surgery requires an under- standing of the mechanisms of peritoneal healing and of the development of intra-abdominal fibrous adhesions (scars). In one large study, 31% of all cases of intestinal obstruction were due to adhesions, and of these patients 79% had undergone previous abdom- inal surgery, whilst 18% had inflammatory adhesions and 3% had congenital bands.

The process of healing and repair of a peritoneal defect is very different to that of an ulcerated epithelial surface, as the mesothelial surface cells do not grow over the defect from its edges. If even large peritoneal defects are left open (not sutured), macrophages migrate into the area to remove necrotic debris.

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Peritoneum and healing II

This is followed by a proliferation and migration of peritoneal perivascular connective tissue cells(which resemble primitive mesenchymal cells) into the defect, which eventually fills with these cells. The con- nective tissue cells on the ‘new’ surface then undergo metaplasia into mesothelial cells. As a result, peritoneal defects heal very rapidly, large defects heal as rapidly as small ones, and peritoneal healing occurs without formation of adhesions. If, however, peritoneal defects are sutured, the suture compresses or tensions the mesothelium and underlying connective tissue, which tends to become relatively ischaemic as a result. As a result, angiogenesis (new blood vessel formation) is stimulated, and capillaries (and later fibroblasts) migrate into the area.

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Peritoneum and healing III

If fibrin and/or foreign material such as starch (used to lubricate the inside of surgical gloves) are on the peritoneal surface, the capillaries and fibroblasts grow into the area, and are likely to cause adhesions to adjacent peritoneal surfaces, which may ultimately cause intestinal obstruction. In abdominal and pelvic surgery, therefore, peritoneal surfaces which are left unsutured are less likely to cause adhesions, and both removal of fibrin and prevention of contamination by foreign body materials will reduce the chances of adhe- sion formation.

Peritoneal mesothelial cells have fibrinolytic activity, but damage to these cells at surgery reduces their ability to remove the peritoneal fibrin which promotes development of adhesions. In addition, growth factors such as epidermal growth factor (EGF) and transforming growth factor beta (TGFà) may directly influence cell growth in peritoneal healing. However, TGFà (released in large quantities from platelets at sites of haemorrhage) and tumour necrosis factor (TNF) both probably increase plasminogen-activator inhibitor-1 (PAI-1) activity in peritoneal mesothelial cells, blocking fibrinolytic activity (and hence fibrin removal), and thereby promoting adhesion formation.

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Bone healing I

(See diagram)

Cellular mechanisms involved in the healing of bone fractures are similar to those in healing in other tissues

Haemorrhage at the fracture site (inside and around the bone) produces a haematoma, in which there are fragments of necrotic bone, bone marrow, and soft tissues. As is the case in other sites, these necrotic tissues are removed by macrophages.

Organisation of the haematoma in bone is accomplished by ingrowth of capillaries and fibroblasts (as in other sites in the body), but is modified in bone by ingrowth of osteoblasts; the resulting proliferation of these cells produces an irregular mass of new irregularly woven bone, called ‘callus’. Internal callus forms within the medullary cavity of the bone; external callus forms in relation to the periosteum, where it acts as a splint until it is finally removed by resorption and remodelling. Eventually, woven bone of the callus is remodelled into lamellar bone, with lamellae oriented according to the direction of mechanical stress on the bone.

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Bone healing II

Occasionally bone is lost at the time of fracture (for example, the fractured end of a bone may be removed by the surgeon if heavy contamination has occurred when a compound fracture has penetrated the skin). Under such circumstances the two ends of the bone may be pinned and externally fixed and oriented on an external frame. After initial contact, the bone ends may be gradually separated by increasing traction over several weeks, allowing the bone to be drawn to its correct length whilst the healing process occurs.

Bone healing may be delayed or inhibited as a result of movement, gross misalignment, soft tissues inter- posed between the ends of the bone, infection, bone disease (such as osteoporosis or Paget’s disease, or primary or secondary neoplasms), severe systemic illness or malnutrition. Excessive movement and soft tissue interposition may prevent bone fusion, and fibrous union of the bone may occur (perhaps producing a ‘false joint’).

Note that multiple fractures of different ages seen on x-ray may indicate an underlying bone disease such as severe osteoporosis or congenital osteogenesis imperfecta. In infants, children and weak dependant adults, however, such fractures may be the result of non-accidental injury (physical abuse).

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Liver healing

In severe chronic hepatitis, extensive hepatocyte loss is followed by scarring, as is the case in the skin or other damaged tissues. Hepatocytes, like the skin epidermal cells, have massive regenerative potential, and surviving hepatocytes may proliferate to form nodules. Hyperplasia of hepatocytes and fibroblasts is presumably mediated by a combination of hormones and growth factors, although the mechanisms are far from clear. Regenerative nodules of hepatocytes and scar tissue are the components of cirrhosis of the liver.

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Heart healing

Myocardial cells are permanent cells and so cannot divide in a regenerative response to tissue injury. In myocardial infarction, a segment of muscle dies and, if the patient survives, it is replaced by hyperplastic myofibroblast scar tissue. As the remainder of the myocardium must work harder for a given cardiac output, it undergoes compensatory hypertrophy (with- out cell division) (see Fig. 4.12). Occasionally, there may be right ventricular hypertrophy as a result of left ventricular failure and consequent pulmonary hypertension.

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Hypertrophy and hyperplasia: Myocardium

Many conditions are characterised by hypertrophy or hyperplasia of cells. In some instances, this is the principal feature of the condition from which the disease is named. The more common examples are summarised below.

Myocardium
The myocardium responds to an increased work load by increasing muscle mass by hypertrophy (myocardial cells cannot undergo mitosis). Right ventricular hyper- trophy occurs in response to pulmonary valve stenosis, secondary to a ventricular septal defect, or in pulmon- ary hypertension. Left ventricular hypertrophy takes place in response to aortic valve stenosis or systemic hypertension.

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Hypertrophy and hyperplasia: Arteries

Hypertrophy of arterial smooth muscle arterial walls occurs in hypertension, in response to increased work load. Myointimal cell hyperplasia occurs as an import- ant component of the development of atherosclerosis, when they proliferate in response to platelet-derived growth factors.

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Hypertrophy and hyperplasia: Capillary vessels

In the eye, capillaries grow from the retina into the vitreous gel, where they may cause reduced vision, especially if they bleed and stimulate scarring. Capillary hyperplasia is a response to retinal hypoxia, or (as prolif- erative retinopathy) as an important sight-threatening complication of diabetes mellitus.

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Hypertrophy and hyperplasia: Bone marrow

Erythrocyte precursor hyperplasia occurs in response to increased circulating erythropoietin concentrations, due to increased secretion by the kidney resulting from decreased arterial oxygen tension (for example, as a result of living at high altitude, or due to anaemia).

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Hypertrophy and hyperplasia: Cytotoxic T lymphocytes

Hyperplastic expansion of T lymphocyte populations (Fig. 4.13) occurs in cell-mediated immune responses to, for example, organ transplants.

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Hypertrophy and hyperplasia: Breast

Juvenile hyperplasia of the breast may occur in females as an exaggerated response to female sex hormones at puberty. In males, breast hyperplasia (gynaecomastia) may occur at puberty, or be due to high oestrogen levels (e.g. in cirrhosis or oestrogen treatment of prostate

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Autonomous hyperplasia: Psoriasis

In some apparently hyperplastic conditions, cells appear autonomous, and continue to proliferate rap- idly despite the lack of a demonstrable stimulus or control mechanism. The question then arises as to whether these should he considered to be hyperpla- sias at all, or whether they are autonomous or even neoplastic (which seems unlikely). If the cells could be demonstrated to be monoclonal (derived as a sin- gle clone from one cell) this might indicate that the lesion was neoplastic, but clonality is often difficult to establish.

• Psoriasis: a common skin condition (2% of population) characterised by inflamed scaly rash and marked epidermal hyperplasia. Recent evidence suggests multifactorial genetic and environmental factors may be involved.

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Hypertrophy and hyperplasia: Paget's

• Paget’s disease of bone: in which there is hyperplasia of osteoblasts and osteoclasts resulting in thick but weak bone, affects around 10% of adults by the age of 90 years. There appears to be some genetic predisposition, with some geographical clustering, and a viral aetiology has been suggested.

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Hypertrophy and hyperplasia: Fibromatoses

• Fibromatoses: which are a group of conditions characterised by apparently autonomous proliferations of myofibroblasts, occasionally forming tumour-like masses; exemplified by palmar fibromatosis (Dupuytren’s contracture), desmoid tumour, retroperitoneal fibromatosis and Peyronie’s disease of the penis.

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Transcription control

As most differentiated cells have an identical genome, differences between them cannot be due to amplification or deletion of genes. The cells of the body differ because they express different genes; genes are selectively switched on or off to control the synthesis of gene products.

The synthesis of a gene product can in theory be controlled at several levels:

• transcription: controlling the formation of messenger (mRNA);

• transport: controlling the export of mRNA from the nucleus to the ribosomes in the cytoplasm

• translation: controlling the formation of gene product within the ribosomes.

In fact, many of the important ‘decision’ stages of differentiation in embryogenesis are under transcrip- tional control, and the manufacture of gene product is proportional to the activity of the gene.

For a cell to differentiate in a particular way, given that it contains the potential of activation of the whole of the genome, some groups of genes must be switched on and other groups off. There is now ample evidence that the regulation of transcription of several (or many) individuals within a group of genes is mediated by the gene products of a small number of ‘control’ genes, which may themselves be regulated by the prod- uct of a single ‘master’ gene

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Sex chromosomes: Klinefelters

Chromosomal disorders affecting the sex chromo- somes (X and Y) are relatively common, and usually induce abnormalities of sexual development and fer- tility. In general, variations in X chromosome numbers cause greater mental retardation.

Klinefelter’s syndrome (47,XXY) Affects 1 in 850 male births. There is testicular atrophy and absent spermatogenesis, eunuchoid bodily habitus, gynaeco- mastia, female distribution of body hair and mental retardation. Variants of Klinefelter’s syndrome (48,XXXY, 49,XXXXY, 48,XXYY) are rare and have cryptorchidism and hypospadias in addition to more severe mental retardation and radio-ulnar synostosis.


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Sex chromosomes: Double Y

Double Y males (47,XYY) Form 1 in 1000 male births; they are phenotypically normal, although most are over 6 feet tall. Some are said to have increased aggressive or criminal behaviour.

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Sex chromosomes: Turner's syndrome

Turner’s syndrome (gonadaldysgenesis 45,X) Occurs in 1 in 3000 female births. About one-half are mosaics (45,X/46,XX) and some have 46 chromosomes and two X chromosomes, one of which is defective. Turner’s syn- drome females may have short stature, primary amenor- rhoea and infertility, webbing of the neck, broad chest and widely spaced nipples, cubitus valgus, low posterior hairline and coarctation of the aorta.

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Sex chromosomes: Multiple X females

Multiple X females (47,XXX, 48,XXXX) Comprise 1 in 1200 female births. They may be mentally retarded, and have menstrual disturbances, although many are normal and fertile.
True hermaphrodites (most 46,XX, some 46, XX/47,XXY mosaics) Have both testicular and ovar- ian tissue, with varying genital tract abnormalities.

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Parts of chromosomes: Cri-du chat

The loss (or addition) of even a small part of a chromo- some may have severe effects, especially if ‘controlling’ or ‘master’ genes are involved, as these affect many other genes.

An example of a congenital disease in this group is cri-du-chat syndrome (46,XX,5p- or 46,XY, 5p). This rare condition (1 in 50,000 births) is associ- ated with deletion of the short arm of chromosome 5 (5p-), and is so named because infants have a characteristic cry like the miaow of a cat. There is microcephaly and severe mental retardation; the face is round, there is gross hypertelorism (increased distance between the eyes) and epicanthic folds.

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Defects in receptors or cellular transport

The lack of a specific cellular receptor causes insensitivity of a cell to substances such as hormones.

In one form of male pseudohermaphroditism (androgen insensitivity syndrome), for example, insensitivity of tissues to androgens, caused by lack of androgen receptor, prevents the development of male characteristics during fetal development. These individuals develop as normal but sterile females, because they respond to estrogens produced by the adrenal gland, but they lack a uterus and oviducts, and have testes in their abdomen.

Cellular transport deficiencies may lead to condi- tions such as cystic fibrosis, a condition in which there is a defective cell membrane transport system across exocrine secretory cells.

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Failure of cell and organ migration: Kartagener's

Failure of migration of cells may occur during embryogenesis.

Kartagener’s syndrome In this rare condition there is a defect in ciliary motility, due to absent or abnormal dynein arms, the structures on the outer doublets of cilia which are responsible for ciliary movement. This affects cell motility during embryogenesis, which often results in situs inversus (congenital lateral inversion of the position of body organs resulting in, for example, left-sided liver and right-sided spleen). Complications in later life include bronchiectasis and infertility due to sperm immobility.

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Failure of cell and organ migration: Hirschsprung’s disease

This is a condition leading to marked dilatation of the colon and failure of colonic motility in the neonatal period, due to absence of Meissner’s and Auerbach’s nerve plexuses. It results from a selective failure of craniocaudal migration of neuroblasts in weeks 5–12 of gestation, due (in one form) to the homozygous absence of the endothelin-B receptor gene. It is, interestingly, ten times more frequent in children with trisomy 21 (Down’s syndrome), and is often associated with other congenital anomalies.

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Failure of cell and organ migration:Undescended testis (cryptorchidism)

This is the result of failure of the testis to migrate to its normal position in the scrotum. Although this may be associ- ated with severe forms of Klinefelter’s syndrome (e.g. 48,XXXY), it is often an isolated anomaly in an other- wise normal male. There is an increased risk of neo- plasia in undescended testes.