UNSW Embryology ANAT 3311 Notes Developmental Anomalies					Embryology Home Page
	These are an excerpt from the current course notes outlining the course content.
Session 1	Session 2	Pig Homepage	Human Homepage	Anat 2007 Notes

COELOMIC CAVITY	NERVOUS SYSTEM	NEURAL CREST	HEART AND CVS
HEAD AND NECK	LIMBS AND MUSCULAR SYSTEM	RESPIRATORY	ENDOCRINE SYSTEM
GASTRO-INTESTINAL SYSTEM	URINARY AND REPRODUCTIVE SYSTEMS	VISION, AUDITION, EQUILIBRIUM AND OLFACTION		Teratology

COELOMIC CAVITY AND ITS DERIVATIVES

Reading Moore Ch9: p174-184 Larson Ch6: p111-125

Developmental Anomalies

DIAPHRAGMATIC HERNIA (POSTERO-LATERAL)

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Reading Moore Ch18: p385-419 Larson Ch5: p93-107

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Central Nervous System Developmental Anomalies

SPINA BIFIDA (MENINGOMYELOCELE)

The main objective in using Spina Bifida as a teaching model is to stress the main features in an integrated approach to the total care of the Spina Bifida patient.

Questions related to Spina Bifida

(a) Describe the possible processes involved in the abnormal development of the C.N.S. in Spina Bifida. At what time in development would these abnormal events occur?

(b) What is amniocentesis? Would this procedure be useful in the diagnosis of Spina Bifida? Give reasons for your answer.

(c) What is the effect of the lesion on the bladder, bowel and limbs? Describe the differences on these areas between lesions at the following levels:

a. Cervical

b. Thoraco-Lumbar

c. Sacral

(d) If the lesion is at higher thoracic levels, why would the prognosis for the patient be poor?

(e) Compare and contrast the following:

(i) Transection

(ii) Brown-Sequard Syndrome (Hemisection)

(iii) Spina Bifida

Reading Moore Ch18: p385-419 Larson Ch5: p105-109

HIRSCHSPRUNG'S DISEASE (INTESTINAL AGANGLIONOSIS)

Management:

Temporary relief is obtained by making a colostomy proximal to the obstruction. The child will then thrive normally until fit for resection of the aganglionic segment, restoration of anal continuity and closure of the colostomy. (See Diag. D - The Duhamel Operation. This is a modified form of the resection operation. Retention of the anterior half of the rectum protects rectal sensations while overcoming the obstruction).

Associated Malformations:

No associated malformations. (It is important to recognise that the aganglionic always extends to the ano-rectal junction; the proximal extent varies from patient to patient). See Diag. E. The Okamoto and Ueda demonstration.

Genetic History:

There is a familial disposition which is greatest in the long segment examples.

Genetic Locus for this disease discovered by Westmead Hospital Research Group in collaboration with US group in 1995.

Reading Moore Ch14: p304-349 Larson Ch7: p131-161

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DEVELOPMENTAL ANOMALIES

I. PATENT DUCTUS ARTERIOSUS (P.D.A.)

Treatment. PDA is ligated simply and with little risk. The operation is always recommended even in the absence of cardiac failure. It can often be deferred until early childhood.

II. ATRIAL SEPTAL DEFECT (A.S.D.)

Treatment The surgical repair requires a cardiopulmonary bypass and is recommended in most cases of ostium secundum ASD, even though there is a significant risk involved. Ostium primum defects tend to present earlier and are often associated with endocardial cushion defects and defective mitral or tricuspid valves. In such cases, valve replacement may be necessary and the extended operation has a considerable chance of mortality.

III. TETRALOGY OF FALLOT

Diagnosis. Tetralogy of Fallot by definition consists of:

(i) ventricular septal defect

(ii) pulmonary stenosis (valvular or infundibular)

(iii) (ii) results in an overriding aorta and

(iv) right ventricular hypertrophy

COMPARE AND CONTRAST MALFORMATIONS OF THE C.V.S. WHICH OCCUR IN THE HEART AND OUTSIDE THE HEART.

Reading Moore Ch10: p186-222 Larson Ch12: p311-340

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Developmental Anomalies of Head and Neck and Pharyngeal Arches

The malformations CLEFT LIP and palate and PIERRE ROBIN SYNDROME during the lecture series and demonstration materials will be provided during the practical class.

Cleft lip and palate develop between the 4th and 8th week of gestation and is dominated by changes resulting in the formation of the nose. Palatal development occurs between the 7th and 12th week of gestation and is divided into the formation of the primary palate (prolabium), premaxilla and cartilaginous septum) and formation of the secondary palate (hard and soft palate).

In the treatment and repair of cleft lip the following results are hopefully achieved:

(i) a symmetrical lip

(ii) a natural appearing philtral ridge and dimple

(iii) negligible scarring

(iv) a symmetrical nose and restoration of the nostril floor.

The major objectives of the repair of the cleft palate includes construction of a competent, functioning and watertight valve at the junction of the soft palate and pharynx; repair is performed early enough to allow the child to begin speech with a functioning velopharyngeal valve. Presentation of normal hearing must also be maintained along with normal development and bone growth in the central facial region along with a functional and attractive dentition.

Reading Moore Ch16,17: p370-373, 375-382 Larson Ch11: p281-299

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Musculo-skeletal System Developmental Anomalies

The "figures" referred to below are on posters in the practical classroom.

Clinical Introduction:

1. Normal growth and development of the limb requires (a) normal cell numbers; (b) normal locomotor elements, e.g. bone, joint, muscle; (c) normal blood and nerve supply.

2. Retardation of limb growth is produced by (a) deficient nerve supply; (b) impaired blood supply or (c) systemic abnormalities affecting the growth plate.

3. Increased limb growth is produced by some nerve malformations and by increased blood supply to the growth plate.

I. GROWTH PLATE DISORDERS

(a) Hurler's Syndrome

(b) Morquios Syndrome

(c) Achondroplasia

(d) Osteogenesis imperfecta (Fragilitas ossium) (Brittle Bone disease)

(e) Marfan's Syndrome

(a) Hurler's Syndrome: Photo GP1 ((a & b) Genetic Mucopolysaccharides)

A seemingly normal infant, in a matter of a few years, may be transformed into a mentally retarded, physically deformed, severely handicapped individual. No organ or tissue appears to be spared the inbuilt error of metabolism, which is the accumulation of mucopolysaccharides (chondroitin sulphate B and heparin sulphate). The form inherited as an autosomal recessive is most severe: the sex linked recessive form affects males only and is less severe. Death occurs in childhood or early adult life. The main histological features are the presence of inclusion bodies composed of mucopolysaccharides within cells of the growth plate, the C.N.S. and parenchymal and connective tissue cells.

(b) Morquios Syndrome: Photo GP2

In this disease keratosulphate accumulates in cartilage and cornea. (The patients excrete excessive keratosulphate in the urine - a diagnostic criterion).

Severe stunting becomes apparent in the second and third year of life. The joints then become involved and osteoporosis becomes prominent. The cartilage has abnormal chemistry, and the problem is a systemic metabolic disorder.

(c) Achondroplasia: Photo GP3 (An autosomal dominant)

This is a deficiency of endochondral ossification and all growth plates are affected - other forms of cartilage such as articular cartilage and hyaline cartilage are normal. These are the characteristic circus dwarfs, healthy, well muscled, short adults with limbs short relative to the trunk. A major problem in this disease is the failure of the germinal cells of the growth plate to proliferate.There are two possible mechanisms for this disease :-

1. An abnormality of vascular invasion of calcified cartilage leading to an accumulation of uncalcified cartilage.

2. An abnormality of cartilage which precludes calcification.

(d) Osteogenesis imperfecta - Fragilitas ossium. Brittle bone disease (autosomal dominant with variable expressivity). Photo GP4

This is a generalised disorder of connective tissue which has a variable expression. In its most severe form there are brittle bones, lax joints and hypotonic (floppy) muscles.

The pathological change underlying this disorder is a failure of collagen production throughout the body. Normally collagen becomes a thicker and stronger fibre as it matures. In osteogenesis imperfecta collagen remains in the form of reticulin. In place of normal compact bone, a course fibrillary type of immature bone is found without haversian systems and with a very irregular distribution of abnormal collagen fibres in the bone. Photo GP5; GP6. Photo 5 shows a typical example of Osteogenesis imperfecta with malformation due multiple fractures and Photo 6 the typical appearance of bone.

(e) Marfan's Syndrome Photo 7 (autosomal dominant)

This is a generalised disorder of the connective tissue of the body with manifestations in the skeleton, eye and vascular system. The individuals are tall and thin and there is an overgrowth of endochondrial ossification. There are also systemic and locomotor disabilities. Aortic incompetence often occurs.

There is an abnormality of elastic fibres in this disease but the connections between this and the malfunction of the growth plate is obscure.

II. CONGENITAL DISLOCATION OF THE HIP (C.D.H.)

Introduction (Instability: 1:60 at birth; 1:240 at 1 wk: Dislocation untreated; 1:700).

(a) There is originally a congenital instability of the hip which later dislocates by muscle pulls or gravity if untreated.

(b) There is familial predisposition for this problem and female predominance.

(c) Growth of the femoral head, acetabulum and innominate bone are delayed until the femoral head fits firmly into the acetabulum.

Mechanisms of Production

(a) There is familial displasia of the hip.

(b) There is a relationship between placental transmission of material joint softening hormones (e.g. Relaxin) which are inhibited by androgens in the male foetus. When a and b are present there is instability of the hip.

(c) Dislocation is produced by the small head slipping out of the shallow acetabulum in the extended position of the hip and is inhibited by the abducted position of the hip.

Treatment

Treatment must be instituted early to avoid a growth deformity of the hip. To ensure there is no instability, infants are tested at birth for hip stability and unstable hip children are nursed in the Frog Position (abducted hip posture).

Photo CDH1 Pawich Brace

Photo CDH2 Frog Plaster

Delay in treatment leads to frank dislocation of the hip (the femoral head comes out of joint), and there is a shallow acetabulum and a small femoral head. See Photo CDH3. If this condition is allowed to occur an operation may be necessary to produce a more horizontal roof to the acetabulum and produce hip stability. See Photo CDH4.

Posterior dislocation of the hip produces flexion deformities of the hip with compensatory Lordosis - exaggerated lumbar curvature. See Photo CDH5 (both female).

Questions

1. In CDH5 the smaller child on the right shows Trendelenberg's Sign - as she raises her right foot the right side of the pelvis lowers instead of raising. In the normal patient the hip rises when the ipsilateral foot is raised from the ground. What muscle is chiefly responsible for the normal tilting of the hip?

2. What conditions may give rise to Trendelenberg's Sign?

III. ARTHROGRYPOSIS (Multiplex Congenita)

Rare

Severe cases are characterised by multiple deformities at birth with gross stiffening of joints and hypotonia or wasting of muscles.

Photo AG1. Such a stiff fetus frequently sustains fractures before or during delivery. AG1 has had a fractured right humerus.

Photo AG2 shows deformities originally thought to be joints, then joints and muscles then finally innervation was also implicated.

Photo AG3 shows normal and abnormal muscles in close proximity. Variations in the degree of severity of joint deformity are expressions of varying degrees of muscular and neurological abnormality.

IV. SYNDACTYLY

Fusion of fingers or toes. This may be single or multiple and may affect

(i) Skin only

(ii) Skin and soft tissues

(iii) Skin, soft tissues and bone

See Knock out Mouse Reference

The condition is unimportant in toes but disabling in fingers and requires operative separation. This is frequently inherited as an autosomal dominant. Photo

V. SCOLIOSIS

This is involved with assymetric growth impairment of the vertebral bodies. There is lateral deviation of the spine with a 3-fold deformity:

1. Lateral flexion

2. Forward flexion

3. Rotation of the vertebral column on the long axis

Photos:

Sco 1: Shows Scoliosis

Sco 2: Rotational deformity producing rib hump when the child bends

Sco 3: X-ray of spine

The deformity is compensated by movement of the vertebral column above and below the affected region producing a primary and two secondary curves. This deformity progresses rapidly in adolescence and becomes fixed once bone growth is completed.

Questions

Why does the deformity progress rapidly in early adolescence?

VI. CONGENITAL LIMB REDUCTION DEFECTS

Thalilomide was the most celebrated limb reducing insult in humans which produced other deformities as well. There was probably a primary neuronal deprivation. There are two elements in the production of limb reduction defects.

(a) Agents - Many substances have been found capable of producing limb reduction defects in experimental animals but few have been related to humans.

(b) Mechanisms - Limb reduction defects may be due to loss of blood supply to part of the limb or to defects in innervation at the spinal or cerebral level. Also there are a number of as yet undefined mechanisms involved.

Limb reduction defects may be apical (congenital amputation) or pre- or post-axial (absence of radius and lateral digits; ulnar and medial digits).

Photo LRD 1 and 2 shows a limb reduction defect and the accompanying X-ray.

Questions

What area is missing in the reduced limb?

What will be the relative growth rates of the right and left humeri in this child?

Other examples of limb reduction defects are shown by :-

Photos: LRD 3:A reduction defect, largely preaxial hemimelia

LRD 4: An apical defect

LRD 5: A severe apical defect, the lobster claw foot.

Question

What problems would a patient with the lobster-claw foot defect encounter when walking?

Reading Moore Ch11: p226-233 Larson Ch9: p205-231

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Respiratory System Developmental Anomalies

I. TRACHEO-OESOPHAGEAL FISTULA (OESOPHAGEAL ATRESIA)

Summary

Oesophageal atresia as suggested by

(a) Polyhydramnios

(b) Reflex increase in salivation

(c) Holdup of the catheter confirmed by the X-ray appearance of the dilated blind proximal oesophagus. The fistula is confirmed by the presence of gas in the intestines.

Management

1. Operative closure of the trachea end of the fistula.

2. Restoration of the continuity of the oesophagus

N.B. This is a serious malformation with significant risk of mortality

Reading Moore Ch12: p248-261 Larson Ch9: p205-230

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Gastro Intestinal System Developmental Anomalies

I. INTESTINAL MALROTATION

Question

What abnormal embryological processes could interfere with normal rotation and fixation of the gut?

II. SITUS INVERSUS VISCERA

Disturbance of the lateralisation of the liver may produce transposition of some or all of the foregut and its derivatives.

1.Stomach

2. Pancreas

3. Duodenum - jejunum

4. Spleen

5. Bile

Also in situs inversus the anatomical relations of the duodenum, pancreas, bile ducts and portal veins may be reversed or disordered.

III. MECKEL'S DIVERTICULUM

IV. HIRSCHSPRUNG'S DISEASE (INTESTINAL AGANGLIONOSIS)

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DEVELOPMENT OF THE URINARY AND REPRODUCTIVE SYSTEMS

Reading Moore Ch13: p265-300 Larson Ch10: p235-275

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Urogenital System Developmental Anomalies

The "figures" referred to below are on posters in the practical classroom.

Preamble: Note that upper G.I.T. obstruction is associated with POLYHYDRAMNIOS whereas failure of fetal micturition is associated with OLIGOHYDRAMNIOS with consequent firm uterine moulding on the fetus, leading to facial, locomotor and palatal deformities.

I. RENAL AGENESIS

(a) In the complete form the child is not viable and the child dies within a few days of birth.

(b) Features associated with this anomaly are:-

(i)Oligohydramnios

(ii) Amnion nodosum (small warty amnion with accretions of squamous cells on the inner wall). This is tangible evidence for oligohydramnios.

(iii) Facial deformities: This results from uterine moulding around the head.

(Figure 1). The ears are low slung and simple, the mandible is small, the nose flattened and the eyes exhibit Pre-epicanthic folds (Figure 2). This is a horseshoe shaped flap of skin from the upper lid to the cheek in front of the epicanthus. (Downs syndrome has an epicanthic fold). Note that the genesis is occasionally incomplete allowing survival (e.g.) Figure 2. Causal factors are largely unknown although there is some familial predisposition.

II. POLYCYSTIC KIDNEYS

This is a diffuse cystic malformation of both kidneys with cystic malformations of the liver and lung etc. often being associated. There is often familial disposition with this malformation. There are TWO types

(i) Infantile (inconsistent with prolonged survival)

(ii) Adult (less severe and allows survival)

III. MULTICYSTIC KIDNEY

(i) This is non familial and is produced by atresia of a ureter

(ii) It is always unilateral

(iii) There is no functional kidney tissue present in the kidney

(iv) The kidney is replaced by a multiocular cyst.

IV. URINARY TRACT OUTFLOW OBSTRUCTION

1. (e.g.) Urethral valves (Figure 9) - This figure is a micturating urethrogram and shows a valve obstruction (arrow) with dilatation of the urethra between the valve and the bladder. This type of pre-natal obstruction produces gross hydronephrosis and hydroureter before birth. Figure 10 shows gross dilatation of the pelves and ureters. There is extensive destruction of renal tissue.

2. Congenital Hydronephrosis is usually due to partial obstruction at the pelvi-ureteric junction (Figure 11). The pelvis is shown to be grossly dilated and there is extensive renal damage before birth.

*This may be familial, may be lateral, and is most commonly an intrinsic defect in the wall of the ureter (structural or functional). The less severe cases may be salvaged by reconstruction of the pelvi-ureteric junction.

V. PRUNE BELLY SYNDROME (Triad Syndrome)

The Triad is

(i) Agenesis of abdominal wall muscles

(ii) Bladder outflow obstruction

(iii) Bilateral undescended testes

*The causes of this malformation are little known, but maternal therapy with Oestrogens in the first trimester has been implicated frequently.

Question: Does oestrogen possibly inhibit the development of the male bladder outflow and genital system?

In some cases there are vestiges of muscle in the abdominal wall and it is not known whether this represents

(a) destruction of muscle, or

(b) failure of development of muscle

Figures 12 and 13 show a typical prune belly.

Survival of the prune belly child depends on the number of functioning remaining nephrons at birth and the operability of the obstruction.

VI. HORSESHOE KIDNEY

In the horseshoe kidney there is fusion of the lower poles of the kidney.During migration from the sacral region the two metanephric blastemas can come into contact as shown in Figure 14 mainly at the lower pole. The ureters pass in front of the zone of fusion of the kidneys. The kidneys and ureters usually function adequately but there is an increased incidence of upper urinary tract obstruction or infection.

VII. EXSTROPHY OF THE BLADDER

Management of Bladder Exstrophy

The deformity is non-familial, of no known cause and is obvious at birth. This malformation produced incontinence. The surgical reconstruction is complex and requires simultaneous repair of the bony pelvis and covering of the bladder and bladder neck. The epispadiac urethra is reconstructed later. (Ref. Snell, Clinical Embryology, p. 215, fig. 15-16).

Questions

How does the kidney develop normally?

At what level is the adult kidney found?

What arterial changes take place during kidney development?

Why does dye remain in the kidney in the IVP of an infantile polycystic kidney?

How do children with non-functioning kidneys survive to birth?

What problems confront the child with bladder exstrophy?

Reading Moore Ch19: p423-439 Larson Ch12: p309-359

Listed selected sections (Eye, Ear)

See also Teratology