Anatomy: Embryology and development

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🧬 Embryology and development. Embryology explains why anatomy is arranged as it is, why congenital anomalies occur where they do, and why pain is referred to distant sites. The UKMLA and MRCP test it through clinical consequences: congenital heart disease, neural tube defects, cleft lip and palate, malrotation, hypospadias and teratogens. This chapter covers the timeline of development, the germ layers and their derivatives, and the development of each major system with its classic anomalies.
Your four questions for any congenital anomaly: Which embryological structure failed to form, fuse, divide or regress? At what stage of development did this happen? Which other structures share that origin (and may also be affected)? Was there an environmental cause (teratogen, infection, maternal disease)?

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Timeline of Human Development

• Gestational age is counted from the first day of the last menstrual period; embryological (post-conception) age is about 2 weeks less.
• Week 1: fertilisation (usually in the ampulla of the uterine tube) → zygote → cleavage → morula → blastocyst (inner cell mass and trophoblast); implantation begins around day 6–7.
• Week 2 ("week of twos"): bilaminar disc (epiblast and hypoblast), two cavities (amniotic cavity and yolk sac), two trophoblast layers (cytotrophoblast and syncytiotrophoblast). hCG from the syncytiotrophoblast maintains the corpus luteum - the basis of pregnancy tests.
• Week 3 ("week of threes"): gastrulation - the primitive streak forms and creates three germ layers; the notochord forms; neurulation begins.
• Weeks 3–8: embryonic period (organogenesis) - most structural anomalies arise here; the heart beats from about day 22.
• Weeks 9–40: fetal period - growth and maturation; teratogens now mainly affect growth and function (e.g. brain, genitalia).
• Ectopic pregnancy - implantation outside the uterine cavity (95% in the tube); risk factors include PID, previous tubal surgery, IVF and IUD failure.

Germ Layers and Their Derivatives

Germ layer	Main derivatives
Ectoderm - surface	Epidermis, hair, nails, sweat and mammary glands, lens, enamel of teeth, anterior pituitary (Rathke's pouch), inner ear
Ectoderm - neural tube	Brain, spinal cord, retina, posterior pituitary, preganglionic autonomic neurons
Ectoderm - neural crest	Peripheral nervous system (dorsal root and autonomic ganglia, Schwann cells), adrenal medulla, melanocytes, parafollicular (C) cells of the thyroid, odontoblasts, pia and arachnoid, craniofacial bones, aorticopulmonary septum, endocardial cushions
Mesoderm	Muscle (skeletal, smooth, cardiac), bone, cartilage, connective tissue, dermis, heart and blood vessels, blood cells, spleen, kidneys and ureters, gonads, adrenal cortex, serous linings (pleura, pericardium, peritoneum)
Endoderm	Epithelial lining of the gut and respiratory tract, liver, pancreas, thyroid follicular cells, parathyroids, thymus, urinary bladder and urethral epithelium, tympanic cavity and auditory tube

• Neural crest disorders (neurocristopathies): Hirschsprung's disease (failure of neural crest migration to the distal colon), neuroblastoma, phaeochromocytoma, DiGeorge syndrome (with pharyngeal pouch defects), Waardenburg syndrome, Treacher Collins syndrome.
• Notochord → nucleus pulposus of intervertebral discs (persisting remnants can form chordomas).

Critical Periods and Teratogens

• Weeks 0–2: "all-or-none" - a teratogen either causes loss of the embryo or no effect.
• Weeks 3–8: greatest susceptibility to major structural anomalies.
• Fetal period: functional and growth effects, minor anomalies, CNS damage.

Teratogen	Effect
Sodium valproate	Neural tube defects, cardiac and limb anomalies, facial dysmorphism, neurodevelopmental disorders (about 30–40%) - Pregnancy Prevention Programme
Carbamazepine, phenytoin	Neural tube defects (carbamazepine), fetal hydantoin syndrome (phenytoin - craniofacial, nail hypoplasia)
Isotretinoin	Craniofacial, cardiac and CNS anomalies
Warfarin	Nasal hypoplasia, stippled epiphyses (weeks 6–12); fetal bleeding later
ACE inhibitors / ARBs	Fetal renal failure, oligohydramnios, skull hypoplasia (2nd and 3rd trimesters)
Lithium	Ebstein's anomaly (risk now thought to be small)
Methotrexate, mycophenolate	Multiple anomalies, miscarriage
Thalidomide	Phocomelia (limb reduction defects)
Alcohol	Fetal alcohol spectrum disorder - smooth philtrum, thin upper lip, short palpebral fissures, growth restriction, learning difficulties
Tetracyclines	Tooth discolouration, bone growth effects
Maternal diabetes	Caudal regression syndrome, congenital heart disease, neural tube defects, macrosomia
Infections (TORCH)	Toxoplasmosis, other (syphilis, VZV, parvovirus B19, Zika), rubella (cataract, deafness, PDA), CMV (commonest congenital infection - deafness, microcephaly), HSV

Heart and Great Vessels

• Heart tube forms from mesoderm by week 3; looping (rightward) in week 4 - failure of normal looping → dextrocardia (with situs inversus in Kartagener's syndrome).
• Septation (weeks 4–7):
  • Atrial septum: septum primum and septum secundum; the foramen ovale allows right-to-left flow in utero. Defects: ostium secundum ASD (commonest ASD), ostium primum ASD (with endocardial cushion defects, Down's syndrome).
  • Endocardial cushions form the AV valves and the membranous septum - defects cause atrioventricular septal defects (Down's syndrome).
  • Ventricular septum: muscular part plus membranous part - the membranous VSD is the commonest congenital heart defect.
  • Outflow tract: the aorticopulmonary (spiral) septum from neural crest divides the truncus arteriosus. Failure → persistent truncus arteriosus; failure to spiral → transposition of the great arteries; anterosuperior displacement → tetralogy of Fallot (VSD, overriding aorta, pulmonary stenosis, right ventricular hypertrophy).
• Aortic arches form the great vessels: 3rd → common carotid and proximal internal carotid; 4th → aortic arch (left) and proximal right subclavian; 6th → pulmonary arteries and ductus arteriosus (left). Abnormal regression → vascular rings, coarctation.
• Recurrent laryngeal nerves: the left hooks under the ductus/ligamentum arteriosum (6th arch), the right under the subclavian (4th arch) - explains the left's longer course and vulnerability (e.g. to lung cancer, aortic aneurysm).

Fetal Circulation and Changes at Birth

• Three shunts bypass the liver and lungs:
  • Ductus venosus - umbilical vein blood bypasses the liver → IVC (becomes the ligamentum venosum).
  • Foramen ovale - right atrium → left atrium (becomes the fossa ovalis).
  • Ductus arteriosus - pulmonary artery → aorta (becomes the ligamentum arteriosum).
• Umbilical vessels: one umbilical vein (oxygenated blood to the fetus → ligamentum teres) and two umbilical arteries (deoxygenated blood to the placenta → medial umbilical ligaments). A single umbilical artery is associated with renal and other anomalies.
• At birth: lung expansion → pulmonary vascular resistance falls → left atrial pressure rises above right → foramen ovale closes functionally. Rising oxygen and falling prostaglandin E₂ close the ductus arteriosus (functionally within 1–3 days).
• Clinical: patent ductus arteriosus - continuous "machinery" murmur, common in preterm infants (closed with NSAIDs such as indometacin or ibuprofen, or paracetamol); prostaglandin E₁ (alprostadil) keeps the duct open in duct-dependent congenital heart disease (e.g. transposition, critical coarctation).

Pharyngeal Arches, Pouches and the Face

Arch	Nerve	Muscles	Skeletal
1st	Trigeminal (V3)	Muscles of mastication, mylohyoid, anterior digastric, tensor tympani, tensor veli palatini	Maxilla, mandible, malleus, incus (Meckel's cartilage)
2nd	Facial (VII)	Muscles of facial expression, stapedius, posterior digastric, stylohyoid	Stapes, styloid process, lesser horn and upper body of hyoid (Reichert's cartilage)
3rd	Glossopharyngeal (IX)	Stylopharyngeus	Greater horn and lower body of hyoid
4th and 6th	Vagus (X) - superior laryngeal (4th), recurrent laryngeal (6th)	Pharyngeal constrictors, cricothyroid (4th); intrinsic laryngeal muscles (6th)	Laryngeal cartilages

• Pouches (endoderm): 1st → middle ear cavity and auditory tube; 2nd → palatine tonsil; 3rd → inferior parathyroids and thymus; 4th → superior parathyroids and parafollicular cells (ultimobranchial body).
• DiGeorge syndrome (22q11.2 deletion): 3rd and 4th pouch failure → CATCH-22 - cardiac defects (conotruncal), abnormal facies, thymic hypoplasia (T-cell deficiency), cleft palate, hypocalcaemia (absent parathyroids).
• Branchial cleft cyst - lateral neck lump at the anterior border of sternocleidomastoid (2nd cleft remnant).
• Thyroglossal duct cyst - midline neck lump that moves on tongue protrusion (thyroid descends from the foramen caecum).
• Cleft lip - failure of fusion of the maxillary and medial nasal processes; cleft palate - failure of the palatine shelves to fuse. Both are linked to folate deficiency, anticonvulsants and genetic syndromes.

Gut Development and Rotation

• Foregut (coeliac trunk) - oesophagus to the second part of the duodenum, liver, gallbladder, pancreas, spleen (mesoderm); pain referred to the epigastrium.
• Midgut (superior mesenteric artery) - second part of duodenum to the proximal two-thirds of the transverse colon; pain referred to the umbilical region.
• Hindgut (inferior mesenteric artery) - distal third of transverse colon to the upper anal canal; pain referred to the suprapubic region.
• Midgut herniation and rotation: physiological herniation into the umbilical cord (week 6), 270° anticlockwise rotation around the SMA, and return by week 10–12.
  • Malrotation with volvulus - bilious vomiting in a neonate is a surgical emergency (Ladd's bands may obstruct the duodenum).
  • Exomphalos (omphalocele) - failure of the gut to return; covered by peritoneum; associated with chromosomal anomalies (trisomies 13, 18) and Beckwith–Wiedemann syndrome.
  • Gastroschisis - paraumbilical (usually right) body wall defect; gut not covered by a membrane; usually isolated; young mothers.
• Vitelline (omphalomesenteric) duct remnants: Meckel's diverticulum - rule of 2s (2% of the population, 2 feet from the ileocaecal valve, 2 inches long, 2 types of ectopic tissue - gastric and pancreatic; presents before age 2) - painless rectal bleeding.
• Oesophageal atresia with tracheo-oesophageal fistula - polyhydramnios, drooling, choking with feeds, inability to pass a nasogastric tube; part of VACTERL association.
• Duodenal atresia - "double bubble" on X-ray; associated with Down's syndrome.
• Pyloric stenosis - not congenital in the embryological sense; hypertrophy develops at 2–8 weeks; projectile non-bilious vomiting, hypochloraemic hypokalaemic metabolic alkalosis.
• Hirschsprung's disease - failure of neural crest cells to migrate to the distal bowel → aganglionic segment; delayed passage of meconium.

Kidney, Urinary Tract and Gonads

• Three kidney generations: pronephros (regresses), mesonephros (contributes the mesonephric/Wolffian duct), metanephros - the permanent kidney from the ureteric bud (collecting system: ureter, pelvis, calyces, collecting ducts) and the metanephric blastema (nephrons).
• Ascent: the kidneys ascend from the pelvis; the horseshoe kidney (fused lower poles) is trapped under the inferior mesenteric artery (Turner's syndrome association).
• Bilateral renal agenesis → oligohydramnios → Potter sequence (pulmonary hypoplasia, flattened facies, limb deformities).
• Duplex kidney and ureter - from a bifid ureteric bud; the upper-pole ureter may be ectopic (continuous dribbling in girls).
• Posterior urethral valves - boys; bladder outflow obstruction, bilateral hydronephrosis, oligohydramnios.
• Urachus (allantois remnant) - patent urachus → urine from the umbilicus; urachal cysts and adenocarcinoma.
• Gonads: the SRY gene (Y chromosome) → testis; Sertoli cells produce anti-Müllerian hormone (paramesonephric ducts regress) and Leydig cells produce testosterone (mesonephric ducts → epididymis, vas deferens, seminal vesicles). Dihydrotestosterone (DHT) masculinises the external genitalia and prostate.
• Without SRY: ovary; paramesonephric (Müllerian) ducts → uterine tubes, uterus, upper vagina.
• Anomalies: hypospadias (urethral opening on the ventral penis - failure of urethral fold fusion; do not circumcise - foreskin used in repair), cryptorchidism (undescended testis - refer by 3 months, orchidopexy at 6–12 months; increased cancer and infertility risk), bicornuate uterus, congenital adrenal hyperplasia (virilised XX infant), androgen insensitivity syndrome (XY, female phenotype, testes present).

Nervous System and Neural Tube

• Neurulation (weeks 3–4): the notochord induces the overlying ectoderm to form the neural plate → neural folds → neural tube; the anterior neuropore closes about day 25 and the posterior neuropore about day 27–28.
• Neural tube defects (failure of closure): anencephaly (anterior neuropore - incompatible with life), spina bifida (posterior) - occulta (tuft of hair, dimple), meningocele, myelomeningocele (exposed cord, paralysis, neurogenic bladder, Arnold–Chiari II malformation and hydrocephalus). Raised maternal AFP; prevention with folic acid (400 micrograms, or 5 mg if high risk) before conception.
• Brain vesicles: prosencephalon (forebrain → telencephalon and diencephalon), mesencephalon (midbrain), rhombencephalon (hindbrain → metencephalon - pons and cerebellum; myelencephalon - medulla).
• Holoprosencephaly - failure of forebrain division (trisomy 13, sonic hedgehog mutations).
• Chiari malformations - herniation of the cerebellar tonsils through the foramen magnum; type II is associated with myelomeningocele.
• Spinal cord growth: at birth the cord ends at about L3; in adults at L1–L2 - hence lumbar puncture at L3/4 or L4/5.

Limbs, Somites and the Body Wall

• Somites (paraxial mesoderm) → sclerotome (vertebrae, ribs), myotome (skeletal muscle), dermatome (dermis) - the segmental pattern explains dermatomes and myotomes.
• Limb buds appear in week 4 (upper before lower); the apical ectodermal ridge drives proximal–distal growth; the zone of polarising activity (sonic hedgehog) patterns digits. Upper limbs rotate laterally (thumb lateral); lower limbs rotate medially (big toe medial) - explains the spiral dermatome pattern of the leg.
• Anomalies: syndactyly, polydactyly, limb reduction defects (thalidomide), developmental dysplasia of the hip (not strictly embryological - risk factors breech, female, family history, first-born, oligohydramnios).
• Diaphragm - septum transversum, pleuroperitoneal membranes, body wall and oesophageal mesentery; innervated by C3, 4, 5 (phrenic nerve) because the septum transversum originates in the neck - explains shoulder-tip pain from diaphragmatic irritation. Congenital diaphragmatic hernia (usually left posterolateral, Bochdalek) → pulmonary hypoplasia.
• Inguinal canal - the processus vaginalis accompanies testicular descent; failure to close → indirect inguinal hernia or hydrocele (communicating) in infants.

Embryology at a Glance

Structure	Remember
Germ layers	Ectoderm (skin, nerves), mesoderm (muscle, bone, blood, kidney), endoderm (gut and respiratory linings, glands)
Neural crest	PNS, adrenal medulla, melanocytes, C cells, outflow tract septum
Critical period	Weeks 3–8 for structural anomalies
Fetal shunts	Ductus venosus, foramen ovale, ductus arteriosus
Pouches	3rd - inferior parathyroids and thymus; 4th - superior parathyroids
Gut	Foregut epigastric, midgut umbilical, hindgut suprapubic pain
Neural tube	Closes by day 28; folic acid prevents NTDs
Diaphragm	C3, 4, 5 → shoulder-tip referred pain

Spot the Diagnosis

• A newborn has a midline neck swelling that rises when the tongue is protruded. → Thyroglossal duct cyst.
• A neonate has bilious vomiting on day 2. → Malrotation with volvulus until proven otherwise - urgent surgical review.
• A baby with absent thymus, hypocalcaemic seizures and truncus arteriosus. → DiGeorge syndrome (22q11.2 deletion).
• A toddler has painless bright red rectal bleeding with a normal abdomen. → Meckel's diverticulum (technetium scan).
• A cyanosed newborn with a "boot-shaped" heart on CXR. → Tetralogy of Fallot.
• An infant with a continuous machinery murmur born at 28 weeks. → Patent ductus arteriosus.

Exam-style Scenarios

• Scenario. A woman with epilepsy on sodium valproate is planning pregnancy. What advice is needed?
  Answer: Valproate carries about a 10% risk of major malformations (including neural tube defects) and a 30–40% risk of neurodevelopmental disorders. Under the Pregnancy Prevention Programme, she should have urgent specialist review to switch to a safer antiepileptic (e.g. lamotrigine or levetiracetam) before conception, and take folic acid 5 mg daily.
• Scenario. A newborn has severe cyanosis that does not improve with oxygen; echo shows transposition of the great arteries. What immediate treatment keeps the baby alive?
  Answer: Prostaglandin E₁ (alprostadil) infusion to keep the ductus arteriosus open, then balloon atrial septostomy (to mix blood across the atrial septum) before arterial switch surgery.
• Scenario. Why does gallbladder inflammation cause right shoulder pain?
  Answer: Irritation of the diaphragmatic peritoneum (supplied by the phrenic nerve, C3–5) is referred to the C4 dermatome over the shoulder, because the diaphragm develops in the neck region (septum transversum) and descends, taking its nerve supply with it.

Key Points

• Weeks 3–8 are the critical period for structural anomalies.
• Neural crest derivatives explain many syndromes (Hirschsprung's, DiGeorge, phaeochromocytoma, neuroblastoma).
• Know the fetal shunts and their adult remnants.
• The 3rd pouch gives the inferior parathyroids and thymus; the 4th the superior parathyroids.
• Midline neck lump moving with tongue protrusion = thyroglossal cyst.
• Folic acid before conception prevents most neural tube defects.

Further Reading

• Sadler TW. Langman's Medical Embryology
• Moore KL, Persaud TVN. The Developing Human: Clinically Oriented Embryology
• MHRA: Valproate use by women and girls - Pregnancy Prevention Programme
• NHS Fetal Anomaly Screening Programme: 20-week screening scan conditions