Embryology Overview

Embryology answers a single question: which developmental event went wrong? Almost every congenital malformation can be reverse-engineered to a specific process in a specific developmental window. This page sketches the timeline and the pathways that re-appear at every level; the rest of the chapter dives into each event in depth.

• Week 1, cleavage and implantation. Morula → blastocyst → implantation by day ~7. Disruption here is "all-or-none": embryonic loss or unaffected continuation, not malformation.
• Week 2, bilaminar disc. Epiblast and hypoblast form. Twin types depend on timing: dichorionic-diamniotic (cleavage day 1–3), monochorionic-diamniotic (day 4–8), monochorionic-monoamniotic (day 8–12), conjoined (>day 13).
• Week 3, gastrulation. Primitive streak forms; the trilaminar disc (ectoderm, mesoderm, endoderm) appears. The notochord induces the overlying ectoderm to thicken into the neural plate. Caudal failure of mesoderm migration → caudal regression / sirenomelia.
• Weeks 3–4, neurulation. Neural plate folds; anterior neuropore closes day ~25, posterior day ~27. Neural crest cells delaminate from the dorsal lips of the closing tube and begin a long migration.
• Weeks 4–8, organogenesis. Pharyngeal arches form, limb buds bud out, the heart loops, the gut tube rotates, and somites segment the trunk into vertebrae and ribs. This is the period of peak teratogenic vulnerability for structural defects.
• Weeks 9–term, fetal period. Growth and histogenesis. Insults here cause growth restriction, microcephaly, and functional deficits (brain, kidney) more often than structural malformations.

The "fourth germ layer" framing for neural crest is so clinically important that it deserves its own row. Tracing a phenotype to a single germ layer (or a single mesoderm subtype) usually localizes the defect.

The same handful of pathways pattern multiple structures, which is why mutations in one gene can produce wildly different syndromes depending on context.

• SHH (sonic hedgehog): midline patterning, ZPA (limb anteroposterior axis), neural tube ventralization, gut. Loss → holoprosencephaly. Gain (PTCH1 loss) → Gorlin / nevoid basal cell carcinoma. Regulatory-region (ZRS) gain → preaxial polydactyly.
• BMP: ventral mesoderm, cardiac, bone formation. Antagonized by noggin/chordin dorsally.
• WNT: posterior body axis, limb dorsoventral patterning (WNT7a), brain development. Mutations in pathway → familial colorectal cancer (APC/β-catenin).
• FGF: limb outgrowth (FGF8 at AER), skeletal patterning. FGFR3 gain-of-function → achondroplasia, hypochondroplasia, thanatophoric dysplasia. FGFR2 → Apert, Crouzon, Pfeiffer.
• NOTCH: lateral inhibition, somite clock, cardiac, hematopoietic. JAG1 → Alagille; DLL3/MESP2/LFNG → spondylocostal dysostosis.
• Retinoic acid: rostral-caudal patterning (Hox gene activation), heart, neural crest. Excess (isotretinoin) → microtia, cardiac, CNS defects.

• Patterning genes (Hox) are activated rostral-to-caudal along the body axis and determine "what kind of vertebra/limb segment" forms at each level. Hox mutations produce homeotic transformations (one body segment taking the identity of another).
• Body cavities form by lateral plate splitting into somatic (parietal) and splanchnic (visceral) layers. Failure of diaphragm closure → congenital diaphragmatic hernia (most often left posterolateral, the "Bochdalek hernia").
• Apoptosis is constructive. Interdigital webbing resolves by programmed cell death in weeks 7–8. Failure → cutaneous syndactyly. Loss of apoptosis at the cloacal membrane → imperforate anus.