Fetal Development and Teratology

Pathological processes are in italics.

Organ System Development and Associated abnormalities

(1) CNS:

week 4½ – formation of neural plate Þ neural crest and tube Þ brain and spine

week 6 – division of brain into three vesicles:

(1) prosencephelon (forebrain) Þ diencephalon and telencephalon

Pathology: EtOH Þ disrupts forebrain induction Þ holoprosencephaly: deformed frontonasal process, skull, midface

(2) mesencephalon (midbrain) – encompassed along with diencephalon by telencephalon (forms hemispheres)

(3) rhombencephelon (hind brain) Þ metencephalon (medulla) and myelencephalon (pons and cerebellum)

choroid plexus – CSF-producing zone on either side of the midline of the rhombencephelon roof plate where the pia and the ependyma make minute fingerlike projections into the 4^th ventricle and create a single median hole (foramen of Magendi) and two lateral holes (foramen of Luschka) through which CFS gains access to the subarachnoid space

Pathology: Malformation results in Dandy-Walker cyst/malformation, a cerebellar ataxia.

weeks 8-20 – corpus callosum forms; gyri and sulci continue to form through out gestation

(2) neural tube closure (failure of the neural tube to close results in NTD (Neural Tube Defect)

Pathology: anencephaly –disrupted closure of the neurospore by day 38 Þ brain is exposed mass of undifferentiated neural tissue

week 5 – somite formation Þ spinal cord

week 6 – neural tube complete Þ cranial caudal zipping from midpoint; cranial closure on day 39, caudal on day 41

Pathology: Cranial/Caudal defect > Midpoint defects due to zipping pattern

week 8 – end of gestation: mineralization of somites

(3) Cardiac

week 5 – mesenchymal angioblast form blood islands within embryo and yolk sac; cavitation Þ blood vessel networks

heart forms from the fusion of paired tubes in the thorax with bi-directional flow becoming unidirectional pulsatile flow

atrium is single and caudal; ventricle is medial; bulbus cordus (outflow portion) is rostral

heart tube rotates, causing bulbus cordus to be on the right and ventricle to be more caudal and ventral relative to atrium

week 6 – endocardial cushions appear in the atrioventricular area and grow toward each other

ventricular septum grows in from the apex from endocardial cushions

Pathology: Single atrium/ventricle result from endocardial cushion defects

week 7 – aortopulmunary septum divides the truncus arteriosus into the aorta and pulmonary artery outflow paths

Pathology: Truncus septation errors Þ transposition, truncus, double outlet ventricles, Tetralogy of Fallot

Pathology: Early aortic and pulmonary outflow blockage Þ Hypoplastic heart syndromes.

week 9 – interventricular septum completed; septum primum fuses with cushions and divides atrium, eventually breaks down to form forms foramen secundum

Pathology: intraventricular septum defects are the most common and occur in the superior membranous portion

(4) Urinary System – 3^rd in frequency of anomalies (> 10% in embryo and fetal autopsy)

weeks 4-5 – intermediate cervical mesoderm Þ nonfunctional pronephros: these degenerate leading to mesonephros, composed of tubules connecting the extraembryonic coelum and a long duct

functional until week 10 then regress, except for ducts in males (become epidydimis, rete testes and ductus deferens)

week 6 – metanephros (definitive kidneys) appear from sacral intermediate mesoderm Þ nephrons and glomeruli

week 7 – uteric buds form from the mesonephric duct and penetrates the metanephric blastema of metanephros

uteric buds induce blastema into nephrons which reciprocally inducing buds into ureter, renal pelvis, calyces and CT

Pathology: inductive deficiency Þ cystic and/or displastic kidneys

Pathology: total lack of induction (due to absence of bud or response of blastema) Þ uni or bi-lateral renal agenesis

Pathology: branching of uteric bud prior to entering blastema Þ ureteral duplication

Pathology: persistence of the blastema may provide precursors for Wilm’s tumor

week 8 – cloaca divides into rectum and urogenital sinus while allantois and superior end of presumptive bladder regress

distal urinary system arises from endoderm

Pathology: defects Þ persistence of cloaca or urachus, imperforate anus, bladder duplication, congenital fistulas

Pathology: defective extrophy of bladder results from abdominal wall defects via non mesodermal penetration of the cloaca

Pathology: upper abdominal wall defects result from problems with the normal gut herniation phase or vascular accidents.

Pathology: Uretral valves in males or urethreal atresisa in females Þ obstruction of distal tract

week 11 – urine production (metanephric system)

week 16 – majority of amniotic fluid is renally derived

week 20 – term: fetal urine goes from 2cc/hr to 26cc/hr

Pathology: inadequate amniotic fluid (Oligiohydramnios) prior to week 26 is associated with lethal pulmonary hypoplasia

(5) Thorax: Forgut Þ tracheobroncial tree

Pathology: Forgut malformations Þ sequestration, esophageal duplication, enteric and bronchogenic cyst, T-E fistula

week 10 – diaphragm fusion (left side before right side)

(6) Gastrointestinal Tract: most dorsal aspect of yolk sac Þ primitive gut

forgut Þ pharynx, lower respiratory tract, esophagus, stomach, duodenum, liver, pancreas, and billiary tract

midgut Þ small intestine, duodenum, cecum, ascending and colon, and transverse colon

hindgut Þ descending colon, sigmoid, rectum and upper anal canal

weeks 3-4 – internal cavity is formed; esophagus separates from laryngeal tube by septation and lengthens

Pathology: Defects here Þ Esophageal atresia and often T-E fistula (trachea- esophageal fistula)

week 5 – stomach dilates and rotates clockwise; duodenum is occluded until recanalization in week 8

week 6-11 – intestinal rotation in part in the umbilical stalk

(7) Genital System: default is female.

TDF (testicular differentiating factor) is coded for on short arm of Y chromosome by SRY along with zinc finger Y

week 7 – mesothelium and mesenchyme Þ gonad (undifferentiated until week 9)

germ cells from yolk sac seed primary sex cords

week 9 – Y chromosome Þ testicular cords, tunica albuginea and seminiferous tubules

week 10 – testosterone produced by mesenchymal Leydig cells (preserves the mesonephric ducts Þ genital ducts)

week 11 – Sertoli cells from seminiferous tubules produce MIF (Mullerian inhibiting factor)

week 14 – external genital differentiation induced by conversion of testosterone to DHT by 5a -reductase

week 12 – rudimentary ovarian structures appear

week 13 – germ and granulosa cells form

week 16-18 – follicular cells appear

week 15 – all oocytes arrest in diplotene phase of mitotic prophase I (pairing and cross over completed)

Paramesonephric ducts Þ Mullerian system

Pathology: Differentiation disorders and Gonadal dysgenesis caused by: chromosomal abnormalities, receptor disorders, exogenous virulizing hormones, 5a -reductase deficiency, MIF deficiency and testosterone synthetic disorders

(8) Endocrine System

week 6 – LH-RH and HRF (hormone releasing factor) detectable; adrenal gland begins to develop

week 7 – superior parathyroid glands complete migration from the 4^th pouch (pharyngeal)

week 9 – thyroid gland reaches its final site after migrating from buchal endoderm near the Foramen cecum

week 10 – dual zones appear in the adrenal and become responsive to ACTH by week 16

Pathology: adrenal malfuntion can Þ growth retardation

Pathology: 21-hydroxylase deficiency Þ shunting of substrate to androgens Þ virilization of females and salt wasting

week 11 – somatostatin increases until week 22

week 12 – TRH, PRL and TSH are detectable

GH appears in spite of a lack of GnRH and peaks at week 26

Concentration of iodide and thyroid hormone synthesis occurs

Pathology: Iodine deficiency during this period Þ irreversible cretinism postnatally

week 14 – hypothalamus/pituitary/endocrine axis is functional

parathyroid gland is functional: disorders Þ abnormal mineralization and fracture

week 15 - insulin production has already begun

Pathology: maternal diabetes Þ beta cell hyperplasia in fetus and is associated with macrosomia and postnatal hypoglycemia

(9) Skeletal System

Pathology: abnormalities have diverse causes: umbilical amputation, genetic malformation, infection, maternal metabolic disorders

General Points about Diagnosis of Congenital Abnormalities

most critical time for teratogenisis is between weeks 4-8

known causes of birth defects:

(1) chromosomal abnormalities: 50% of 1^st trimester losses; 0.5% of term births
(2) single gene disorders: 8% of anomalies; 1-2% of live births
(3) multifactorial inheritance
(4) environmental teratogens

detection is inherently limited by natural course of fetal development.

week 8-12 – bowel is normally eviscerated through umbilical cord

week 12 – fetal kidney function begins Þ fetal urine in amniotic fluid.

Pathology: Oligiohydramnios (inadequate amniotic fluid) caused by renal malfunction can’t be detected prior to week 16

week 13 – abdominal wall defects can not be reliably excluded prior to this point

week 24 – fetal swallowing begins

Pathology: related problems (e.g., esophageal atresia) are undetectable prior to this point

many abnormalities take time to manifest and are undetectable until the 3^rd trimester:

viral and teratogenic obstruction of CSF Þ ventricular calcification and hydrocephaly

polycystic kidney disease, cardiomyopathies and ventricular hypoplasia microcephaly and achrondoplasia

some lesions can spontaneously resolve:

reflux dependent hydronephrosis, cystic adenomatoid lung malformation, cystic hygroma, ventriculomegaly, mild hydropic changes