E03 - Body Cavities, Respiratory System, Limbs , 4th week to birth.pdf

4th week to Birth, Body Cavities, Diaphragm, Respiratory System, & Limb Formation Embryology Objectives Outline the developmental milestones from the 4th week until the 38th week of gestation Describe the development of body cavities; pleural, pericardial, and peritoneal, and the formation of the di...

4th week to Birth, Body Cavities, Diaphragm, Respiratory System, & Limb Formation Embryology Objectives Outline the developmental milestones from the 4th week until the 38th week of gestation Describe the development of body cavities; pleural, pericardial, and peritoneal, and the formation of the diaphragm Clinical correlate: Congenital diaphragmatic hernia Highlight the major events in the development of the lungs Clinical Correlates: respiratory distress syndrome, tracheoesophageal fistula Describe the sequential development of the limbs, long bones Describe the rotation of the limbs Congenital anomalies of limb, amniotic band. 4-12 Somite Embryo (Day 22-23) Starting to fold Neural tube forming Rostral and caudal neuropores open rostral neuropore somite fusing neural folds (neural tube) caudal neuropore 13 Somite Embryo (Day 24) rostral neuropore 1st pharyngeal arch heart prominence somite Pharyngeal arches appear Rostral neuropore closing Eye begins to form Heart developing + beating! 27 Somite Embryo (Day 26) forebrain lens placode (developing eye) heart prominence otic pit (developing ear) pharyngeal arches 30-35 Somite Embryo (Day 28-30) lens pit (developing eye) nasal placode (developing nose) lower limb bud pharyngeal arches heart prominence upper limb bud Week 5 Rapid head growth (brain and face development) Primordial kidneys Week 6 Digital rays, eye, external ear begin to develop Umbilical herniation of intestines Week 7 Fingers start to separate in hand plates Week 8 More human-like characteristics Relatively large head, toes separating 8 Weeks – End of Embryonic Period *All major organ systems have been established Fetal Period Week 9 – Birth Fetal Period Embryo → Fetus by Week 9 Rapid growth and differentiation Body growth accelerates relative to head Timeline of Fetal Development 9-12 Weeks 13-16 Weeks 1o ossification centers Intestines return to body (10) External genitalia differentiate (12) Rapid growth – CRL doubles (12) Urine formation Waste exchange with maternal circulation 17-20 Weeks Timeline of Fetal Development 9-12 Weeks 13-16 Weeks 17-20 Weeks Lower limbs lengthen Limb movements Sex may be determined (12-14) Ovaries with follicles (16) Ossification (16) Eyes toward final position Timeline of Fetal Development 9-12 Weeks 13-16 Weeks 17-20 Weeks Quickening felt Vernix caseosa Hair and eyebrows Brown fat (heat) Uterus formed Testes begin descent Timeline of Fetal Development 21-25 Weeks 26-29 Weeks Substantial weight gain REM begins (21) Surfactant secretion (24) Survival may be possible! 30-38 Weeks Timeline of Fetal Development 21-25 Weeks 26-29 Weeks 30-38 Weeks Lung development CNS controls breathing and temperature White fat (storage) Bone marrow makes blood (28) Timeline of Fetal Development 21-25 Weeks 26-29 Weeks 30-38 Weeks Pupillary light reflex (30) Chance of survival great (32) Nervous system mature More white fat Testes in scrotum Body folding and Cavities Event Sequence Mesoderm organizes (notochord, paraxial, intermediate, & lateral plate) Cavitation (by apoptosis) within the lateral mesoderm creates a horseshoe-shaped cavity and creates 2 subdivisions 1. 2. Somatic mesoderm (pleural, mesoderm+ectoderm) Splanchnic mesoderm (visceral, mesoderm+endoderm) Embryo folds in the cranio-caudal axis because of growth of neural tube ‒ Cranial folding brings the future pericardial space, cardiogenic region, and septum transversum (future diaphragm) anterior and ventrally. Embryo folds in the lateral plane due to somite growth ‒ Visceral mesoderm folds around endoderm, this folding will give rise to primitive gut tube and its surrounding musculature ‒ Somatic mesoderm + endoderm folds around the body of the embryo and fusing antero-ventrally to form the body wall ‒ Folding drags the amniotic cavity around the entire embryo suspending the embryo within its fluid filled space. Intraembryonic Mesoderm Intraembryonic mesoderm get divided into 3 columns: Paraxial, intermediate and lateral plate mesoderm Paraxial mesoderm is initially one column then get segmented The cubical segments are known as somites – formed from occipital to caudal region. 42-44 pairs, some disappear, finally 35 pairs of somites. Number of somites help in determining age. Somite compartments Sclerotome - Ventromedial part migrates medially to form vertebral column and ribs Dermatome – Lateral part, give rise to dermis and subcutaneous tissue Myotome – Intermediate part, skeletal muscles Formation of Coelomic spaces Formation of Coelomic spaces Intraembryonic coelom Somatic layer (body wall) Visceral layer (around gut tube) Heart primordia Pericardial cavity Septum transversum Pericardial cavity communicates with peritoneal cavity through 2 pericardio-peritoneal canals Pleuroperitoneal folds (membranes) – separate the pleural cavities from the peritoneal cavity Pleuroperitoneal folds Diaphragm arises from four sources: 1. Septum transversum - the central tendon of the diaphragm. 2. Pleuroperitoneal membranes - posterolateral parts of diaphragm 3. Dorsal mesentery of the esophagus - forms the crura and median portion of the diaphragm 4. Body wall - forms the periphery of the diaphragm Diaphragm develops initially at the level of cervical somites 3-5 and it descends to the level of L1 as the embryo grows. Hence nerve supply comes from the phrenic nerve C3,4,5. Congenital diaphragmatic hernia Absence of pleuroperitoneal membrane Commonly on the left side Large defect in pleuroperitoneal membrane on left side Herniated intestinal loop and stomach X-ray of newborn with abnormal viscera in the left thoracic cavity, through congenital diaphragmatic hernia Separation of pleural and peritoneal cavities Lung buds grow into the pericardio-peritoneal canals (primordial pleural cavities). As the lung buds grow into the pericardio-peritoneal canals, a pair of folds starts developing: Pleuropericardial folds & membranes Lung growth within the pleural cavity drives growth of the pleuropericardial folds until they meet isolating the pericardial and pleural cavities. Parts of the primitive gut Foregut After the embryonic folding, intraembryonic part of the yolk sac is divided into Midgut 1. Foregut (within head fold), 2. Midgut (connected to yolk sac) 3. Hindgut (within tail fold). Yolk stalk / vitellointestinal duct/ vitelline duct connects midgut with the yolk sac Yolk stalk Yolk sac Hindgut Primitive gut Epithelial lining & glands – primitive gut tube endoderm Smooth muscle & connective tissue – from mesoderm Development of Esophagus Develops in the neck from a portion of the foregut (separated from the trachea by the tracheoesophageal septum) Epithelium & glands – from endoderm Striated muscles - 4th & 6th arch mesoderm Smooth muscles - from splanchnic mesoderm Epithelium of the esophagus proliferates & occludes the lumen & recanalizes Failure of recanalization can lead to: – – Esophageal stenosis - Partial recanalization of esophagus results in narrowing of the lumen Esophageal atresia - complete absence of lumen occurs due to total failure of recanalization Partitioning of the Foregut Tracheoesophageal septum divides the cranial part of foregut into: 1) laryngo-tracheal tube 2) pharynx / esophagus Lung Development Develops from Somatopleuric mesoderm Develops from Splanchnopleuric mesoderm Pseudo-glandular period Canalicular period Terminal sac period Alveolar period Type 1 alveolar epithelial cells are flat cells lining the alveoli. In last 2 months of IUL, another cell type develops known as type II alveolar epithelial cells. Type II alveolar epithelial cells produce surfactant, a phospholipid-rich fluid. Surfactant is capable of lowering surface tension in the alveoli, so the alveoli do not collapse during expiration. Premature infants: Surfactant is insufficient, surface tension inside alveoli is high and cause alveoli to collapse. Results in respiratory distress syndrome (RDS). In these cases, collapsed alveoli contain hyaline membranes, derived from the surfactant layer. (previously known as hyaline membrane disease). Accounts for nearly 20% of deaths among newborns. Diagnosis: ❑ Measuring Lecithin in amniotic fluid. Lecithin-to-Sphingomyelin Ratio (L/S ratio) ratio of less than 2.0 is significant for immature fetal lung development. Treatment preterm babies with artificial surfactant and treatment of mothers in premature labor with glucocorticoids to stimulate surfactant production. Agenesis – failure of lungs to develop; unilateral agenesis is compatible with life Tracheoesophageal fistula (TEF) – abnormal communication between trachea & esophagus due to defective development of the tracheoesophageal septum - Infants with TEF cough & choke when swallowing, due to accumulation of fluid in the mouth, fluid may pass into the lungs – causes pneumonitis / lung infection Normal Swallowed fluid fills esophageal pouch and goes in trachea TEF may be associated with poly-hydramnios (excessive quantity of amniotic fluid) – as fluid cannot go to the intestines due to esophageal atresia. Normally - Fetus swallow amniotic fluid, which is absorbed by the GI tract and then excreted into the amniotic cavity by the kidneys. If the amniotic fluid can not be swallowed, will lead to excess quantity of amniotic fluid (polyhydramnios) TEF may be a component of VACTERL – Vertebral anomalies, Anal atresia, Cardiac defects, TEF, Esophageal atresia, Renal anomalies, Limb defects. TEF and VACTERAL – favorites of USMLE Kartagener syndrome (subtype of Primary ciliary dyskinesia) Triad of situs inversus, recurrent sinusitis, and bronchiectasis Rare AR, dysmotility of cilia Defect in dynein arm of microtubules of cilia Recurrent otitis, sinusitis, and nasal polyps Conductive deafness Infertile men due to reduced sperm motility Nasal Nitric oxide test – NO very low EM: abnormal cilia CXR: bronchiectasis, dextrocardia Kartagener Normal Dynein arm present - arrows Bronchiectasis - walls of bronchi are thickened and damaged Development of Limbs Important Genes involved in Embryogenesis Sonic hedgehog gene – Involved in patterning anteroposterior axis and CNS development. Its mutation can cause holoprosencephalon (an abnormality of brain development in which the brain doesn't properly divide into the right and left hemispheres. Wnt-7 gene – Proper organization of dorsal-ventral axis FGF gene (Fibroblast growth factor gene) – for lengthening of limbs Homeobox (Hox) gene – for segmental organization. Mutation can cause appendages at wrong location. Thalidomide was first marketed in 1957 in West Germany, was used for morning sickness. Caused Phocomelia there is a severe shortening of the limb/s, due to proximal elements (long bones) being reduced or missing. Role of SALL4 gene in thalidomide phocomelia was identified in 2018. Development of the limb buds A. At 4 weeks, outpocketings along the lateral body wall form ridges. B. At 5 weeks, the limb bud stage is attained. C. At 6 weeks, hand and footplates are formed. D. By 8 weeks, fingers and toes are present. Hind limb development lags behind forelimb development by l to 2 days. Apical ectodermal ridge (AER) secret fibroblast growth factor (FGF). Cells father away from AER and exposed to retinoic acid secreted by mesenchymal cells. As development continues the differentiation moves from distal to proximal side under influence of SHH and other genes. AER stimulate outgrowth of limb bud. Early loss of FGF signaling will lead to Amelia (absence of entire limb). Limb Rotation Upper limb will rotate 90 degrees laterally Lower limb will rotate 90 degrees medially Happens during the 7th week of development Brachydactyly – short digits Polydactyly – extra digit Syndactyly – fused digits Cleft foot Amniotic bands may cause ring construction or amputation. Origin of band is not clear. There is adhesions between the amnion and the fetal structure. Skeletal system Mesenchyme Bone Development All bones are developed from intraembryonic mesoderm (mesenchyme, embryonic connective tissue) Two different processes: Intramembranous ossification (membranous bone formation), mesenchymal models of bone form during the embryonic period, and direct ossification of the mesenchyme begins in the fetal period – bones of the skull. Endochondral ossification (cartilaginous bone formation), cartilage models of bones are formed from mesenchyme during fetal period, Then the cartilage models are replaced by bones. Cartilage Bone Epiphysis is at the ends of long bone Diaphysis is the shaft of long bone Metaphysis is part of diaphysis adjacent to epiphysis. Epiphysis develops from secondary centers of ossification Diaphysis develops from primary centers of ossification Thalidomide was first marketed in 1957 in West Germany, was used for morning sickness. Caused Phocomelia - there is a severe shortening of the limb/s, due to proximal elements (long bones) being reduced or missing. Role of SALL4 gene in thalidomide phocomelia was identified in 2018. Frances Kathleen Oldham Kelsey, (July 24, 1914 – August 7, 2015) refused to authorize thalidomide for market because she had concerns about the lack of evidence regarding the drug's safety.