Week 1 Flashcards
Embryology & Genetics
Trilaminar embryonic disc has what three parts?
- Endoderm
- Mesoderm
- Ectoderm
Disc thickening happens at which end?
The cranial end
Ectoderm
all contact with outside world + CNS, PSN - some cells are neuroectodermal cells
What are neuroectodermal cells?
Form the neural plate
Invagination
Inpocking which forms the neural groove, neural folds, and neural tube
Subcutaneous neural crest cells are found where?
Top most level of the dorsal side
What happens in the 4th week in utero in terms of head/neck development?
Differentiated cells develop - placodes, somites, and pharyngeal apparatus
What are placodes?
Thickened areas of embryonic ectoderm that the sensory organs arise from
What are the three kinds of placodes?
Nasal, otic, and optic placodes
What are somites?
Paired masses of cells that develop caudally (from top to bottom) from the mesoderm at about day 20
What do somites become?
The axial skeleton, muscles, and dermis
Describe how somites develop
Caudally to about 42 pairs on the sides of the neural tube
What is the pharyngeal apparatus?
Pharyngeal arches that correspond to primitive gill bars/branchial arches. They consist of a core of mesenchyme covered externally by ectoderm and internally by endoderm.
Pharyngeal arches are separated externally by…
pharyngeal clefts
Pharyngeal aches are separated internally by…
pharyngeal pouches
When are ectodermal structures evident?
Around the fourth week
What do ectodermal structures participate in?
Ectodermal structures participate in the formation of nasal and oral structures
Where is mesenchymal tissue derived from?
Mesenchymal tissue is derived from mesoderm
What does mesenchymal tissue form?
Mesenchymal tissue forms the muscles associated with each arch
What creates the mesenchymal tissue?
Neural crest cells create mesenchymal tissue
Describe neural crest cell migration.
These cells migrate to form the skeletal portion arising from each arch. They’re underneath the ectodermal level dorsally and they migrate around what will be the face.
Pharyngeal Arch #1
“Mandibular” arch - associated with…
CN V
Muscles of mastication
Malleus, incus, maxillary process, and part of the mandible
Pharyngeal arch #2
“Hyoid” arch - associated with…
CN VII
Muscles of facial expression
Stapes & upper hyoid
Pharyngeal arch #3
Associated with…
CN IX
Stylopharyngeus
Lower hyoid
Which pharyngeal arches are somewhat joined together in terms of function?
Pharyngeal arch #4, #5, and #6
Pharyngeal arches #4-6
Associated with…
CN X
Cricothyroid, levator palatini, pharyngeal constrictors, intrinsic laryngeal muscles
Larynx
Pharyngeal pouches associated with pharyngeal arch #1
Tympanic cavity, auditory tube, eustachian tube
Pharyngeal groove associated with pharyngeal arch #1
External auditory meatus
Pharyngeal membrane associated with pharyngeal arch #1
Tympanic membrane
Pharyngeal puches, grooves, and/or membranes associated with pharyngeal arch #2
Tonsils
Pharyngeal pouches, grooves, and/or membranes associated with pharyngeal arch #3
Parathyroid gland, thymus
Pharyngeal pouches, grooves, and/or membranes associated with pharyngeal arch #4
Sup. parathyroid gland
When does facial development occur?
Facial development occurs between weeks 4-9
How is facial development organized?
Facial development is organized around central opening (stomodeum)
Describe how neural crest cells migrate in terms of facial development.
Neural crest cells migrate to stomodeal area from neural folds to form facial primordial.
What structures do the neural crest cells develop in facial development?
- Frontonasal prominence (forebrain behind, nasal placodes on sides)
- Maxillary prominences (upper part of arch #1)
- Mandibular prominences
How many facial primordia are there?
5
- Frontonasal prominence
- Paired maxillary prominences
- Paired mandibular prominences
The medial nasal prominences merge with…
The medial nasal prominences merge with each other and with lateral nasal and maxillary prominences
What is the nasolacrimal groove?
The nasolacrimal groove is between the lateral nasal and maxillary prominences and becomes the nasolacrimal duct.
What is the intermaxillary segment
The inter maxillary segment is the merger of the medial nasal prominences and it gives rise to the philtrum, premaxillary bones, and primary palate
Frontonasal prominence turns into… (3)
The forehead, dosum, & apex of the nose
The lateral nasal prominence turns into… (1)
The sides of the nose
The medial nasal prominence turns into… (4)
The nasal septum, philtrum, premaxilla, and primary palate
The maxillary prominence turns into… (3)
The upper cheek, most of the upper jaw, and the lip
The mandibular prominence turns into… (4)
The lower jaw, chin, lower lip, and lower cheek
Excess tissue in the frontonasal prominence (or frontonasal dysplasia) results in:
A broad nasal bridge, hypertelorism (wide set eyes), cleft nose, & median cleft lip. - often associated with other defects (cognitive, neurological, etc.)
Deficient tissue in the frontonasal prominence (or holoprosencephaly) results in:
Defective formation of forbrain (prosencephalon) which manifests as mid facial deficits. Wide range of facial defects ranging from short, upturned nose, deficient philtrum, arched palate, and microcephaly to medial nasal prominences, inter maxillary process fail to form, absence of nasal septum & ethmoid bone, single nostril (cebocephaly), hypotelorism or even cyclopia with proboscis
Describe the development of the nose
Around the 4th week, the nasal placodes form on frontonasal process. The medial and lateral nasal prominences with the depression in between will be the nostril. Nasolacriminal groove separates the lateral prominences from the maxillary prominences.
Describe the development of the inner ear.
~4th week the otic placodes invaginate and form otic pits which pinch themselves off from the ectodermal surface. - These auditory vesicles will form the membranous labyrinth of the inner ear and eventually the receptor cells of the inner ear.
~7th week: the auditory vesicle will differentiate into 3 parts
In the ~7th week, the auditory vesicle of the inner ear will differentiate into what? (3)
- The endolymphatic duct with the endolymphatic sac at the end.
- The utricle as well as utricular diverticula
- The saccule, the cochlear duct, and the spiral organ of corti.
Describe the development of the middle ear.
The endoderm of the 1st pharyngeal pouch will line the ME cavity & auditory tube - bones of the ME are derived from the cartilage of the 1st & 2nd pharyngeal arches
When does the middle ear start to develop?
As the inner ear differentiates (~week 7)
What does the middle ear develop from?
The 1st and 2nd pharyngeal arches
When does the outer ear begin to develop?
~week 7
Describe the development of the outer ear
Six auricular hillocks arise on the pharyngeal arches. They begin to enlarge, differentiate, & fuse together to take the early form of the pinna. They move during the fetal period from the side of the neck to the sides of the head
When does the formation of the primary palate take place?
Formation of the primary palate takes place at the end of the 6th week (begins in week 5 but weeks 6-9 are most critical)
Describe the development of the primary palate
The maxillary and lateral nasal prominences merge at the nasolacrimal groove. Medial nasal prominences merge together and with maxillary and lateral nasal prominences to form inter maxillary segment. The segment produces the philtrum, pre maxilla, alveolar ridge - the primary palate
What forms the primary palate?
The inter-maillary segment (produces the philtrum, pre maxilla, & alveolar ridge)
What are the lateral palatine processes?
Ingrowths from maxillary prominences - eventually project horizontally above the tongue - fuse with each other, primary palate, and nasal septum
What is the nasal septum?
Downgrowth of medial nasal prominence - fusion with lateral palatine processes starts anteriorly, then moves back
What is the hard palate?
Includes part of the primary palate (pre maxilla) and the lateral palatine processes (maxilla)
What is the soft palate?
Unossified portion of lateral palatine processes.
Where does the PRIMARY palate end?
At the incisive foramen
What are the boarders of the SECONDARY palate?
SECONDARY palate consists of hard & soft palates, starting at the posterior boarder of the pre maxilla (incisive foramen) to the uvula.
Describe the development of the SECONDARY palate.
~6-12 weeks: lateral palatine processes (shelves) are formed - mandible creates space for tongue to drop (from nasal to oral cavities) - shelves become horizontal & fuse first with the pre maxilla at incisive foramen and then from front to back along the median palatine suture line (~8-10 weeks)- vomer descends and fuses w/superior palate - velum and uvula follow
Causes of clefts (most common birth defect) (4)
- Chromosomal disorders
- Genetic disorders
- Environmental teratogens
- Mechanical factors (some kind of pressing in utero)
Cleft lip & palate has a : ratio, males:females
2:1 (males:females)
Cleft palate has a : ratio, females:males
2:1 (females:males) - females are more likely to have cleft palate ALONE because their palate takes longer to form, prolonging their sensitive period
A unilateral cleft means what?
One shelf is attached to vomer
Kernahan classification: prolabium
Separated philtral tissue
Kernahan classification: Premaxilla
Extends to bone beneath (alveolus and anterior portion of the maxilla - 4 front teeth)
Kernahan classification: Fistulae through dehiscence
After an attempt to close the palate - it’s too snug so it tears back open (tight dress example)
Incidence of cleft lip (+/- cleft palate)
1 in 750
Incidence of cleft palate (only)
1 in 2500
Unilateral cleft lip development
Forms as a persistent labial groove - this groove should disappear as the maxillary prom. fuse with merged medial nasal prom. Stretching of epithelium causes tissue breakdown & cleft formation.
Simonart band
Bridge of tissue spanning the cleft
Bilateral cleft lip development
Forms as a persistent labial groove - this groove should disappear as the maxillary prom. fuse with merged medial nasal prom. Stretching of epithelium causes tissue breakdown & cleft formation. - central soft-tissue mass that moves freely
Columella
provides extension of the nose off of the face - otherwise you would appear flat at profile
Anterior cleft anomalies
Clefting of the alveolar process of maxilla as well as lip - complete extends to incisive foramen - results from failure of lateral palatine process to fuse to prim. palate
Posterior cleft anomalies
Clefts extend through both soft & hard palate to incisive foramen - isolates anterior & posterior portion of the palate - results from failure of lateral palatine processes to grow medially and fuse to each other
Embryological basis of anterior cleft palate (primary palate)
Lateral palatine processes fail to fuse with primary palate
Embryological basis of posterior cleft palate (secondary palate)
Lateral palatine processes fail to fuse with each other AND with nasal septum
Complete cleft palate (primary & secondary)
Lateral palatine processes fail to fuse with (1) each other, (2) with the nasal septum, and (3) with the primary palate
Cleft lip: mechanism (2)
- Hypoplasia (not enough tissue) in maxillary prom. leading to inadequate contact w/medial nasal prom. & intermaxillary segment
- Due to: (1) inadequate migration of neural crest cells (2) excessive cell death (apoptosis)
Cleft lip: Underlying cause
Multifactorial (genetics, teratogens)
Teratogenic drugs: anticonvulsants (dilantin), vitamin A, vitamin analogs: oral anti-acne drug (Accutane)
Cleft palate: mechanism (5)
- Failure of lateral palatine process to fuse.
- Due to: (1) inadequate growth, (2) failure to elevate above tongue, (3) excessively wide head, (4) failure to fuse, (5) secondary rupture after fusing
Cleft palate: Underlying cause
Multifactorial (genetics, teratogens)
- Genetics: Trisomy 13
- Teratogenic drugs: anticonvulsants
what is a sub mucous cleft?
Tissues closed on the outside, but the muscles are cleft on the inside - there is no communication between the oral & nasal cavities, however, it’s only separated by tissue and no muscle
Classic triad of stigmata of sub mucous cleft
- Bifid uvula
- Zone pellucida (bluish, thin mucosa)
- Notch at posterior border of hard palate (V-notch
Malformation (def & ex)
A morphologic defect of an organ, part of an organ, or larger area of the body resulting from an intrinsically abnormal developmental process.
Ex: Cleft lip
Deformation (def & ex)
Abnormal form or position of a body part caused by non disruptive mechanical forces - usually late in fetal development - mechanical, malformational or functional
Ex: malformation of cleft palate results in a DEFORMATION which is that everything is open.
Disruption (def & ex)
Defect of an organ, part of an organ, or a larger area of the body due to interference with a normal process - sporadic & rare
Ex: Amniotic bands leading to amputations
Sequence (def & ex)
Multiple defects that occur as a result of a single presumed structural anomaly
Ex: Pierre Robin sequence (mandible not growing/moving forward is original malformation - triggers the sequence of tongue not descending and maxillary arches not closing)
-“A series of unfortunate events”
Syndrome (def & ex)
Pattern of multiple anomalies believed to be pathogenetic ally related and not representing a sequence - pathogenesis less understood
Ex: Treacher-Collins syndrome (facial hypoplasia, cleft palate, hearing loss)
- If we see 3 different things in a child, that typically indicates a syndrome
Association (def & ex)
Nonrandom occurrence of a group of anomalies in multiple individuals, not known to be a sequence or syndrome - alert clinicians to look for related problems.
Ex: CHARGE (a group of problems that are associated w/each other)
The team approach includes: (11)
Parents, plastic/craniofacial surgeon, pediatrician, otolaryngologist, geneticist, SLP, AuD, anesthesiology, orthodontist/dentist, developmental specialist, teachers, etc.
Management issues: (5)
Upper airway obstruction general health hearing loss speech disorders developmental / cognitive / social issues
Typical syndromal health management concerns (4)
- Neonatal nasal obstruction (if they cannot breath through their nose, they cannot feed)
- Neonatal oropharyngeal obstruction
- Obstructive apnea
- Airway maintenance for surgery
Neonatal Nasal Airway Obstruction
- Obligate nose breathers until >3 months
- Problems when mouths closed / feeding
- Ex: bilateral choanal/midface hypoplasia
- Treatment with oral airway
Neonatal oropharyngeal airway obstruction
- Posterior displacement of tongue
- Neonates with retro/micrognathia
- Treatment: positioning (NO ‘BACK TO SLEEP!’), DOG (distraction osteogensis - break the bone, pull it apart a little, it will grow back together), tracheotomy if life threatening
- Usually relived by 9 months
Causes of obstructive apnea in children (5)
Variety of causes:
- Maxillary hypoplasia
- narrow nasopharynx
- retrognathia
- micrognathia
- overcorrect VIP
Operative procedures for children with obstructive apnea (6)
- Adenotonsillectomy
- tongue tethering
- laser reduction of tongue base
- mandible advancement
- laser reduction of supra glottis
- tracheotomy
Airway problems w/surgery
- Endotracheal intubation or tracheotomy
- Indications for tracheotomy
- Tracheotomy less common today
- Perform w/airway control
Indications for tracheotomy
- Endotracheal intubation impossible, difficult extubation
- Facilitate surgery & post-operative care
- Inability to intubate nasally
What % of cleft lip +/- palate is syndromal?
50%
Common syndromes (6)
- Apert & Crouzon syndromes (craniosynostosis)
- Velocardiofacial syndrome (velum, heart, face)
- Pierre Robin sequence
- Hemifacial microsomia (half the face - small formation of face)
- Treacher-Collins syndrome
- CHARGE association
What is craniosynostosis?
Premature closure of cranial sutures
Primary craniosynostosis
Due to abnormalities of skull development
Secondary craniosynostosis
Due to failure of brain growth and expansion - produces microcephaly
Incidence of craniosynostosis
1 in 2,000-3,000 - more more common in males! - is a feature in 150+ syndromes
Craniosynostosis mechanism
Unknown, perhaps cranial base abnormalities cause dural forces that disrupt normal suture development
How is craniosynostosis classified?
On sutures closed
- Sagittal (down midline)
- Coronal (parallel to face)
- Lambdoid (horizontal by back of head)
Scaphocephaly (form of craniosynostosis)
- Most common form; more common in males
- Premature closure of the SAGITTAL suture
Frontal Plagiocephaly (form of craniosynostosis)
- Second most common form; more common in females
- Premature closure of the CORONAL suture on ONE SIDE
Occipital Plagiocephaly (form of craniosynostosis)
- More common in immobile children
- Premature closure of LAMBDOID suture on ONE SIDE
Trigonocephaly (form of craniosynostosis)
Premature closure of metopic suture
Turricephaly (form of craniosynostosis)
Premature closure of CORONAL suture
Crouzon Syndrome
- Craniosynostosis
- Hypertelorism (wide spaced eyes)
- Exopthalamus (bulging eyes)
- Hydrocephalus (too much fluid in ventricles)
- Hearing loss
Apert Syndrome
- Craniosynostosis
- Hypertelorism (wide spaced eyes)
- Expothalamus (bulging eyes)
- Beaked nose (little nose)
- Cleft palate (sometimes high/vaulted only)
- Upper airway obstruction
- Syndactyly (fingers/toes fused together)
- Mid-face hypoplasia -> HYPOnasal
- More mental retardation / cognitive issues than Crouzon
Pfeiffer Syndrome
- Clover leaf skull
- Hypertelorism (wide spaced eyes)
- Exopthalamus (bulging eyes)
- Broad toes & thumbs
Crouzon & Apert are both…
Autosomal dominate with an incident of ~15 to 16 per 1,000,000 birthds
Airway concerns w/craniosynostosis
- Compromise of nasopharyngeal & oropharyngeal airway
- Serious risk for respiratory distress, obstructive sleep apnea, cor pulmonale and sudden death
Treatment for airway concerns w/craniosynostosis
- Endotracheal intubation
- Tracheotomy
- Sleep study for obstructive sleep apnea
Hearing concerns w/craniosynostosis
- Conductive hearing loss due to Eustachian tube dysfunction from decreased nasopharyngeal space
- Tympanostomy tubes often necessary
SLP Concerns for Apert/Crouzons (5)
- Chronic airway issues
- Hyponasality
- Hearing management
- Phonological development
- Language development / cognitive delay
Velocardiofacial Syndrome (VCFS)
- Most frequently occurring syndrome involving clefts & VP function
- Prevalence: 1/2,000 - autosomal dominant
- Deletion on the long arm of chromosome 22
Characteristics of Velocardiofacial Syndrome (7)
- 180+ known associated anomalies
- Congenital heart defects
- Growth deficiency
- Hypernasal speech / cleft palate
- Poor fine motor skills
- Learning disabilities
- Psychosis
- Vascular anomalies common (most commonly head/neck vessels)
Unusual facial features in Velocardiofacial Syndrome (7)
- Thin upper lip
- Narrow palpebral fissures
- Large nose
- Flattened nasal bridge
- Flat malar region
- Basicranial angulation
- Causes long face, puffy eyelids, retruded mandible, increased pharyngeal depth
Why do you have to be careful in planning for VPI surgery in patients with Velocardiofacial Syndrome?
These patients have vascular anomalies common in the head and neck vessels. Often, their carotid artery is more medial, therefore it is more likely to accidentally get cut in surgery
Airway concerns in patients with Velocardiofacial Syndrome
- Common for infants
- Due to generalized hypotonia (esp. pharyngeal), retrognathia, laryngeal webs, and reactive airway disease
- Endoscopic assessment critical
- Trach rare
- Cleft palate & UAO
Hearing concerns in VCFS
Minor ear anomalies - SNHL in 15% - usually unilateral & mild
SLP concerns for VCFS (5)
- Palatal anomalies (75%)
- Increased pharyngeal depth
- Severe hypernasality
- Phonological developmen
- Apraxia
Palatal anomalies in VCFS
75% have palatal anomalies
- 80% occult, 20% overt
- 44% w/submucous cleft & bifid uvula
Pierre Robin Sequence (PRS)
- Triade of palatal cleft, micrognathia, and glossoptosis (backfalling / drooping back of tongue)
- Incidence: 1 in 8,500
- Etiology can be multiple (positional, genetic, neurologic, syndromal)
Airway Concerns in PRS
- Management w/nasopharyngeal airway initially (~8 weeks)
- Trach may be necessary if other treatments fail
PRS & other syndromes
- 32% stickler syndrome
- 11% VCFS
- 10% FAS
- 5% mandibulofacial dysostosis
-17% non-syndromal
Hearing concerns in PRS (3)
- Chronic otitis media w/effusion common
- Palatal abnormality –> Eustachian tube dysfunction
- Required multiple tympanostomy tubes
SLP concerns for PRS (6)
- Effect of trach on laryngeal function
- Effect of glossopexy (attach the tongue to the lip/elsewhere)
- Effect of tube feeding on swallowing
- Articulation
- Effect of hearing on overall development
- Socialization & development
Treacher-Collins Syndrome (T-C)
- Mandibulofacial dysostosis (development didn’t occur properly)
- Autosomal dominant
- 1 in 25,000-50,000 births
- Bilateral abnormalities of 1st and 2nd pharyngeal arches
T-C Characteristics (2)
- Hypoplasia of maxilla, zygoma, and mandible
- Downward slanting eyes w/colobomas (defects in the eyelids) or lower eyelid and absence of eyelashes
Airway concerns in T-C (3)
- Respiration easily compromised, especially if choanal atresia/stenosis present
- Airway management extremely difficult
- Obstructive sleep apnea may develop - responds to tonsillectomy and/or mandibular advance
Hearing concerns in T-C (5) - major issue in this pop!
- Auricles are malformed / absent
- Varying degrees of ME hypoplasia and ossicular malformation
- Bilateral CHL - 50 to 70 dB
- Surgery difficult at best, change for success is poor
- Hearing aids usually necessary
SLP concerns for T-C (3)
- hearing management
- management of possible clefting / VPI
- normal cognitive development
Hemifacial Microsomia Oculoauriculovertebral Syndrome (HFM)
- Heterogenous spectrum of disorders w/multiple origins
- Most common congenital anomaly after cleft lip/palate
- Unilateral craniofacial malformation (mild-severe)
- 1st & 2nd arches
- 1 in 5,600 births
- Sporadic (mostly)
- Vascular anomaly in fetal life (?)
Hemifacial Microsomia Oculoauriculovertebral Syndrome - Characteristics
- Facial asymmetry, unilateral ear deformities, & vertebral malformations
- Upper eyelid colobomas
- Auricular malformations, external auditory canal stenosis, ossicular abnormalities
- Facial weakness in 10 to 20%
- OMENS classification
Hearing concerns (HMF)
- > 50% of patients
- Usually conduction (ossicular malformation/absense, EAC atresia)
- SNHL occasionally
SLP Concerns in HMF
- Hearing sequelae
- Articulation from mandibular malocclusion
- Ankyloglossia
- VPI
- Support
What should you check for in EVERY craniofacial kid?
Ankyloglossia
CHARGE Association
- Coloboma (defect of the iris / eyelid)
- Heart defect (tetraolgy of Fallot, ASD, VSD)
- Atretic choanae
- Retarded growth
- Genitourinary anomalies
- Ear malformations
- Must have 4 out of 6
Airway concerns in CHARGE
- Choanal Atresia - bilateral more common
- Bilateral - immediate airway support w/oral airway / intubation
- If definitive surgery delayed b/c of other anomalies, trach is necessary
Hearing Concerns in CHARGE
- External ear anomalies (vary widely)
- Middle ear anomalies (absence of stapes, abnormal incus, absence of oval window)
- Inner ear anomalies
- Deafness is of mixed type
Approach to diagnosis
- 3,000+ known syndromes
- History (medical pedigree, maternal/paternal age, consanguinity (marry a close relative), previous abortions, teratogens)
- Physical examination (compare other siblings/family member photos, major/minor abnormalities
- Reference books!
What does DNA stand for?
Deoxyribonucleicacid
What does DNA do?
It acts as our bodies instruction manual used in the development and functioning of all known living organisms
What is DNA made of?
Sugar, phosphate, and a base pair. - Adenine (A) Guanine (G) Thiamine (T) and Cytosine - this is called a nucleotide
What does each codon represent?
An animo acid
What makes a gene and what does it do?
Amino acids put together in a specific order makes a gene and codes for a specific protein that has a specific function in the body
What is the coding portion of a gene called?
Exons
What is the noncoding portion of the gene called?
Introns - “junk DNA”
What are chromosomes?
Carry all the DNA in the human body in a condensed structure - each has two arms separated by a centromere. - Essential unit for cellular division and must be replicated, divided, and passed successfully to their caught cells
How many chromosomes are there in the human body?
46 chromosomes - come in 23 pairs - last pair is sex chromosomes X and Y
What causes genetic disorders?
Both genetic and environmental factors
What are four types of genetic disorders?
- Chromosomal (ex: Down’s)
- Single gene
- Mitochondrial
- Multifactorial
What is morphogenesis?
An extremely complicated and very poorly understood interaction between genetic and environmental factors that results in the formation of an organism
The normal steps of morphogenesis include:
- Cell migration
- Cell division
- Interactions between adjacent tissues
- Adhesive association of like cells
- Cell death (apoptosis)
- Hormonal influence
Incidence of structural abnormalities
- Major: 2-3% of all births
- Minor: 10% of all births
Environmental factors that cause anomalies include:
Teratogens, drugs, chemicals, infections, ionizing radiation, maternal factors
What are the three basic principles in teratogenesis?
- Critical periods of development
- Dosage of the drug or chemical
- Genotype (genetic constitution) of the embryo & mother
What are teratogenic agents?
Agents that may cause birth defects when present in the fetal environment.
May include: drugs, chemicals, infections, physical and metabolic agents.
Variability in range of effects of teratogenic agents is dependent on what?
- Dosage
- Developmental timing of exposure
- Differences in susceptibility
- Interaction among environmental exposures
Is there an established dose / response relationship for FAS?
NO
FAS facial characteristics
- Epicanthal folds
- Small eye openings
- flat mid face
- upturned nose
- smooth philtrum
- thin upper lip
- CNS dysfunction: intellectual, neurologic & behavioral
- Growth deficiency - pre & postnatal
What is mendelian inheritance?
Mendelian inheritance is established by a combination of clinical diagnosis with a compatible pedigree pattern
What are the four mendelian inheritance patterns?
- Autosomal Recessive
- Autosomal Dominant
- X-linked Recessive
- X-linked Dominant
Autosomal Recessive
-Both genes are abnormal in an affected individual - both parents have 1 abnormal gene (both parents are carries & phenotypically normal)
-Risk of affected child = 1/4 or 25%
Males & females affected equally
Autosomal Recessive ex: Peroxisomal Disorder
Caused by the failure to import enzyme into the peroxisome for degradation.
Craniofacial features: flat occiput, large fontanels, high forehead w/flat face, epicentral folds, congenital cataracts, severe brain abnormalities - other features: severe mental retardation, hepatomegaly, growth retardation
-Most die w/in first year of life
Autosomal Dominant
-One abnormal gene is enough to cause the disease - vertical transmission is seen - males & females affected equally - Affected gene seen in every generation - offspring of an affected parent has 1/2 chance of also being affected
Examples of Autosomal Dominant
Velocardiofacial syndrome (VCFS), apert, crouzon, achondroplasia
X-linked Inheritance
- Females are XX - Males are XY
- Females are called “carriers” & may be unaffected if they have one abnormal x
- Males are affected
X-linked Recessive Inheritance
-If mother is a carrier:
1/2 chance that each son will be affected
1/2 chance that each daughter will be a carrier
-If father is a carrier:
all daughters are obligate carriers
NO males are affected
Non-Mendelian Inheritance Patterns: Multifactorial Inheritance
- Common disorders where a # of genetic & environmental factors are involved
- No single gene
- Increased risk among closest relatives and decreased rapidly w/distance of relationship
Multifactorial Disorders ex: Cleft lip / palate
- Most are isolated; sometimes seen w/a recognizable syndrome
- Cleft palate can be etiologically distinct from cleft lip & palate
Down’s Syndrome Features
Craniofacial: up-slanted palpebral tissues & epicanthal folds (eyes) - small, over folding of angulated upper helix, hearing loss, otitis media (ear) - brachycephaly w/flat occiput - hypoplasia, irregular placement, fewer than usual (dentition)
Other: hypotonia, simean crease, wide spaced nipples, wide spaced first toe, mental retardation, endocardial cushion, GI issues, kidney, genitalia, leukemia
*Chromosome 21 has an extra!
Non-Mendelian Inheritance: Chromosome Translocations – Robertsonian Translations
Balanced translocation: two acrocentric chromosomes attach at the centromere; the total chromosome number changes from 46 to 45
Which chromosomes are “acrocentric” chromosomes?
13, 14, 15, 21, 22
