key developmental pathways in inborn errors of development
2) Sonic Hedgehog, SHH
3) Fibroblast Growth Factor Receptor, FGFR
study of human congenital anomalies (birth defects), esp those affecting the morphology (anatomy) of the individual
aka study of abnormal form
devaition from the usual, something different, peculiar, abnormal
congenital anomaly: something that's unusual & different at birth
how common are major and minor congenital anomalies in newborns?
what % of infant deaths are because of anomalies?
20-30% infant deaths, 30-50% pediatric deaths
how common are anomalies?
congenital anomalies: present in >2000 inherited conditions
multiple congenital anomalies: present in more than 1000 inherited conditions
significant cosmetic, medical, & surgical consequence
eg: congenital heart disease, cataract
insignificant consequence, normal variant; don't create functional problem; is cometic, removable
eg: skin tag, single palmar crease, overlapping toes
what are ectopic cordis, neural tube defect, diaphragmatic hernia examples of?
what are accessory nipple, double whorl, polydactyl examples of?
if see many isolated minor anomalies on physical exam, what could it indicate?
most common isolated anomalies?
heart, craniofacial region, limbs, genitalia, nervous system
categories of isolated anomalies?
deformation, disruption, dysplasia, malformation
depends on etiologic factors involving various developmental processes, intrinsic and external forces, or diff tissues
what is deformation?
developmental process is normal
mechanical force alters structure, causes anomaly
eg: oligohydramnios can be secondary to renal hypoplasia, breech presentation or internal forces cause neuromuscular abnormality
what are potter's fascies and clubbed feet examples of?
developmental process is normal, but interrupted
usually caused by placental problem insufficiency
for ex., causes vascular accident, b/c of amniotic band sequence or fetal cocaine exposure
example of vascular disruption so fetal brain doesn't develop
morphological, macroscopic defect from an intrinsically abnormal developmental process
sign of a genetic disorder
holoprosencephaly, congenital heart disease, neural tube defect, cleft lip and palate are examples of?
abnormal microscopic tissue organization & development
eg: skeletal or connective tissue dysplasias; ectodermal dysplasias
categorizations of multiple anomalies?
sequence, syndrome, association
series of congenital anomalies derived from a single anomaly
can be part of a syndrome, or an isolated event
pierre robin sequence is example of?
primary anomaly: micrognathia
leads to superior displacement of tongue
leads to failure of palatal shelves to close
leads to "U" shaped cleft and glossoptosis
recognizable pattern of anomalies, presumed to be causally related, and NOT due to a sequence
> 700 human genetic syndroms have craniofacial anomalies
> 500 human genetic syndromes have limb abnormalities
trisomy 13 is an example of?
bilateral cleft, emphalaceal, polydactely
very fatal, usually baby isn't born
sequence vs. syndrome?
sequence: single origin results in variably expressed group of secondary and tertiary defects; entire cascade of events is known
syndrome: groups of anomalies containing multiple malformations and/or sequences which are variably expressed, results in overall pattern of anomalies; pathogenic relationship of group of anomalies not always understood
group of congenital anomalies that oc-occur more frequently that expected by chance
what is VACTERL
V: vertebral anomalies/dysgenesis, vascular anomalies
A: anal atresia
C: cardiac anomalies
T: tracheo-esophageal (T-E) fistula
E: esophageal atresia
R: renal anomalies, radial dysplasia
L: limb anomalies
breakdown of causes of human congenital anomalies?
50-60%: unknown etiology
7-10%: environmental agents
8%: mutant genes
7%: chromosomal defects
most common environmental teratogen?
fetal alcohol syndrome
physical impairment results from alcohol exposure during pregnancy
leading cause of intellectual disability
growth retardation, microcephaly, mental retardation, short palpebral fissures, short nose, smooth philtrum, thin upper lip, small distal phalanges and hypoplastic finger nails, cardiac defects
exposure during pregnancy that has harmful effect on developing fetus
examples of teratogenic exposures?
phenylalanine - maternal pheylketonuria
glucose - maternal diabetes
anticonvulsants (hydantoins, valproate)
retinoic acid embryopathy
what is maternal PKU?
what does it cause?
syndrome per environmental exposure to phenylalanine
growth retardation, mental retardation, microcephaly, cardiac anomalies
what does maternal diabetes cause re: syndrome in fetus?
environmental cause of syndrome
macrosomia, hypoglycemia, hypocalcemia, CNS anomalies, cardiac anomalies, caudal regression
non syndromic/isolated anomalies caused by?
genes which cause rare developmental syndromes
i.e. Van der Woude syndrome
cleft lip and palate is ex. of?
when is it most common?
common isolated anomaly
cleft lip pallet (CLP) is more common than cleft lip alone (CLA), and bilateral is more common tha unilateral
more common in males
incidence higher in asian, latino, native american descent
van der woude is? example of?
autosomal dominant cleft lip and palate disorder w/ mutations in DNA binding domain
give away: lip pits and cleft lip/cleft palate
70% caused by mutation in IRF6 gene
examples of allelic heterogeneity in IRF6?
interferon regulatory factor, IRF6
70% mutations in IRF6 = cause of Van der Woude syndrome
but genetic variants in IRF6 also assoc w/ popliteal pterygium syndrome, excess skin on extremities and contraction of arms/knees
what causes non-syndromic/isoalted cleft lip and palate?
IRF6 V274I overtransmission
so polymorphism, rare variance, in general population
valine confers triple recurrents risk
types of disease proteins in developmental disorders?
txn factors: 25-34%
structural proteins: 18
tumor suppressors: 5
what is homeobox gene cluster?
homeobox genes are organized v. close to each other chromasomally, have spatial expression; number them based on expression in flies, mice
hox gene mutations cause?
lower number = more cranial, so head, higher numbers = more caudal syndromes, tail
what are implicated in syndromes of congenital anomalies?
mutations in genes coding for txn factors, enzymes, structural proteins, receptors, tumor suppressors
what do mutations in a pathway affect?
development of multiple organ systems, b/c pathways/processes are utlized many times in diff tissues through organism's lifetime
muations of factors in FGFR3 pathway causes?
1) long bones of skeleton, causes limb development issues - achondroplasia, hypochondroplasia, skeletal issues result
2) craniosynostosis syndromes - skull doesn't fuse properly
craniosynostosis syndromes classification? cause?
autosomal dominant syndromes
gain of function mutations
what is craniosynostosis?
premature fusion of skull bones
makes head particular shape depending on FGFR mutation and which head shape results
how do clinicians redefine/reclassify conditions?
by relating phenotype w/ the genotype
mutations in genes/compoents of a common developmental pathway/process may result in?
overlapping phenotypic features
way that researchers relate phenotype w/ genotype to redefine, reclassify dysmorphic conditions
what does knowing syndrome's molecular basis allow?
what are RASopathies?
clincally overlapping syndromes
all based on RAS pathway defects, cannot always tell 1 from another based on clinical observations
Noonan syndrome, costello syndrome, cardiofacial cutaneous syndrome
characteristics of RASopathies?
autsosomal dominant, sparse, brittle hair, ASD, pulmonic stenosis, hypertrophic cardiomyopathy, ectodermal skin changes, +/- intellectual handicaps
examples of SHH pathway problems? what does this illustrate?
that mutations in inductive signals involved in establishing cell fates and pattering in developing embryo can cause phenotypically similar syndromes
Holoprosencephaly, Greig Cephalopolysyndactyly, Pallister Hall Syndrome, GLI3 mutations examples of this re: SHH
what do phenotypes of SHH pathway mutations have in common?
genetic heterogeneity / autosomal dominant
what does mTOR pathway control? mutations in it cause?
mTOR pathway: promtoes growth
mutations in mTOR: related to overgrowth, predisposition to cancer
what causes tuberous sclerosis?
what is research into it?
normally, dimerizing of hamartin, tuberin inhibits Rheb GDP which inhibits mTOR pathway
if have mutation in one of these proteins, hamartin or tuberin, get signaling of mTOR pathway, therefore tumor growth
treatment for tuberous sclerosis?
targeted therapy: mTOR inhibitors
examples of developmental signaling pathways?
fibroblast growth factor, glial cell-derived neurotrophic factor, notch, P13K-LKB1, RAS/MAPK, SHH, TGF-beta, Tumor Necrosis factor, Wnt (wingless-type)
what do whole exome/genome, expression, epigenetic sequencing or mutageneis screens show?
new pathways/networks of interacting environmental and genetic factors involved in normal variation in morphology and abnormal development
relationship between TWIST and FGFR?
TWIST is an inhbitor of FGFR
if LOF of TWIST, get FGFR gain of function