Chap 14: Developmental Genetics and Birth Defects Flashcards
Craniosynostosis
proptosis
large toes turned inward
thumbs point away
cloverleaf skull
Pfeiffer syndrome
- FGFR1* - mild
- FGFR2* - mild to severe
Gain of function mutations
Craniosynostsis
toes everted
TWIST
Loss of function mutation
Sarthre-Chitzen Syndrome
Craniosynostosis
fusion of metacarpels and metatarsal bones
most common syndromic craniosynostosis
p.Pro250Arg
Muenke Syndrome
Autosomal dominant- variable phenotype
FGFR3
Hearing loss in 72%
Bilateral coronal synostosis
brachycephaley
synostosis of the fingers and toes
Apert Syndorme
FGFR2
Craniosynostosis
Normal Intelligence
Crouzon Syndorme
FGFR2
X linked
Craniosynostosis
+/- cleft lip
females more severly affected than males
Craniofrontonasal Syndrome
EFNB1
What is exclusive about de novo fibroblast growth factor receptor mutations
Paternal origin
increases with paternal age
Defect of the developing forbrain
prosencephalon
Holoprosencephaly
Period of development when holoprosencehphaly takes place
gastrulation
Single central inciser
Holoprosencephaly
- SHH*
- ZIC2*
- SIX3*
- TGIF*
- FGFR1*
Most common genes associated with holoprosencephaly
Most common envoronmental/maternal factor associated with holoprosencephaly
Uncontrolled DM
Birth Defect
caused by external mechanical forces
mechanical stress
low recurrance risk
usually in the last trimester
- Deformations
- Ex. Twins
- Uterine abnormality
- Reduced amniotic fluid
- Potter sequence
Birth defect
occurs in structure that were forming normally
extrinsic breakdown
- Disruptions
- Amniotic band
- Limb-body wall complex
Birth Defect
abnormal celllular orginization and function
involves one tissue type
- Dysplasia
- ex: ectodermal dysplasia
Birth Defect
Abnormal development
permanat change
intrinsic abnormality
can involve multiple tissue types
Malformations
cleft lip and palate
holoprosencephaly
Birth Defect
localization of multiple defect
develop from same embryonic field
- Complex
- Example: OEIS complex (Ompalocele-Exstrophy-Imperforate Anus-Spinal defects)
- Example: Pentalogy of Cantrell: Inferior sternal defect, anterior diaphragmatic defect Ompalocele cardiac defect
recognizable pattern with a predictable natual history
Syndrome
Pattern of anomalie
result from a single identifiable event
- Sequence
- Ex: Potter sequence–> Low amniotic fluid
- Pierre-Robin Sequence–>Early mandibular hypoplasia–>posterior displacement of tough–>cleft palate
- Poland Sequence–>Hypoplasia of the pectoralis major muscle secondary to a vascular disruption
phenotypic similarities
distinct mutation or different genetic mechanism
Heterogeneity
Multiple phenotypic (organs) effected
single gene alteration
effects are not obvious
Pleitrophy
ex: charge syndrome, pancreatic insufficiency in CF
Radial Ray Defects
increase risk for AML, Myelodysplastic syndrome
Fanconi Anaemia
Radial ray defects
upper limbs
Heart : VSD, ASD, conduction defects
thumbs: absent, small or triphalangeal, bifid
phocomelia
Holt-Oram Syndrome
Autosomal dominant
TBX5
Radial Ray defects
1q21.1 microdeletion
preservation of thumbs
TAR
Thrombocytopenia abcent radius syndrome
RBM8A
Radial Ray defect
Red cell aplasia
Diamond-Blackfan Anaemia
Radial ray defects
anal atresia
thumb abnormalities
Townes-Brock syndrome
Autosomal dominant
SALL1
Central or postaxial polydactly
hypothalamic harmartoma
bifid epiglottis, laryngeal cleft, pulmonary segmentation anomalies
Pallister-Hall
- GLI3*
- A*utosomal recessive
frameshift/nonsense truncation mutations
3’ of zinc finger to codon 1161, repressor
Preaxial polydactyly of feet
postaxial polydactyly of hands
macrocephaly, wide spaced eyes, broad nasal root
Greig cephalopolysyndactyly
5’ or inclusive zinc finger domain
Autosomal dominant
preaxial polydactyly of the feet
post axial polydactyly of the hands
macrocephaly
wide spaced eyes
broad nasal root intellectual disability
Seizures
Greig cephalopolysyndactly contiguous gene syndrome
deletion in chromosome 7(p13–p14).
