Genetics: Congenital Anomalies
Factor with highest recurrence risk for congenital heart defects
>2 affected 1st degree relatives (50%)
Prader-Willi Syndrome
severe hypotonia in early infancy excessive eating later in childhood morbid obesity delayed motor milestones & language development, cognitive impairment Caused by loss of paternal gene expression 15q11-13
Osteogenesis imperfecta tx
bisphosphonates
Dysplasia
Lack of normal organization of cells into tissues Defect of tissue differentiation (e.g. hemangiomas, renal dysplasia, skeletal dysplasias)
Fetal Alcohol Syndrome features
Poor growth Hypotonia Developmental Delay Microcephaly Heart defects Characteristic facies Flat smooth ph
Loss of paternal gene expression, think
Prader-Willi Syndrome
the high recurrence risk seen in >2 affected 1st degree relatives in congenital heart defects (50%), you would suspect
dominant inheritance
If have one minor malformation
doubles the likelihood that there are other major malformations
20-30% of all infant deaths are due to
genetic disorders
Velo-Cardial-Facial Syndrome (DiGeorge Syndrome) (22qdel Syndrome)
has a lot of variability in physical/mental features; can have several family members affected with very different presentations
Omphalocele
intestines grow outside body associated with trisomy 21?
If see anomalies like sandle gap toe or ear crease/pit, you would
look carefully for other malformations, and watch kid's development more closely
Smith-Magenis syndrome tx
melatonin
Can test contiguous gene syndromes with
microarray
if have two or more malformations
more concern for major malformations
bilateral cleft lip and palate have a higher
recurrence risk seen in sibs
Angelman Syndrome
severe developmental delay severe speech impairment gait ataxia tremulousness of the limbs Inappropriate happy demeanor Caused by loss of maternal gene expression - 15q11-13
Syndrome
"Group of anomalies that are due to a single etiology" -chromosomal disorders -contiguous gene deletions -single gene defects -triplicate repeat syndromes -teratogens
Multiple genetic condition - recurrence risk is higher, if:
-- proband is 1st degree vs. 2nd degree relative -- more than one family member is affected -- proband is more severely affected -- proband is less frequently affected sex
Common malformations with multifactorial inheritance
-Neural tube defects -Cleft lip/palate -Congenital hip dislocation -Club foot -Pyloric stenosis -Cardiac defects
Mechanisms of malformation
1. Genetic (single gene, chromosomal, polygenic) 2. Vascular (disruption of blood flow during fetal development) 3. Multiple Births (higher risk for malformations, disruptions and deformations) 4. Teratogens
Major anomalies mostly occur in
1st trimester
Cleft lip palate - greatest recurrence risk:
2 siblings (10%) sibling and parent affected (10%) child of proband (4.3%) sibling to proband (4.0%)
Malformation
A defect of organ differentiation Can be isolated or multiple May either be : Major (significant) or Minor (insignificant)
Anomaly
A structural feature that departs from the normal
Rubinstein-Taybi Syndrome genetics
AD mutations in CREBBP and EP300
Loss of maternal gene expression, think
Angelman Syndrome
Contiguous Gene Deletion syndrome
Angelman syndrome (puppet-like demeanor) Prader-Willi Syndrome Bechwith-Wiedemann Syndrome
Congenital Rubella features
Congenital Cataracts Microcephaly Skin rash at birth Developmental delay Seizures Deafness Thin philtrum
Abnormal morphogenesis
Deformation Disruption Malformation Dysplasia
Williams Syndrome
Delayed speech, developmental delay/ADD Short Stature Overly friendly/trusting personality Characteristic facial appearance Microdeletion 5q
Dysmorphic
Describes a body part that has not followed the normal pattern of growth or formation and is often disproportionate when compared to a normal one
Radial aplasia
Doesn't develop thumb/radius
Single palmar crease seen in
Down Syndrome
Diet tx
Dwarfing conditions Prader-Willi syndrome
Turner syndrome Tx
Growth hormone
Evaluating dysmorphic child
History Physical Exam Diagnostic Tests Consultations
minor malformations
Medically, surgically or cosmetically insignificant 15-40% of healthy people have a minor malformation 50% of minor malformation are in the head and neck region May act as clues to genetic disease
Treacher-Collins Syndrome features
Midface hypoplasia Micro/retroagnathia External ear abnormalities Lower eyelide abnormalities Hearing loss (40-50%) Vision problems Cleft palate +/- lip (28%)
Treacher-Collins Syndrome genetics
Most cases caused by autosomal dominant mutations - TCOF1
Disruption
Normal tissue Acted upon by a destructive force (e.g. amniotic bands, teratogens)
Deformation
Normal tissue Acted upon by mechanical forces (extrisic and intrinsic) (e.g. abnormal uterus, multiple gestation)
Family hx
Pedigree History of consanguinity. Occurrence of any of the following: - birth defects - mental retardation - early infant deaths - miscarriages
Bechwith-Wiedemann Syndrome
Somatic overgrowth Hemihyperplasia Macroglossia Visceromegaly Omphalocele Ear creases/pits Hypoglycemia Tumours
Prominent tongue think
Trisomy 21 or Beckwith-Wiedemann syndrome
Apert syndrome
Varying degrees of developmental delay/intellectual disability (50%) Turribrachycephalic skull shape; moderate-to-severe midface hypoplasia Soft tissue and bony ('mitten glove') syndactyly of fingers and toes involving variable number of digits; occasional rhizomelic shortening, elbow ankylosis
Rubinstein-Taybi Syndrome features
arched brows, downslanting palpebral fissures, nasal septum extending below alae nasi, and grimacing smile broad terminal phalanges, radially deviated thumbs moderate-severe intellectual disability
Most Bechwith-Wiedemann Syndrome are
sporadic (85%)
dysmorphology
the study of birth defects (congenital anomalies) and normal physical variation
Down syndrome Tx
thyroid hormone
Factor with highest recurrence risk for neural tube defect
two siblings affected
Downside of ordering microarray
you will receive information that you don't know what it means