Genetics: Congenital Anomalies

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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


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