Chapter 5 - Inborn Errors Flashcards
1
Q
How do X-linked dominant disorders differ between males and females who inherit them?
A
such disorders tend to be more severe or lethal in males
2
Q
Which classic inheritance pattern tends to only affect males?
A
X-linked recessive
3
Q
Describe the inheritance of Angelman and Prader-Willi syndrome?
A
- both are due to genomic imprinting
- in the case of Angelman syndrome, the paternal allele is imprinted and silent; the maternal allele is either abnormal or there is paternal disomy
- in the case of Prader-Willi syndrome, the maternal allele is imprinted and silent; the paternal allele is either abnormal or there is maternal disomy
4
Q
What is the difference between a malformation, deformation, and disruption?
A
- malformation: an intrinsically abnormal process forms abnormal tissue
- deformation: mechanical forces exerted on normal tissue result in abnormal tissue
- disruption: normal tissue becomes abnormal after being subjected to destructive forces such as decreased blood flow
5
Q
Ultrasound is used in the prenatal period to asses what?
A
gestational age, fetal growth, and major anomalies
6
Q
Elevated maternal serum AFP is a marker for what seven items?
A
- neural tube defects
- multiple gestation pregnancies
- underestimated gestational age
- ventral abdominal wall defects
- fetal demise
- conditions causing edema
- skin defects
7
Q
Low maternal serum AFP is a marker for what three items?
A
- overestimated gestational age
- trisomy 18 or 21
- intrauterine growth retardation
8
Q
What do we mean by the term “triple marker”?
A
a term which refers to maternal serum AFP, unconjugated estriol, and B-hCG which are used as non-invasive methods for assessing the fetus for trisomy syndromes
9
Q
What triple marker profiles are consistent with trisomy 18 or trisomy 21?
A
- AFP, estriol, and B-hCG are all low in trisomy 18
- AFP and estriol are low but B-hCG is high in trisomy 21
10
Q
What is chorionic villus sampling? When is it done during the gestational period? What is it used for?
A
- it is a collection of virus tissue from the chorion of the trophoblast
- done at 10-13 weeks gestation
- used for karyotyping, DNA extraction, and enzyme analyses
11
Q
What is amniocentesis? When is it done during the gestational period? What is it used for?
A
- it is a collection of amniotic fluid which contains sloughed fetal cells
- done at 16-18 weeks gestation
- used for karyotyping, DNA extraction, and enzyme analyses
12
Q
What is percutaneous umbilical blood sampling? What is it used for?
A
- it is a collection of fetal blood
- used to assess for hematologic abnormalities, genetic disorders, infections, and fetal acidosis
- can also be used to administer medications or blood transfusions for the fetus
13
Q
What is the difference between chorionic villus sampling and amniocentesis?
A
- CVS is done earlier at 10-13 weeks compared to amniocentesis at 16-18
- CVS is a collection of chorion tissue whereas amniocentesis is a collection of sloughed fetal cells
- both are used for the same analytic purposes
14
Q
Marfan Syndrome
A
- an autosomal dominant connective tissue disorder with primarily ocular, cardiovascular, and skeletal problems
- due to a mutation of the fibrillin gene on chromosome 15, which codes for an elastin scaffold
- skeletal findings include tall stature, elongated extremities and fingers, joint laxity, pectus excavatum, scoliosis or kyphosis, and a decreased upper-to-lower segment ratio (symphysis pubis is the divider)
- ocular findings include upward lens subluxation and retinal detachment
- cardiovascular findings include aortic root dilatation, aortic dissection, mitral valve prolapse, and aortic regurg
- it is a clinical diagnosis but may be confused with homocystinuria, which shares many features
- complicated by endocarditis, retinal detachment, and aortic dissection resulting in sudden cardiac death; hypertension and trauma both increase risk of dissection
- manage with beta-blockers, avoidance of contact sports, endocarditis prophylaxis, and regular eye exams
15
Q
Prader-Willi Syndrome
A
- a condition arising from the absence of a normal region of the paternally-derived chromosome 15 since the maternal copy is imprinted and silenced
- FISH detects the deletion in almost all patients
- hypotonia leads to poor sucking and feeding problems, causing failure to thrive in the first year of life, then hyperplagia leads to obesity later in childhood
- appearance includes almond-shaped eyes and a fishlike mouth, short stature, and obesity
- often present with mental retardation and hypogonadism
- complications arise from obesity and include obstructive sleep apnea, cardiac disease, and type II diabetes
16
Q
Angelman Syndrome
A
- a condition arising from the absence of a normal region of the maternally-derived chromosome 15 since the paternal copy is imprinted and silenced
- symptoms include paroxysms of inappropriate laughter, a happy demeanor, severe mental retardation with speech delay, and ataxia with jerky arm movements
- appearance includes a small wide head, large mouth, widely spaced teeth, tongue protrusion, prognathia, and blond hair with deep-set blue eyes
- diagnosed using FISH
17
Q
Noonan Syndrome
A
- often described as the male version of Turner syndrome though it can be found in females
- inheritance is typically sporadic, occasionally AD, and mapped to chromosome 12
- presents with short stature, shield chest, webbed neck, low hairline, hypertelorism (widely spaced eyes), epicentral skin folds, downslanting palpebral fissures, low-set ears
- in contrast to Turner syndrome, heart lesions are mostly right-sided and pulmonary valve stenosis is most common
18
Q
DiGeorge Syndrome
A
- a defect in the structures derived from the third and fourth pharyngeal pouches due to a chromosome 22q11 deletion
- CATCH: cardiac anomalies (aortic arch anomalies, VSD, and Tetralogy of Fallot), abnormal facies (short palpebral fissures, small chin, ear anomalies), thymus hypoplasia (cell-mediated immunodeficiency and infection), cleft palate, hypocalcemia (complicated by seizures)
- inheritance can be sporadic or autosomal dominant
- diagnosis is made via FISH probes
19
Q
Velocardiofacial Syndrome
A
- a syndrome related to but separate from DiGeorge and also due to a chromosome 22 deletion
- craniofacial findings include cleft palate, wide prominent nose, squared nasal root, short chin, and fish-shaped mouth
- cardiac findings are VSD and right-sided aortic arch
- neurologic findings include hypotonia, learning disability, and perseverative behaviors
- diagnosed via FISH probes
20
Q
Ehlers-Danlos Syndrome
A
- a condition caused by defective type V collagen
- inheritance is autosomal dominant
- presents with hyperextensible joints with dislocation and scoliosis; fragile skin such that minor lacs result in large wounds with tissue paper-thin scars; ease of bruising, mitral valve prolapse, and aortic root dilatation; and constipation, rectal prolapse, and hernias
- major complications are GI bleeding and aortic dissection
21
Q
Osteogenesis Imperfecta
A
- a condition resulting from abnormal type I collagen
- presents with blue sclera, yellow or gray-blue teeth, and easy bruisability
- fragile bones result in frequent fractures, genu valgum (aka knock-knees), scoliosis or kyphosis, joint laxity, and early conductive hearing loss
22
Q
VACTERL Association
A
a group of sporadic, mesoderm malformations
- Vertebral defects
- Anal atresia
- Cardiac anomalies (VSD)
- TE
- Renal anomalies and genital defects
- Limb defects including radial hypoplasia, syndactyly, and polydactyly
23
Q
CHARGE Association
A
a group of sporadic malformations
- Colobomas, most often of the retina, and impaired vision
- Heart defects, usually Tetralogy of Fallot
- Atresia fo the nasal choanae
- Retardation of growth and cognition
- Genital anomalies
- Ear anomalies, namely cup-shaped ears and hearing loss
24
Q
Williams Syndrome
A
- a condition caused by a deletion on chromosome 7 involving the elastin gene
- inheritance is autosomal dominant
- presents with elfin facies, mental retardation, and loquacious personality
- as well as supravalvular aortic stenosis, idiopathic hypercalcemia, and connective tissue abnormalities, leading to hoarse voice and hernias
25
Q
Cornelia de Lange
A
- a syndrome notable for a single eyebrow and very short stature without skeletal abnormalities
- symptoms include small for gestational age, failure to thrive, infantile hypertonia, microcephaly with mental retardation, small hands and feet, and cardiac defects
- behavioral signs include autistic features, lack of facial expression, and self-destructive tendencies
26
Q
Russell-Silver Syndrome
A
- known for the features of short stature, skeletal asymmetry, and normal head circumference
- other features include small for gestational age, a small triangular face which may make the head appear large despite the normal circumference, limb asymmetry, cafe-au-lait spots, and excessive sweating
27
Q
Pierre Robin Syndrome
A
- a sequence of micrognathia, cleft lip/palate, and large protruding tongue
- often complicated by recurrent otitis media and upper airway obstruction frequently requiring tracheostomy
28
Q
Cri-du-chat Syndrome
A
- one caused by a partial deletion the short arm of chromosome 5
- presents with slow growth, microcephaly with mental retardation, hypertelorism, and a characteristic cat-like or high-pitched cry
29
Q
Trisomy 21
A
- the most common trisomy (1:660 live births) with risk primarily tied to maternal age which increases the occurrence of nondisjunction within the ovum
- clinical features include craniofacial abnormalities, hypotonia, mental retardation, MSK abnormalities, GI abnormalities, and cardiac defects
- craniofacial findings include upward slanting palpebral fissures, brushfield spots, and protruding tongue
- MSK abnormalities include clinodactyly, single palmar crease, and widely spaced first and second toes
- GI abnormalities include duodenal atresia, Hirschsprung’s, omphalocele, and pyloric stenosis
- the most common cardiac finding is an endocardial cushion defect
- complicated by atlantoaxial cervical spine instability, leukemia, celiac disease, early onset Alzheimer’s, obstructive sleep apnea, conductive hearing loss, hypothyroidism, and cataracts/glaucoma/refractive errors
30
Q
Describe the complications of trisomy 21 and how they are managed as pediatric patients.
A
- atlantoaxial cervical spine instability requires flexion-extension cervical spine radiographs by 3-5 years of age
- celiac disease requires a total IgA and IgA anti-endomysium antibody screening at 2 years of age
- conductive hearing loss necessitates hearing tests every 1-2 years
- hypothyroidism requires annual TSH screening
- risk for cataracts, glaucoma, and refractive errors requires annual ophthalmologic exams
- leukemia, early onset Alzheimer’s, obstructive sleep apnea are also common
31
Q
Trisomy 18
A
- the second most common trisomy and more common in females
- neurologic findings include mental retardation and hypertonia with scissoring of the lower extremities
- delicate, small facial features
- clenched hands with overlapping digits, dorsiflexed big toes, and rocker bottom feet
- most die within the first year of life
32
Q
Trisomy 13
A
- a trisomy associated with midline defects
- neurologic findings include holoprosencephaly, microcephaly, seizures, and severe mental retardation
- ocular findings include microphthalmia, retinal dysplasia, and colobomas
- cleft lip and palate are common
- death is usually within the first month of life
33
Q
Turner Syndrome
A
- a phenotype associated with the XO genotype in women
- appearance includes short stature, webbed neck, shield chest, and scoliosis or kyphosis
- congenital lymphedema leads to swelling of the dorsal of the hands and feet
- ovarian dysgenesis results in streak ovaries and causes pubertal delay
- cardiac defects are usually left-sided and include coarctation of the aorta, bicuspid aortic valve, and hypoplastic left heart
34
Q
Klinefelter Syndrome
A
- an XXY genotype in males
- the most common cause of male hypogonadism and infertility; it is seen in 1:500 live male births and risk increases with maternal age
- have tall stature, long extremities, gynecomastia, and variable intelligence
- hypogonadism leads to delayed puberty and infertility
- behavioral findings include antisocial behavior and excessive shyness or aggression
35
Q
Fragile X Syndrome
A
- an X-linked disorder arising from a variable number of CGG repeats that demonstrate anticipation
- typically more severe in males but females may demonstrate some intellectual disability
- presents with mild to severe mental retardation as well as emotional instability, autistic features, and ADHD
- craniofacial findings include large ears, macrocephaly, and a thickened nasal bridge
- large testes develop during puberty
36
Q
Define rhizomelia.
A
a classification for skeletal dysplasia defined by proximal long bone abnormalities
37
Q
Define mesomelia.
A
a classification for skeletal dysplasia defined by medial long bone abnormalities
38
Q
Define acromelia.
A
a classification for skeletal dysplasia defined by distal abnormalities such as small hands or feet
