Genetics

Question 1

Recurrence risk:
Risk factor - increasing maternal age
- <35 years: RR = age-related risk +1%
- >35 years: RR = age-related risk

The overall recurrence risk for having a live-born child who has any trisomy is ~1% added to the mother’s age-related risk for having a child who has a trisomy, which increases over time.

Answer 1

Recurrence risk:
Risk factor - increasing maternal age
- <35 years: RR = age-related risk +1%
- >35 years: RR = age-related risk

The overall recurrence risk for having a live-born child who has any trisomy is ~1% added to the mother’s age-related risk for having a child who has a trisomy, which increases over time.

Question 2

Germline mosaicism needs to be considered when an apparently new _____ trait develops.

• Suspect when an apparently normal parent has >1 child affected with an AD condition.
• This means that one of the parents has the mutated gene only in their germline cells (ie sperm or eggs) and therefore has the ability to pass the mutation to their children despite having no symptoms themselves.

Answer 2

Germline mosaicism needs to be considered when an apparently new AD trait develops.

• Suspect when an apparently normal parent has >1 child affected with an AD condition.
• This means that one of the parents has the mutated gene only in their germline cells (ie sperm or eggs) and therefore has the ability to pass the mutation to their children despite having no symptoms themselves.

Question 3

A mother carrying a mitochondrial DNA (mtDNA) mutation passes it on to all her offspring whereas the father carrying the mutation passes it to none of his offspring

Answer 3

A mother carrying a mitochondrial DNA (mtDNA) mutation passes it on to all her offspring whereas the father carrying the mutation passes it to none of his offspring

Question 4

Same risk as having no known relatives = Only 1 2nd-degree relative affected
- Do not require counseling

Moderate risk = 1 1st-degree relative with disease onset at average age or 2 affected 2nd-degree relatives on the same side of the family
- Only need counseling in unusual circumstances

High risk - should be sent for counseling

• Premature disease in a 1st degree relative
• > 2 1st degree relatives on the same side of the family
• > 2 2nd degree relatives on the same side of the family affected with at least 1 having premature disease onset
• > 3 affected on the same side of the family
• Moderate-risk status on both sides of the family

Answer 4

Same risk as having no known relatives = Only 1 2nd-degree relative affected
- Do not require counseling

Moderate risk = 1 1st-degree relative with disease onset at average age or 2 affected 2nd-degree relatives on the same side of the family
- Only need counseling in unusual circumstances

High risk - should be sent for counseling

• Premature disease in a 1st degree relative
• > 2 1st degree relatives on the same side of the family
• > 2 2nd degree relatives on the same side of the family affected with at least 1 having premature disease onset
• > 3 affected on the same side of the family
• Moderate-risk status on both sides of the family

Question 5

AAP has advised against the predictive genetic testing of children for adult-onset genetic disorders until the child reaches adulthood at least 18yo

Answer 5

AAP has advised against the predictive genetic testing of children for adult-onset genetic disorders until the child reaches adulthood at least 18yo

Question 6

TRISOMY 21 DOWNS

• Most cases of trisomy 21 (94% of patients) result from meiotic nondisjunction yielding 3 complete copies of chromosome 21 (47 chromosomes), rather than a translocation. This risk increases with maternal age, most significantly after age 35 years.
  
  • If women <35 yo has trisomy 21 from 3 copies, her recurrence risk for another child with trisomy 21 is __%. If mother is >35yo, the risk is similar to _____.
• Recurrence risk for trisomy 21 with a ____ translocation ___:___ (45 chromosome) inherited from an infant’s mother is higher ____%, but only 1-2% if inherited from the father
• Recurrence risk is higher if the mother is a carrier of a balanced translocation and lowest if the child has a freestanding chromosome 21

Answer 6

TRISOMY 21 DOWNS

• Most cases of trisomy 21 (94% of patients) result from meiotic nondisjunction yielding 3 complete copies of chromosome 21 (47 chromosomes), rather than a translocation. This risk increases with maternal age, most significantly after age 35 years.
  
  • If women <35 yo has trisomy 21 from 3 copies, her recurrence risk for another child with trisomy 21 is 1%. If mother is >35yo, the risk is similar to age-specific risk.
• Recurrence risk for trisomy 21 with a Robertsonian translocation 14:21 (45 chromosome) inherited from an infant’s mother is higher 10-15%, but only 1-2% if inherited from the father
• Recurrence risk is higher if the mother is a carrier of a balanced translocation and lowest if the child has a freestanding chromosome 21

Question 7

Trisomy 21
Classic signs
- Hands and feet:
- Hands are short and broad with single transverse palmar crease (as 10% of the general population does)
- Sandal toe (wide gap between 1st and 2nd toes), brachydactyly (short broad fingers and toes)
- 5th finger middle phalanx hypoplasia/clinodactyly

• Congenital heart disease. Septal heart defects (⅓ AV canal defects, ⅓ VSDs, ⅓ ASDs)
  
  • ________ defects (AV septal defect or endocardial cushion defect) as the most common defect associated
  • ____ is mandatory for all children with suspected Down syndrome.
• At risk for pulmonary HTN from either congenital heart disease or pulmonary vascular bed abnormalities (pulmonary hypoplasia).
• Atlantoaxial instability
  
  • Increased tone or spasticity in the limbs, hyperreflexia
• GI concerns:
  
  • Duodenal atresia and Hirschsprung
    
    • Look for the classic double-bubble sign
• Hematologic disorders
  
  • _____ risk is 10-20x higher in DS.
  • A unique condition in Down syndrome: Transient ________
  • Tx:
    
    • Closely monitor pts with a hx of transient myeloproliferative disorder as they grow older bc there is a 10-20x increased risk for developing AML.
• Endocrine
  
  • Trisomy 21 increases risk for both congenital ____ and acquired _____.
    
    • Therefore, thyroid screening tests are recommended at __, __ months, __ months, ___ months, and annually thereafter
• Ocular: Congenital cataracts, strabismus

Answer 7

Trisomy 21
Classic signs
- Hands and feet:
- Hands are short and broad with single transverse palmar crease (as 10% of the general population does)
- Sandal toe (wide gap between 1st and 2nd toes), brachydactyly (short broad fingers and toes)
- 5th finger middle phalanx hypoplasia/clinodactyly

• Congenital heart disease. Septal heart defects (⅓ AV canal defects, ⅓ VSDs, ⅓ ASDs)
  
  • Atrioventricular canal defects (AV septal defect or endocardial cushion defect) as the most common defect associated
  • Echo is mandatory for all children with suspected Down syndrome.
• At risk for pulmonary HTN from either congenital heart disease or pulmonary vascular bed abnormalities (pulmonary hypoplasia).
• Atlantoaxial instability
  
  • Increased tone or spasticity in the limbs, hyperreflexia
• GI concerns:
  
  • Duodenal atresia and Hirschsprung
    
    • Look for the classic double-bubble sign
• Hematologic disorders
  
  • ALL risk is 10-20x higher in DS.
  • A unique condition in Down syndrome: Transient myeloproliferative disorder/Transient leukemia
  • Tx:
    
    • Closely monitor pts with a hx of transient myeloproliferative disorder as they grow older bc there is a 10-20x increased risk for developing AML.
• Endocrine
  
  • Trisomy 21 increases risk for both congenital hypothyroidism and acquired autoimmune hypothyroidism (Hashimoto thyroiditis).
    
    • Therefore, thyroid screening tests are recommended at birth, 3 months, 6 months, 12 months, and annually thereafter
• Ocular: Congenital cataracts, strabismus

Question 8

Trisomy 21
Diagnosis
- ____ analysis may be used as fast diagnostic tool, but it must be followed by ____ for etiologic diagnosis and recurrence risk.
- Nondisjunction: Karyotype shows 47 chromosomes instead of usual 46 chromosomes.
- Robertsonian translocation: If karyotyping reveals an unbalanced translocation as the reason, then cytogenetic analysis or karyotypes of both parents is recommended to determine which (if either) parent contributed the chromosome in order to provide proper genetic counseling and determine recurrence risk.

Management

• AAP guidelines:
  
  • All routine immunizations
  • Because of high risk of congenital heart disease, all patients with Trisomy 21 require an Echo prior to hospital discharge from the newborn nursery or NICU.
  • Ophthalmologic evaluation before 6 months of age
  • Hearing evaluation during newborn screening and again by 6 months of age
  • Thyroid studies: newborn screening for hypothyroidism, then annual T4 and TSH throughout childhood and adulthood
  • Vision screening at 4yo.

Answer 8

Trisomy 21
Diagnosis
- Rapid fluorescence in situ hybridization FISH analysis may be used as fast diagnostic tool, but it must be followed by karyotyping for etiologic diagnosis and recurrence risk.
- Nondisjunction: Karyotype shows 47 chromosomes instead of usual 46 chromosomes.
- Robertsonian translocation: If karyotyping reveals an unbalanced translocation as the reason, then cytogenetic analysis or karyotypes of both parents is recommended to determine which (if either) parent contributed the chromosome in order to provide proper genetic counseling and determine recurrence risk.

Management

• AAP guidelines:
  
  • All routine immunizations
  • Because of high risk of congenital heart disease, all patients with Trisomy 21 require an Echo prior to hospital discharge from the newborn nursery or NICU.
  • Ophthalmologic evaluation before 6 months of age
  • Hearing evaluation during newborn screening and again by 6 months of age
  • Thyroid studies: newborn screening for hypothyroidism, then annual T4 and TSH throughout childhood and adulthood
  • Vision screening at 4yo.

Question 9

TRISOMY 18 EDWARDS
- 2nd most common autosomal trisomy.

• Pt:
  
  • 50% of affected children die in the 1st week of life, with another 40% dying by 1yo.
  • Most die bc of _____.
  • Closed fists w overlapping fingers (2nd and 5th digits overlap w 3rd and 4th digits), Hands with hypoplastic nails
  • Short sternum
  • Rocker bottom feet
  • Micrognathia
  • Congenital anomalies- most often ______ (holosystolic murmur at L border) with multiple dysplastic valves

Answer 9

TRISOMY 18 EDWARDS
- 2nd most common autosomal trisomy.

• Pt:
  
  • 50% of affected children die in the 1st week of life, with another 40% dying by 1yo.
  • Most die bc of central apnea.
  • Closed fists w overlapping fingers (2nd and 5th digits overlap w 3rd and 4th digits), Hands with hypoplastic nails
  • Short sternum
  • Rocker bottom feet
  • Micrognathia
  • Congenital anomalies- most often VSD (holosystolic murmur at L border) with multiple dysplastic valves

Question 10

TRISOMY 13 PATAU

• Clinical findings: Think _____ defects!
  
  • Craniofacial malformations- Microcephaly, scalp defects (cutis aplasia, missing skin on scalp), small eyes/microphthalmia, close-set eyes, malformed/low set ears, broad flat nose with hypertelorism, cleft lip/palate, micrognathia
  • Clenched hands
  • ________ of the limbs
• Survival
  
  • Survival is poor with a median survival of 2.5 days.
  • About 70% will die in the first 3 months of life, and 95% will die by 3yo.
  • Survivors have severe intellectual disability, seizures, FTT, and they rarely live past 10yo.

Answer 10

TRISOMY 13 PATAU

• Clinical findings: Think midline defects!
  
  • Craniofacial malformations- Microcephaly, scalp defects (cutis aplasia, missing skin on scalp), small eyes/microphthalmia, close-set eyes, malformed/low set ears, broad flat nose with hypertelorism, cleft lip/palate, micrognathia
  • Clenched hands
  • Postaxial Polydactyly of the limbs
• Survival
  
  • Survival is poor with a median survival of 2.5 days.
  • About 70% will die in the first 3 months of life, and 95% will die by 3yo.
  • Survivors have severe intellectual disability, seizures, FTT, and they rarely live past 10yo.

Question 11

Klinefelter syndrome (47, XXY karyotype)

• Pt:
  
  • Classic presentation is an older male adolescent or young adult with small testes, _____ (38%), tall stature, long arms and legs, and possibly learning or behavioral difficulties.
    
    • Low upper-to-lower segment ratio (relatively long legs).
  • Primary _______ failure with small, firm testes. Size of testes is small for age.
  • ____ disability and psychiatric problems occur early. In boys with psychiatric problems, esp fire setting, suspect Klinefelter’s.
    
    • As the number of X chromosomes increases above the normal XX or XY, the incidence of intellectual disability increases markedly.
  • Azoospermia (90%+) and infertility are the norm.
  • Pubic hair development is normal - there is nothing wrong with their adrenal glands.
• Labs: ___ gonadotropin levels, ____ testosterone level
• Tx:
  
  • Administer long-acting ______ when these children are around 11-12yo, esp when elevations in LH/FSH are noted.

Answer 11

Klinefelter syndrome (47, XXY karyotype)

• Pt:
  
  • Classic presentation is an older male adolescent or young adult with small testes, gynecomastia (38%), tall stature, long arms and legs, and possibly learning or behavioral difficulties.
    
    • Low upper-to-lower segment ratio (relatively long legs).
  • Primary hypogonadism/testicular failure with small, firm testes. Size of testes is small for age.
  • Intellectual disability and psychiatric problems occur early. In boys with psychiatric problems, esp fire setting, suspect Klinefelter’s.
    
    • As the number of X chromosomes increases above the normal XX or XY, the incidence of intellectual disability increases markedly.
  • Azoospermia (90%+) and infertility are the norm.
  • Pubic hair development is normal - there is nothing wrong with their adrenal glands.
• Labs: Consistent with hypergonadotropic hypogonadism: High gonadotropin levels, low testosterone level
• Tx:
  
  • Administer long-acting testosterone when these children are around 11-12yo, esp when elevations in LH/FSH are noted.

Question 12

47,XXX Syndrome / Triple X Syndrome

• Pt:
  
  • Girls are normal females and not recognized routinely in infancy.
  • By 2yo, however, speech and language delays manifest, followed by poor coordination, poor academic performance, and immature behavior.
  • Girls tend to be tall and gangly, commonly with behavioral disorders.
  • No unusual dysmorphology or physical features and normal sexual development and fertility.

Answer 12

47,XXX Syndrome / Triple X Syndrome

• Pt:
  
  • Girls are normal females and not recognized routinely in infancy.
  • By 2yo, however, speech and language delays manifest, followed by poor coordination, poor academic performance, and immature behavior.
  • Girls tend to be tall and gangly, commonly with behavioral disorders.
  • No unusual dysmorphology or physical features and normal sexual development and fertility.

Question 13

47, XYY Male

• Pt: ___ than average, have severe ______, but otherwise not different from general population.
  
  • They do NOT have hypogonadism.
  • Classic features include taller than normal stature, speech and language delay, cystic acne in adolescence, lack of facial dysmorphology, and learning disabilities.
  • ______ intelligence is expected;

Answer 13

47, XYY Male

• Pt: Taller than average, have severe nodular-cystic acne, but otherwise not different from general population.
  
  • They do NOT have hypogonadism.
  • Classic features include taller than normal stature, speech and language delay, cystic acne in adolescence, lack of facial dysmorphology, and learning disabilities.
  • Normal intelligence is expected;

Question 14

Turner syndrome
- 45X

• Pt:
  
  • At birth: Small birth size, broad webbed neck (from fetal cystic hygroma), marked edema of the dorsa of hands and feet, posteriorly rotated ears, shieldlike chest, lymphedema of hands/feet, short 4th metacarpals, cubitus valgus, and evidence of congenital heart disease.
    
    • ___________ at birth is sometimes the only clue that the pt has Turner’s!
  • ________ is apparent in childhood and may be the only presenting feature (100% of patients).
    
    • Short stature is due to the absence of 1 SHOX (Short stature HomeobOX) gene
  • GU: Primary ovarian failure, delayed puberty
  • 50% have Cardiac anomalies: Bicuspid aortic valve, coarctation of the aorta (15-20%)
  • Renal anomalies: Pelvic kidney, horseshoe kidney
  • Development: Intelligence is usually ______ but difficulties in math and visual-spatial skills are common.
  • Autoimmune diseases: About 10-20% have autoimmune thyroid disease
• These pts require prophylactic gonadectomy to remove internal streak gonads.
• Dx: Blood Karyotype analysis
• Tx:
  
  • Tx using _____ increases height velocity and final height.
  • Estrogen therapy is indicated but must be weighed against attenuating final height. Turner Syndrome Study Group recommendations are to begin estrogen replacement at 12yo due to bone health and the psychological impact of delaying pubertal maturation too long.

Answer 14

Turner syndrome
- 45X

• Pt:
  
  • At birth: Small birth size, broad webbed neck (from fetal cystic hygroma), marked edema of the dorsa of hands and feet, posteriorly rotated ears, shieldlike chest, lymphedema of hands/feet, short 4th metacarpals, cubitus valgus, and evidence of congenital heart disease.
    
    • Puffy hands and feet at birth is sometimes the only clue that the pt has Turner’s!
  • Short stature is apparent in childhood and may be the only presenting feature (100% of patients).
    
    • Short stature is due to the absence of 1 SHOX (Short stature HomeobOX) gene
  • GU: Primary ovarian failure, delayed puberty
  • 50% have Cardiac anomalies: Bicuspid aortic valve, coarctation of the aorta (15-20%)
  • Renal anomalies: Pelvic kidney, horseshoe kidney
  • Development: Intelligence is usually NORMAL but difficulties in math and visual-spatial skills are common.
  • Autoimmune diseases: About 10-20% have autoimmune thyroid disease
• These pts require prophylactic gonadectomy to remove internal streak gonads.
• Dx: Blood Karyotype analysis
• Tx:
  
  • Tx using hGH increases height velocity and final height.
  • Estrogen therapy is indicated but must be weighed against attenuating final height. Turner Syndrome Study Group recommendations are to begin estrogen replacement at 12yo due to bone health and the psychological impact of delaying pubertal maturation too long.

Question 15

Turners

• __ valve problems
• ___ intelligence. May have difficulty in math and problem solving

Noonan

• ___ karyotype
• ___ stenosis
• intellectual ____ in 25%

Answer 15

Turners

• Aortic valve problems
• Normal intelligence. May have difficulty in math and problem solving

Noonan

• Normal karyotype
• Pulmonary stenosis
• intellectual disability in 25%

Question 16

4p Deletion (_____ Syndrome)

• Pt:
  
  • Distinctive facial features: microcephaly, prominent _____, frontal bossing, ocular hypertelorism, epicanthus, high-arched eyebrows, short philtrum, downturned mouth, and relative smallness of the lower part of the face particularly the jaw, small ears with bilateral ear pits
  • Congenital cardiac anomalies (50%): Most common is _____ followed by pulmonic stenosis, VSD, tetralogy of fallot, and PDA
  • _____ (90%)
  • CNS malformations (80%): Most common CNS anomaly is thinning of the _____

Answer 16

4p Deletion (Wolf-Hirschhorn Syndrome)

• Pt:
  
  • Distinctive facial features: microcephaly, prominent glabella “Greek helmet”, frontal bossing, ocular hypertelorism, epicanthus, high-arched eyebrows, short philtrum, downturned mouth, and relative smallness of the lower part of the face particularly the jaw, small ears with bilateral ear pits
  • Congenital cardiac anomalies (50%): Most common is ASD followed by pulmonic stenosis, VSD, tetralogy of fallot, and PDA
  • Seizures (90%)
  • CNS malformations (80%): Most common CNS anomaly is thinning of the corpus callosum

Question 17

5p Deletion (_____ Syndrome)

• Pt:
  
  • Classic high-pitched ______ due to an anatomic change in the larynx
  • Intellectual disability, typically severe
  • Microcephaly
  • Low birthweight
  • Hypotonia
  • Facial features:
    
    • Small head
    • “Moon face” round with telecanthus (widely spaced eyes) in infancy and early childhood
    • Down-slanting palpebral fissures
    • Epicanthal folds, hypertelorism, downward-slanting palpebral fissures
    • Low-set ears
    • Micrognathia
    • Wide and flat nasal bridge
    • High-arched palate.
  • Cardiac manifestations in about 33% of affected children: With septal defects, with ______ occurring most often

Answer 17

5p Deletion (Cri-Du-Chat Syndrome)

• Pt:
  
  • Classic high-pitched “cat’s cry” due to an anatomic change in the larynx
  • Intellectual disability, typically severe
  • Microcephaly
  • Low birthweight
  • Hypotonia
  • Facial features:
    
    • Small head
    • “Moon face” round with telecanthus (widely spaced eyes) in infancy and early childhood
    • Down-slanting palpebral fissures
    • Epicanthal folds, hypertelorism, downward-slanting palpebral fissures
    • Low-set ears
    • Micrognathia
    • Wide and flat nasal bridge
    • High-arched palate.
  • Cardiac manifestations in about 33% of affected children: With septal defects, with tetralogy of Fallot occurring most often

Question 18

18q Deletion (_____ Syndrome)

• Path: Long arm of chromosome 18 is deleted
• Pt:
  
  • Microcephaly
  • Developmental delay
  • Atretic or narrowed ear canals (classic)
  • “_____” position with legs flexed, externally rotated, and in hyperabduction
  • Depressed midface
  • Protruding mandible
  • Deep-set eyes
  • ____ lip (____ mouth)
  • Intellectual disability

Answer 18

18q Deletion (de Grouchy Syndrome)

• Path: Long arm of chromosome 18 is deleted
• Pt:
  
  • Microcephaly
  • Developmental delay
  • Atretic or narrowed ear canals (classic)
  • “Froglike” position with legs flexed, externally rotated, and in hyperabduction
  • Depressed midface
  • Protruding mandible
  • Deep-set eyes
  • Everted lower lip (carplike mouth)
  • Intellectual disability

Question 19

_____ Deletion: Prader-Willi Syndrome

• Path
  
  • 3 genetic mechanisms can result in absence of expression of imprinted gene on ______ derived PWS region:
    
    • Paternal chromosome 15 deletion in 70% of cases
    • Maternal uniparental disomy 15 in 25% of cases
    • Imprinting defect (rare; the imprinting center controls the expression of genes in this region)
  • Uniparental disomy most commonly arises from a pregnancy that starts off as a trisomic conception followed by trisomy rescue.
• Pt:
  
  • Infancy (birth - ___yo)
    
    • Profound global hypotonia and feeding problems w poor suck / failure to thrive in infancy.
    • Facial dysmorphology: bitemporal narrowing, thin upper lip, almond-shaped eyes, hypogonadotropic hypogonadism (often manifested as cryptorchidism or micropenis in boys)
  • ____yo: Global developmental delay
  • Children: Begins around ___yo
    
    • Excessive eating from hypothalamic hyperphagia
    • Short stature, small hands and feet, hypogonadism (small penis with cryptorchidism)
    • Motor delay occurs
    • Usually mild intellectual disability.
• Dx: Standard diagnostic panel begins with karyotype and methylation studies
  
  • Methylation studies
  • To confirm the diagnosis of PWS, _____ testing must be performed.
• Tx: Early diagnosis
  
  • ____ therapy is FDA approved for Prader-Willi.
    
    • Growth hormone therapy in conjunction with nutrition management should begin in the 1st year after birth, along with appropriate anticipatory guidance.

Answer 19

15q11-13 Deletion: Prader-Willi Syndrome

• Path
  
  • 3 genetic mechanisms can result in absence of expression of imprinted gene on paternally derived PWS region:
    
    • Paternal chromosome 15 deletion in 70% of cases
    • Maternal uniparental disomy 15 in 25% of cases
    • Imprinting defect (rare; the imprinting center controls the expression of genes in this region)
  • Uniparental disomy most commonly arises from a pregnancy that starts off as a trisomic conception followed by trisomy rescue.
• Pt:
  
  • Infancy (birth - 2yo)
    
    • Profound global hypotonia and feeding problems w poor suck / failure to thrive in infancy.
    • Facial dysmorphology: bitemporal narrowing, thin upper lip, almond-shaped eyes, hypogonadotropic hypogonadism (often manifested as cryptorchidism or micropenis in boys)
  • 2-6yo: Global developmental delay
  • Children: Begins around 6yo
    
    • Excessive eating from hypothalamic hyperphagia
    • Short stature, small hands and feet, hypogonadism (small penis with cryptorchidism)
    • Motor delay occurs
    • Usually mild intellectual disability.
• Dx: Standard diagnostic panel begins with karyotype and methylation studies
  
  • Methylation studies
  • To confirm the diagnosis of PWS, FISH testing must be performed.
• Tx: Early diagnosis
  
  • GH therapy is FDA approved for Prader-Willi.
    
    • Growth hormone therapy in conjunction with nutrition management should begin in the 1st year after birth, along with appropriate anticipatory guidance.

Question 20

15q11-13 Deletion: Angelman Syndrome

• Handflapping, jerky ataxic movements ________, gait ataxia
• Short stature and hypotonia
• Lifelong ______ (compared to Rett where head growth is normal then plateau)
• Facial features: Wide mouth with wide-spaced teeth, midface hypoplasia, prognathism (large chin, mandible), protruding tongue
• Fair hair
• Severe ________.
• Near absence of expressive language/severe speech delay (Compared to Rett that shows development then regression)

Answer 20

15q11-13 Deletion: Angelman Syndrome

• Handflapping, jerky ataxic movements “happy puppet”, gait ataxia
• Short stature and hypotonia
• Lifelong microcephaly (compared to Rett where head growth is normal then plateau)
• Facial features: Wide mouth with wide-spaced teeth, midface hypoplasia, prognathism (large chin, mandible), protruding tongue
• Fair hair
• Severe intellectual disability.
• Near absence of expressive language/severe speech delay (Compared to Rett that shows development then regression)

Question 21

____ Deletion Williams Syndrome

• Defect in _____ (ELN)
• Pt:
  
  • ______ facies: Broad forehead, bitemporal narrowing, hypertelorism, medial eyebrow flare, large earlobes, shortened upturned nose with flattened nasal bridge, elongated philtrum with prominent down-turned lower lip, wide mouth, small jaw, underdeveloped teeth
  • Gregarious personality “____ personality” “loquacious”
  • _____ pattern of the iris
  • Most common cardiovascular problem seen in Williams is ______ (present in 75%).
  • Intellectual disability
  • Hypercalcemia
• Dx:
  
  • Absent elastin gene is detected using _____
    
    • 2 colored markers; one attaches to each of chromosome 7 copies, other attache to elastin gene
    • Normal - each chromosome 7 shows 2 fluorescence markers, 1 identifying as chromosome 7 and other indicating elastin gene is present
    • Williams - 1 of chromosome 7s is completely missing the fluorescence at the elastin location
  • Also detected by chromosomal _____

Answer 21

7q11. 23 Deletion Williams Syndrome
- Defect in elastin (ELN)
- Pt:
- “Elfin” facies: Broad forehead, bitemporal narrowing, hypertelorism, medial eyebrow flare, large earlobes, shortened upturned nose with flattened nasal bridge, elongated philtrum with prominent down-turned lower lip, wide mouth, small jaw, underdeveloped teeth
- Gregarious personality “cocktail personality” “loquacious”
- Stellate pattern of the iris
- Most common cardiovascular problem seen in Williams is supravalvular aortic stenosis (present in 75%).
- Intellectual disability
- Hypercalcemia

• Dx:
  
  • Absent elastin gene is detected using FISH
    
    • 2 colored markers; one attaches to each of chromosome 7 copies, other attache to elastin gene
    • Normal - each chromosome 7 shows 2 fluorescence markers, 1 identifying as chromosome 7 and other indicating elastin gene is present
    • Williams - 1 of chromosome 7s is completely missing the fluorescence at the elastin location
  • Also detected by chromosomal microarray

Question 22

____ Deletion WAGR Syndrome

• W____, A____ G____, R_____
• Path: Occurs due to absence of 2 genes, PAX6 and Wilms tumor 1 (WT1).

Answer 22

11p13 Deletion WAGR Syndrome

• Wilms tumor, Aniridia, Genitourinary malformation, Intellectual disability (mental retardation)
• Path: Occurs due to absence of 2 genes, PAX6 and Wilms tumor 1 (WT1).

Question 23

\_\_\_\_ Deletion (Velocardiofacial syndrome, DiGeorge syndrome, Shprintzen syndrome, conotruncal anomaly face syndrome)
- Path: Developmental defect of derivatives of the \_\_\_\_\_\_\_ pouches, resulting in agenesis or hypoplasia of the \_\_\_\_ and \_\_\_\_ gland, conotruncal heart defects, and branchial arch defects

• Pt:
  
  • CATCH 22 (c___, a___, t___, c___ h____, on 22nd chromosome)
  • Congenital heart disease
    
    • ________ > Interrupted aortic arch > VSD > truncus arteriosus

Answer 23

22q11. 2 Deletion (Velocardiofacial syndrome, DiGeorge syndrome, Shprintzen syndrome, conotruncal anomaly face syndrome)
- Path: Developmental defect of derivatives of the 3rd and 4th pharyngeal pouches, resulting in agenesis or hypoplasia of the thymus and parathyroid gland, conotruncal heart defects, and branchial arch defects

• Pt:
  
  • CATCH 22 (cardiac defects, abnormal facies, thymic absence / t cell abnormality, cleft palate, hypocalcemia, on 22nd chromosome)
  • Congenital heart disease
    
    • Tetralogy of Fallot > Interrupted aortic arch > VSD > truncus arteriosus

Question 24

Pierre Robin Sequence
- Path: Embryologic defect of ___________. This leads to a displacement of the tongue, which in turn interrupts the closure of the lateral palatine ridges and results in a U-shaped cleft palate.

• Pt:
  
  • Triad of ____ (displacement of the tongue into the airway), ___, ____
    
    • ____ is NOT part of the syndrome.
• Most common genetic disorders associated with PRS are ____, ____ syndrome, and ____ syndrome (eyes and ears)

Answer 24

Pierre Robin Sequence
- Path: Embryologic defect of mandibular hypoplasia. This leads to a displacement of the tongue, which in turn interrupts the closure of the lateral palatine ridges and results in a U-shaped cleft palate.

• Pt:
  
  • Triad of Glossoptosis (displacement of the tongue into the airway), micrognathia, U-shaped cleft palate
    
    • Macroglossia is NOT part of the syndrome.
• Most common genetic disorders associated with PRS are 22q11.2, Treacher Collins syndrome, and Stickler syndrome (eyes and ears)

Question 25

Hemifacial Microsomia

• 2nd most common craniofacial malformation is the association of
  
  • External ___ anomalies
    
    • Microtia - smallness of the auricle of the ear with a blind or absent external auditory meatus
    • Anotia - congenital absence of 1 or both auricles of the ears
    • Canal atresia, and/or
    • Preauricular tags
  • With _______ hypoplasia
• Cervical ____ anomalies occur in nearly 33% with hemifacial microsomia, and ___ anomalies occur frequently as well.
• Be aware that ___ anomalies occur in about 15% of individuals with these ear malformations, so consider renal US for further evaluation

Answer 25

Hemifacial Microsomia

• 2nd most common craniofacial malformation is the association of
  
  • External ear anomalies
    
    • Microtia - smallness of the auricle of the ear with a blind or absent external auditory meatus
    • Anotia - congenital absence of 1 or both auricles of the ears
    • Canal atresia, and/or
    • Preauricular tags
  • With maxillary and/or mandibular hypoplasia
• Cervical vertebral anomalies occur in nearly 33% with hemifacial microsomia, and cardiac anomalies occur frequently as well.
• Be aware that renal anomalies occur in about 15% of individuals with these ear malformations, so consider renal US for further evaluation

Question 26

Goldenhar Syndrome (aka oculoauriculovertebral spectrum)

• Considered the same as hemifacial microsomia, but use the term “Goldenhar syndrome” ONLY if _____ are present.
• Pt:
  
  • Hemifacial microsomia, epibulbar lipodermoids (lateral-inferior, fibrous-fatty masses on the globe), vertebral defects, cardiac anomalies (VSD or outflow tract malformations), and renal anomalies

Answer 26

Goldenhar Syndrome (aka oculoauriculovertebral spectrum)

• Considered the same as hemifacial microsomia, but use the term “Goldenhar syndrome” ONLY if epibulbar dermoids are present.
• Pt:
  
  • Hemifacial microsomia, epibulbar lipodermoids (lateral-inferior, fibrous-fatty masses on the globe), vertebral defects, cardiac anomalies (VSD or outflow tract malformations), and renal anomalies

Question 27

Branchio-Oto-Renal (BOR) Syndrome
- ____inheritance?? disorder

• Pt:
  
  • Branchial cleft fistulas or cysts, preauricular pits, cochlear and stapes malformation, mixed sensory and conductive hearing loss, and renal dysplasia/aplasia.
  • Occasionally, pts have pulmonary hypoplasia.

Answer 27

Branchio-Oto-Renal (BOR) Syndrome
- AD disorder

• Pt:
  
  • Branchial cleft fistulas or cysts, preauricular pits, cochlear and stapes malformation, mixed sensory and conductive hearing loss, and renal dysplasia/aplasia.
  • Occasionally, pts have pulmonary hypoplasia.

Question 28

Treacher-Collins Syndrome (Mandibulofacial Dysostosis)
- _____inheritance??

• Pt:
  
  • Airway abnormalities
    
    • Micrognathia (mandibular and maxillary hypoplasia), zygomatic arch clefts
    • Unilateral or bilateral choanal atresia
    • Feeding difficulties due to airway anomalies
  • Craniofacial dysmorphology
    
    • Glossopexy (tongue-lip adhesion)
    • Absent lower eyelashes
    • Preauricular hair displacement onto the cheekbones.
    • Other characteristic findings include down-sloping palpebral fissures and colobomata (defects) of the lower eyelids (eyelid notch).
    • Prominent nose
  • External ear abnormalities (eg microtia, anotia, atresia)
    
    • 40-50% will have _____
  • Ophthalmologic abnormalities
    
    • Ocular hypertelorism
    • Vision loss
    • Amblyopia, refractive errors, strabismus
  • Dental anomalies
    
    • Tooth agenesis
    • Enamel opacities
    • Maxillary first molar ectopic eruption
  • ____ IQ and intelligence.

Answer 28

Treacher-Collins Syndrome (Mandibulofacial Dysostosis)
- AUTOSOMAL DOMINANT

• Pt:
  
  • Airway abnormalities
    
    • Micrognathia (mandibular and maxillary hypoplasia), zygomatic arch clefts
    • Unilateral or bilateral choanal atresia
    • Feeding difficulties due to airway anomalies
  • Craniofacial dysmorphology
    
    • Glossopexy (tongue-lip adhesion)
    • Absent lower eyelashes
    • Preauricular hair displacement onto the cheekbones.
    • Other characteristic findings include down-sloping palpebral fissures and colobomata (defects) of the lower eyelids (eyelid notch).
    • Prominent nose
  • External ear abnormalities (eg microtia, anotia, atresia)
    
    • 40-50% will have conductive hearing loss
  • Ophthalmologic abnormalities
    
    • Ocular hypertelorism
    • Vision loss
    • Amblyopia, refractive errors, strabismus
  • Dental anomalies
    
    • Tooth agenesis
    • Enamel opacities
    • Maxillary first molar ectopic eruption
  • NORMAL IQ and intelligence.

Question 29

Stickler Syndrome (Hereditary Arthro-ophthalmopathy) (___ and ___ (and ___) “use a stick to his those place”)

• Connective tissue disorder
• AD or AR.
• Path: 70-80% ___ mutation
• Pt:
  
  • Orofacial anomalies: Flattened midface, depressed nasal bridge, short nose, anteverted nares, micrognathia, glossoptosis, palatal abnormalities (cleft lip, cleft palate, and/or bifid uvula)
  • Other associated symptoms: Severe myopia, cataracts, retinal detachment, hearing loss, and joint hypermobility.
  • Skeletal findings seen can include femoral head dysplasia, scoliosis, kyphosis, and joint laxity early in life that progresses to early-onset osteoarthritis.

Answer 29

Stickler Syndrome (Hereditary Arthro-ophthalmopathy) (eyes and ears (and joints) “use a stick to his those place”)

• Connective tissue disorder
• AD or AR.
• Path: 70-80% COL2A1 mutation
• Pt:
  
  • Orofacial anomalies: Flattened midface, depressed nasal bridge, short nose, anteverted nares, micrognathia, glossoptosis, palatal abnormalities (cleft lip, cleft palate, and/or bifid uvula)
  • Other associated symptoms: Severe myopia, cataracts, retinal detachment, hearing loss, and joint hypermobility.
  • Skeletal findings seen can include femoral head dysplasia, scoliosis, kyphosis, and joint laxity early in life that progresses to early-onset osteoarthritis.

Question 30

Waardenburg syndrome I

• ____inheritance?
• > 90% ____ mutation
• Partial albinism, prominent ______, premature graying, telencanthus (lateral displacement of inner canthi of eyes), heterochromia of iris, cleft lip/palate, cochlear deafness, occasional absent vagina, occasional ______ disease

Answer 30

Waardenburg syndrome I

• AD
• > 90% PAX3 mutation
• Partial albinism, prominent white forelock, premature graying, telencanthus (lateral displacement of inner canthi of eyes), heterochromia of iris, cleft lip/palate, cochlear deafness, occasional absent vagina, occasional Hirschsprung disease

Question 31

Cleidocranial dysostosis
- ___inheritance??

• Brachycephaly, frontal bossing, wormian bones (abnormal intrasutural bones), delayed eruption of deciduous and permanent teeth, supernumerary and fused teeth, hypoplastic/absent clavicle, joint laxity
  
  • Abnormal ___
  • Absent/hypoplastic ____
  • ___ anomalies (late or absent)
  • ___ stature

Answer 31

Cleidocranial dysostosis
- AD

• Brachycephaly, frontal bossing, wormian bones (abnormal intrasutural bones), delayed eruption of deciduous and permanent teeth, supernumerary and fused teeth, hypoplastic/absent clavicle, joint laxity
  
  • Abnormal skull bones (delayed closure AF)
  • Absent/hypoplastic clavicles
  • Teeth anomalies (late or absent)
  • Short stature

Question 32

SKELETAL DYSPLASIAS
Achondroplasia
- “Without cartilage formation”
- ____inheritance? disorder (100% penetrance)
- A child who receives both copies of the mutated allele is unlikely to make it to term. If 2 parents are heterozygous for FGFR3 mutation, the chance of producing a viable offspring with achondroplasia is ____.

• Path: Most have a de novo mutation of _____
  
  • The mutation rate increases with advancing ____ age.
• Pt:
  
  • Disproportionately short stature with rhizomelic shortening (short lengths of the most proximal, or “root,” segment of the upper arms and legs compared to the distal segments)
  • Brachydactyly (short fingers and toes)
  • Trident hands
  • Lumbar lordosis
  • Characteristic craniofacial findings: Macrocephaly, flat nasal bridge, prominent forehead (frontal bossing), and midfacial hypoplasia
  • _____ intellect
    
    • Children have delayed gross motor milestones but development in other realms, including cognition, is normal.
  • ______ and/or craniocervical junction abnormalities can occur in infancy and cause compression of the upper cord - resulting in apnea, quadriparesis, growth delay, and hydrocephalus.
  • ______ is a common complication, but it is unusual to see in childhood.
• Dx:
  
  • Confirm with characteristic X-ray findings:
    
    • Squared-off iliac wings
    • Contracted base of the skull
    • Square shape of the pelvis with a small sacrosciatic notch
    • Short pedicles of the vertebrae
    • Flat and irregular acetabulum roofs
    • Thick femoral necks, “ice-cream-scoop shaped” femoral heads, proximal femoral radiolucency
    • Rhizomelic (proximal) shortening of long bones
    • Trident hands
    • Normal-length trunk
    • By midchildhood, a characteristic chevron shape of the distal femoral epiphysis
• Management
  
  • Measure size and shape of fontanelle and measure the ______ (with growth curves standardized for achondroplasia) at every pediatric visit during the first 5 years of life. (due to risk of hydrocephalus)
  • A detailed _____ exam is important; if there are any concerns, neuroimaging and polysomnography are recommended
• Prognosis: Most children with achondroplasia do well.

Answer 32

SKELETAL DYSPLASIAS
Achondroplasia
- “Without cartilage formation”
- AD disorder (100% penetrance)
    - A child who receives both copies of the mutated allele is unlikely to make it to term. If 2 parents are heterozygous for FGFR3 mutation, the chance of producing a viable offspring with achondroplasia is ⅔.

• Path: Most have a de novo mutation of FGFR3
  
  • The mutation rate increases with advancing paternal age.
• Pt:
  
  • Disproportionately short stature with rhizomelic shortening (short lengths of the most proximal, or “root,” segment of the upper arms and legs compared to the distal segments)
  • Brachydactyly (short fingers and toes)
  • Trident hands
  • Lumbar lordosis
  • Characteristic craniofacial findings: Macrocephaly, flat nasal bridge, prominent forehead (frontal bossing), and midfacial hypoplasia
  • Normal intellect
    
    • Children have delayed gross motor milestones but development in other realms, including cognition, is normal.
  • Foramen magnum stenosis and/or craniocervical junction abnormalities can occur in infancy and cause compression of the upper cord - resulting in apnea, quadriparesis, growth delay, and hydrocephalus.
  • Spinal stenosis is a common complication, but it is unusual to see in childhood.
• Dx:
  
  • Confirm with characteristic X-ray findings:
    
    • Squared-off iliac wings
    • Contracted base of the skull
    • Square shape of the pelvis with a small sacrosciatic notch
    • Short pedicles of the vertebrae
    • Flat and irregular acetabulum roofs
    • Thick femoral necks, “ice-cream-scoop shaped” femoral heads, proximal femoral radiolucency
    • Rhizomelic (proximal) shortening of long bones
    • Trident hands
    • Normal-length trunk
    • By midchildhood, a characteristic chevron shape of the distal femoral epiphysis
• Management
  
  • Measure size and shape of fontanelle and measure the occipitofrontal circumference (OFC) (with growth curves standardized for achondroplasia) at every pediatric visit during the first 5 years of life. (due to risk of hydrocephalus)
  • A detailed neurologic exam is important; if there are any concerns, neuroimaging and polysomnography are recommended
• Prognosis: Most children with achondroplasia do well.

Question 33

Thanatophoric Dysplasias Types 1 and 2
- ____inheritance?

• Also involve mutations of _____.
• Pt:
  
  • Most cases are lethal. Death is either due to compression of the cervicomedullary region of the foramen magnum or due to pulmonary hypoplasia
  • Macrocephaly with very short limbs
  • Type 1 have bowed femurs whereas Type 2 exhibit straight femurs. Type 2 infants have a “cloverleaf” skull
• Dx: XR shows platyspondyly (flatness of the bodies of the vertebrae), flared metaphyses of the long bones, and short iliac bones.

Answer 33

Thanatophoric Dysplasias Types 1 and 2
- AD

• Also involve mutations of FGFR3.
• Pt:
  
  • Most cases are lethal. Death is either due to compression of the cervicomedullary region of the foramen magnum or due to pulmonary hypoplasia
  • Macrocephaly with very short limbs
  • Type 1 have bowed femurs whereas Type 2 exhibit straight femurs. Type 2 infants have a “cloverleaf” skull
• Dx: XR shows platyspondyly (flatness of the bodies of the vertebrae), flared metaphyses of the long bones, and short iliac bones.

Question 34

Infantile Cortical Hyperostosis (Caffey Disease)

• ___inheritance? with incomplete penetrance
• Pt:
  
  • Subperiosteal cortical thickening of underlying bone.
  • Soft tissue swelling is painful and indurated
  • The ______ is involved in >95% of cases and is the most commonly affected bone.
    
    • _____ involvement is most helpful in differentiating Caffey disease from nonaccidental trauma.

Answer 34

Infantile Cortical Hyperostosis (Caffey Disease)

• AD with incomplete penetrance
• Pt:
  
  • Subperiosteal cortical thickening of underlying bone.
  • Soft tissue swelling is painful and indurated
  • The mandible is involved in >95% of cases and is the most commonly affected bone.
    
    • Mandibular involvement is most helpful in differentiating Caffey disease from nonaccidental trauma.

Question 35

Noonan Syndrome
- ____inheritance?, de novo (60%)

• Pt:
  
  • Unusual facies and share congenital malformations like those with Turner syndrome but they have a _____ karyotype, which is an important distinction from Turner syndrome
  • Facial features: Low-set ears with fleshy helices, broad or webbed neck, and wide-spaced, downslanting eyes with epicanthal folds, full upper lips
  • Growth: Birth weight and length are normal. Failure to thrive and short stature
  • Neuro
    
    • Early motor milestones delay
    • CNS malformation
    • ____ intellectual disability in 25% of pts with Noonan’s.
  • Ears: High-frequency sensorineural hearing loss
  • Eyes: Nystagmus, strabismus, ptosis, anterior segment problems
  • Dental: Articulation difficulty, high arched palate, micrognathia
  • Congenital heart defects (80% of pts): ____ stenosis, atrial septal defect, _____ cardiomyopathy
  • GU: Cryptorchidism, small testes are hypogonadal or normal

Answer 35

Noonan Syndrome
- AD, de novo (60%)

• Pt:
  
  • Unusual facies and share congenital malformations like those with Turner syndrome but they have a normal karyotype, which is an important distinction from Turner syndrome
  • Facial features: Low-set ears with fleshy helices, broad or webbed neck, and wide-spaced, downslanting eyes with epicanthal folds, full upper lips
  • Growth: Birth weight and length are normal. Failure to thrive and short stature
  • Neuro
    
    • Early motor milestones delay
    • CNS malformation
    • Mild intellectual disability in 25% of pts with Noonan’s.
  • Ears: High-frequency sensorineural hearing loss
  • Eyes: Nystagmus, strabismus, ptosis, anterior segment problems
  • Dental: Articulation difficulty, high arched palate, micrognathia
  • Congenital heart defects (80% of pts): Pulmonary valve stenosis, atrial septal defect, hypertrophic cardiomyopathy
  • GU: Cryptorchidism, small testes are hypogonadal or normal

Question 36

Cornelia de Lange
- ____inheritance?

• > 50% of pts have a mutation of ____, a gene on chromosome 5.
• Pt:
  
  • Growth restrictions, limb anomalies, and cardiac anomalies as well as characteristic dysmorphic feature that can be identified on US.
  • IUGR, microcephaly, hirsutism, ____ mouth, heart defects, microbrachycephaly, micrognathia, low hairline, synophrys (fusion of eyebrows above bridge of nose), long _____, thin upper lip, low-set ears, micromelia (hands/feet) or phocomelia; ________
  • ID from mild to profound. Reflux is common.

Answer 36

Cornelia de Lange
- AD

• > 50% of pts have a mutation of CLDS1, a gene on chromosome 5.
• Pt:
  
  • Growth restrictions, limb anomalies, and cardiac anomalies as well as characteristic dysmorphic feature that can be identified on US.
  • IUGR, microcephaly, hirsutism, down-turned mouth, heart defects, microbrachycephaly, micrognathia, low hairline, synophrys (fusion of eyebrows above bridge of nose), long eyelashes, thin upper lip, low-set ears, micromelia (hands/feet) or phocomelia; 2,3 syndactyly of toes
  • ID from mild to profound. Reflux is common.

Question 37

Dubowitz syndrome

• AR (gene unknown)
• IUGR, telecanthus, ptosis, eczema, hypotrichosis, behavioral and developmental disorders

Answer 37

Dubowitz syndrome

• AR (gene unknown)
• IUGR, telecanthus, ptosis, eczema, hypotrichosis, behavioral and developmental disorders

Question 38

Russell-Silver Syndrome

• Sporadic
  
  • 10% uniparental disomy chromosome 7
  • 35-50% hypomethylation paternal imprinting center 1 on chromosome 11p15.5
• Pt:
  
  • Small height and weight with normal head circumference
  • Triangular face
  • ____
  • ____ spots
  • Delayed __
  • ____ is major issue

Answer 38

Russell-Silver Syndrome

• Sporadic
  
  • 10% uniparental disomy chromosome 7
  • 35-50% hypomethylation paternal imprinting center 1 on chromosome 11p15.5
• Pt:
  
  • Small height and weight with normal head circumference
  • Triangular face
  • Hemihypertrophy
  • Cafe au lait spots
  • Delayed bone age
  • Reflux is major issue

Question 39

Mobius syndrome

• Sporadic
• Cranial nerve abnormalities, hypoplastic tongue and/or digits, limb deficiency, Poland anomaly (absence of the pectoralis major/minor muscles), ipsilateral breast hypoplasia (absence of 2-4 rib segments)

Answer 39

Mobius syndrome

• Sporadic
• Cranial nerve abnormalities, hypoplastic tongue and/or digits, limb deficiency, Poland anomaly (absence of the pectoralis major/minor muscles), ipsilateral breast hypoplasia (absence of 2-4 rib segments)

Question 40

Rubinstein-Taybi syndrome
- Short stature and limbs, microcephaly, beaked nose, broad thumbs and great toes, congenital heart disease, intellectual disability

Answer 40

Rubinstein-Taybi syndrome
- Short stature and limbs, microcephaly, beaked nose, broad thumbs and great toes, congenital heart disease, intellectual disability

Question 41

Holt-Oram Syndrome (“Holter Arm”)

• ____inheritance? disorder due to TBX5 gene mutations.
• Pt: Radial ray abnormalities (triphalangeal thumb), ASD and other congenital heart disease in 75% of individuals, no hematological anomalies
  
  • An abnormal ____ bone is noted in all affected individuals

Answer 41

Holt-Oram Syndrome (“Holter Arm”)

• Autosomal dominant disorder due to TBX5 gene mutations.
• Pt: Radial ray abnormalities (triphalangeal thumb), ASD and other congenital heart disease in 75% of individuals, no hematological anomalies
  
  • An abnormal carpal bone is noted in all affected individuals

Question 42

Pituitary Gigantism and Acromegaly
- Pituitary adenoma very rarely will produce excessive ___

• If excess production is continuous and epiphyses are open, gigantism occurs.
• If epiphyses are closed, as in most adults, ____ results (ie no increase in long bone length, but bones of the hands, feet, and face increase in size)
• Pt: Child has rapid linear growth, coarse facies, and enlarging hands and feet.
• Labs:
  
  • High ____ levels, usually >400ng/mL.
  • In suppression testing, GH levels do not suppress with glucose administration.
• Tx:
  
  • Surgery to remove adenoma, radiation therapy, medications.
  • ____ and lanreotide are somatostatin analogs that suppress and shrink many of these tumors.
  • Pegvisomant (Somavert), a GH receptor antagonist, lowers the effect of high GH.
  • _____, a dopamine agonist often used in the tx of prolactinoma, can also decrease GH secretion.

Answer 42

Pituitary Gigantism and Acromegaly
- Pituitary adenoma very rarely will produce excessive GH

• If excess production is continuous and epiphyses are open, gigantism occurs.
• If epiphyses are closed, as in most adults, acromegaly results (ie no increase in long bone length, but bones of the hands, feet, and face increase in size)
• Pt: Child has rapid linear growth, coarse facies, and enlarging hands and feet.
• Labs:
  
  • High GH levels, usually >400ng/mL.
  • In suppression testing, GH levels do not suppress with glucose administration.
• Tx:
  
  • Surgery to remove adenoma, radiation therapy, medications.
  • Octreotide and lanreotide are somatostatin analogs that suppress and shrink many of these tumors.
  • Pegvisomant (Somavert), a GH receptor antagonist, lowers the effect of high GH.
  • Cabergoline, a dopamine agonist often used in the tx of prolactinoma, can also decrease GH secretion.

Question 43

Prolactinoma
- In adolescents, prolactin-secreting tumors are the most common anterior pituitary tumor.

• Pt:
  
  • Headache, a____, _____.
  • Most prolactinomas are larger in children (macroadenomas), and _____ defects are common.
• MRI of the sella is the best diagnostic tool to find small adenomas (microadenomas).
• Tx:
  
  • ____ and ___ are the drugs of choice.

Answer 43

Prolactinoma
- In adolescents, prolactin-secreting tumors are the most common anterior pituitary tumor.

• Pt:
  
  • Headache, amenorrhea, galactorrhea.
  • Most prolactinomas are larger in children (macroadenomas), and visual field defects are common.
• MRI of the sella is the best diagnostic tool to find small adenomas (microadenomas).
• Tx:
  
  • Cabergoline and bromocriptine are the drugs of choice.

Question 44

Sotos Syndrome (Cerebral Gigantism)
- Overgrowth syndrome. Rapid growth early in childhood but not evidence of an endocrine disorder.

• Path: 80-90% due to mutation in NSD1 gene at 5q35
• Pt:
  
  • Born >90%ile and then grow rapidly in the 1st year of life to >97%ile. Accelerated growth rate persists until 4-5yo and then growth rates return to normal.
    
    • Most end up with normal adult heights.
  • Big ___ and ___ and present as clumsy.
  • _____ is common
• Labs: GH levels and growth factors are ____!

Answer 44

Sotos Syndrome (Cerebral Gigantism)
- Overgrowth syndrome. Rapid growth early in childhood but not evidence of an endocrine disorder.

• Path: 80-90% due to mutation in NSD1 gene at 5q35
• Pt:
  
  • Born >90%ile and then grow rapidly in the 1st year of life to >97%ile. Accelerated growth rate persists until 4-5yo and then growth rates return to normal.
    
    • Most end up with normal adult heights.
  • Big hands and feet and present as clumsy.
  • Learning disability is common
• Labs: GH levels and growth factors are normal!

Question 45

HEMIHYPERPLASIA differential

• Beckwith-Wiedemann syndrome
• Proteus syndrome (PTEN hamartoma tumor syndrome)
• Klippel-Trenaunay -Weber syndrome
• Isolated hemihyperplasia
• Neurofibromatosis type 1

Answer 45

HEMIHYPERPLASIA differential

• Beckwith-Wiedemann syndrome
• Proteus syndrome (PTEN hamartoma tumor syndrome)
• Klippel-Trenaunay -Weber syndrome
• Isolated hemihyperplasia
• Neurofibromatosis type 1

Question 46

Beckwith-Wiedemann Syndrome

• Path: Path: Genetic or epigenetic abnormalities involving chromosome ____
  
  • Most cases due to paternal deletion of 15q11-13
• Pt
  
  • Overgrowth: _____ (enlarged left side of body and face, hepatosplenomegaly, nephromegaly, cardiomegaly), ____, global ____ (95%ile for height and weight)
  • Anterior abdominal wall defects (may present w omphalocele)
  • Pancreatic B-cell hyperplasia causes excessive insulin production with resultant hypoglycemia
  • Neonatal ______
  • Affected children have an increased risk of cancer through 7-8yo, with up to 10% develop embryonal tumor types, most commonly hepatoblastoma, nephroblastoma (Wilms tumor), neuroblastoma, and adrenocortical carcinoma
• Screening
  
  • Serum ___ measurements every __mo (6 weeks) until __yo to screen for ___, and
  • Complete __ every __mo through __yo to screen for ____

Answer 46

Beckwith-Wiedemann Syndrome

• Path: Path: Genetic or epigenetic abnormalities involving chromosome 11p15
  
  • Most cases due to paternal deletion of 15q11-13
• Pt
  
  • Overgrowth: Hemihyperplasia (enlarged left side of body and face, hepatosplenomegaly, nephromegaly, cardiomegaly), macroglossia, global macrosomia (95%ile for height and weight)
  • Anterior abdominal wall defects (may present w omphalocele)
  • Pancreatic B-cell hyperplasia causes excessive insulin production with resultant hypoglycemia
  • Neonatal hypoglycemia
  • Affected children have an increased risk of cancer through 7-8yo, with up to 10% develop embryonal tumor types, most commonly hepatoblastoma, nephroblastoma (Wilms tumor), neuroblastoma, and adrenocortical carcinoma
• Screening
  
  • Serum alpha-fetoprotein measurements every 3mo (6 weeks) until 6yo to screen for hepatoblastoma, and
  • Complete abd US every 3mo through 8yo to screen for Wilm’s tumor.

Question 47

Proteus syndrome (aka Wiedemann syndrome)
- Path: Due to somatic mosaicism for activating AKT1 mutations

• Pt:
  
  • Macrodactyly, soft/connective tissue hypertrophy, hemi____, nevi, lipomas, lymphangiomata, hemangiomata, accelerated growth
  • Disproportional overgrowth of limbs, digits, cranium, vertebrae, external auditory meatus, spleen, or thymus
  • Bilateral _____ or a parotid monomorphic adenoma, lipomas, capillary, venous, or lymphatic malformation
  • Abnormal facies (long face, down-slanting palpebrae, ptosis, depressed nasal bridge, anteverted nares).
  • Do not confuse with Beckwith-Wiedemann syndrome. Proteus has ____. Beckwith-Wiedemann has ___ and ____

Answer 47

Proteus syndrome (aka Wiedemann syndrome)
- Path: Due to somatic mosaicism for activating AKT1 mutations

• Pt:
  
  • Macrodactyly, soft/connective tissue hypertrophy, hemihypertrophy, nevi, lipomas, lymphangiomata, hemangiomata, accelerated growth
  • Disproportional overgrowth of limbs, digits, cranium, vertebrae, external auditory meatus, spleen, or thymus
  • Bilateral ovarian cystadenomas or a parotid monomorphic adenoma, lipomas, capillary, venous, or lymphatic malformation
  • Abnormal facies (long face, down-slanting palpebrae, ptosis, depressed nasal bridge, anteverted nares).
  • Do not confuse with Beckwith-Wiedemann syndrome. Proteus has lipomas and nevi. Beckwith-Wiedemann has cryptorchidism and ear lobe creases/posterior auricular pits

Question 48

VACTERL
- Path: Sporadic. No genetic mutation has been identified for the VACTERL association. FOX1 is associated.

• 1. V______ - are the MOST COMMON anomaly, in up to 80% of patients. Typically, patients have hypoplastic vertebrae or hemivertebrae (only ½ of vertebra is formed)
• 2. A_____ - Most common is anal atresia/imperferate anus (55% of patients)
• 3. C_____ - Up to 75% of patients have some form of congenital heart disease, most commonly a VSD, ASD, and/or tetralogy of fallot. Truncus arteriosus and transposition of the great arteries can be seen as well, but these are less common.
• 4. T______ - In up to 75% of patients. Result of midline defect during development of fetus
     - Esophageal atresia typically presents with poor feeding, nonbilious emesis, and increased oral secretions.
     - Most neonates with esophageal atresia also have tracheoesophageal fistula
• 5. R______ - In 50% of patients.
     - Only 35% of VACTERL patients have a single umbilical artery so the presence of 2 arteries does not rule out renal anomalies in these patients.
• 6. L______ - In up to 70% of patients.
     - Defects include hypoplastic thumbs, polydactyly, syndactyly, and radial aplasia. Patients with bilateral limb defects tend to have bilateral urology/renal defects while unilateral limb defects tend to be located on same side as kidney defect.
• Dx: Presence of 3 of major anomalies.

Answer 48

VACTERL
- Path: Sporadic. No genetic mutation has been identified for the VACTERL association. FOX1 is associated.

• 1. Vertebral anomalies - Vertebral defects are the MOST COMMON anomaly, in up to 80% of patients. Typically, patients have hypoplastic vertebrae or hemivertebrae (only ½ of vertebra is formed)
• 2. Anal defects - Most common is anal atresia/imperferate anus (55% of patients)
• 3. Cardiovascular anomalies - Up to 75% of patients have some form of congenital heart disease, most commonly a VSD, ASD, and/or tetralogy of fallot. Truncus arteriosus and transposition of the great arteries can be seen as well, but these are less common.
• 4. Trachea-Esophageal anomalies - In up to 75% of patients. Result of midline defect during development of fetus
     - Esophageal atresia typically presents with poor feeding, nonbilious emesis, and increased oral secretions.
     - Most neonates with esophageal atresia also have tracheoesophageal fistula
• 5. Renal anomalies - In 50% of patients.
     - Only 35% of VACTERL patients have a single umbilical artery so the presence of 2 arteries does not rule out renal anomalies in these patients.
• 6. Limb defects - In up to 70% of patients.
     - Defects include hypoplastic thumbs, polydactyly, syndactyly, and radial aplasia. Patients with bilateral limb defects tend to have bilateral urology/renal defects while unilateral limb defects tend to be located on same side as kidney defect.
• Dx: Presence of 3 of major anomalies.

Question 49

CHARGE Syndrome
- _____inheritance? disorder. Mutation in the CHD7 gene on chromosome 8q

• Findings
  
  • C___
  • H___
  • A___
  • R___
  • G____
  • E____
• Diagnostic criteria for CHARGE Syndrome:
  
  • Definite: 4 major characteristics or 3 major and 3 minor characteristics
  • Probable: 1 or 2 major characteristics and several minor characteristics
  • Major diagnostic criteria
    
    • Ocular colobomas
    • Choanal atresia
    • Cranial nerve dysfunction or anomaly (eg anosmia, facial palsy, auditory nerve hypoplasia, or swallowing problems)
    • External ear anomalies, middle ear defects, Mondini defect, temporal bone abnormalities
  • Minor diagnostic criteria
    
    • Genital hypoplasia
    • Developmental delay
    • Cardiovascular anomalies
    • Growth deficiency
    • Cleft lip and/or palate
    • Tracheoesophageal fistula or esophageal atresia
    • Facial dysmorphology (square face with prominent forehead, flat midface, broad nasal root)

Answer 49

CHARGE Syndrome
- Autosomal dominant disorder. Mutation in the CHD7 gene on chromosome 8q

• Findings
  
  • Colobomas/CNS disease
  • Heart defects
  • Atresia choanae
  • Retarded growth and development
  • Genital/urinary abnormalities (hypogonadism)
  • Ear abnormalities or hearing loss
• Diagnostic criteria for CHARGE Syndrome:
  
  • Definite: 4 major characteristics or 3 major and 3 minor characteristics
  • Probable: 1 or 2 major characteristics and several minor characteristics
  • Major diagnostic criteria
    
    • Ocular colobomas
    • Choanal atresia
    • Cranial nerve dysfunction or anomaly (eg anosmia, facial palsy, auditory nerve hypoplasia, or swallowing problems)
    • External ear anomalies, middle ear defects, Mondini defect, temporal bone abnormalities
  • Minor diagnostic criteria
    
    • Genital hypoplasia
    • Developmental delay
    • Cardiovascular anomalies
    • Growth deficiency
    • Cleft lip and/or palate
    • Tracheoesophageal fistula or esophageal atresia
    • Facial dysmorphology (square face with prominent forehead, flat midface, broad nasal root)

Question 50

FRAGILE X SYNDROME

• The most common inherited form of intellectual disability syndrome.
• Path: Loss of function mutation in _____ (Fragile X mental retardation 1) gene secondary to increased number of ____ trinucleotide repeats at Xp27.3 and hypermethylation of the FMR1 gene.
  
  • Normal: 6-50 repeats
  • Premutation: ~50-200 repeats
  • Full mutation: >____ repeats
• X-linked, ______ characterized by phenomenon known as ____
• Pt for full mutation (>200 repeat)
  
  • Boys with full fragile X mutation (>200 CGG repeats) will have _______ intellectual disability (avg IQ ~41) in boys
    
    • Girls will have only _____ intellectual disability or learning disabilities and can be intellectually normal in about 50% of cases.
  • Affected boys have characteristic dysmorphology, more evidence as child ages around puberty: Macrocephaly, long face, prominent forehead, ____ ears, ____ hands/feet, postpubertal macro-orchidism
• Pt for Premutation carriers (55-200 CGG repeats)
  
  • 1) ____ intellect and appearance.
    
    • Mild cognitive or behavioral deficits on the fragile X spectrum
  • 2) Female premutation carriers are at risk for______, with cessation of menses before age 40.
  • 3) Male premutation carriers have an increased incidence of fragile X-associated ______ syndrome (FXTAS), which resembles Parkinson-like disorder with intention tremor, gait ataxia, and eventually dementia.
• Dx: DNA testing for defects in the FMR1 gene with either Southern blot or PCR. FMR1 molecular analysis confirms

Answer 50

FRAGILE X SYNDROME

• The most common inherited form of intellectual disability syndrome.
• Path: Loss of function mutation in FMR1 (Fragile X mental retardation 1) gene secondary to increased number of CGG trinucleotide repeats at Xp27.3 and hypermethylation of the FMR1 gene.
  
  • Normal: 6-50 repeats
  • Premutation: ~50-200 repeats
  • Full mutation: >200 repeats
• X-linked, autosomal dominant characterized by phenomenon known as anticipation
• Pt for full mutation (>200 repeat)
  
  • Boys with full fragile X mutation (>200 CGG repeats) will have MODERATE-severe intellectual disability (avg IQ ~41) in boys
    
    • Girls will have only mild intellectual disability or learning disabilities and can be intellectually normal in about 50% of cases.
  • Affected boys have characteristic dysmorphology, more evidence as child ages around puberty: Macrocephaly, long face, prominent forehead, large protruding ears, large hands/feet, postpubertal macro-orchidism
• Pt for Premutation carriers (55-200 CGG repeats)
  
  • 1) Normal intellect and appearance.
    
    • Mild cognitive or behavioral deficits on the fragile X spectrum
  • 2) Female premutation carriers are at risk for primary ovarian insufficiency, with cessation of menses before age 40.
  • 3) Male premutation carriers have an increased incidence of fragile X-associated tremor/ataxia syndrome (FXTAS), which resembles Parkinson-like disorder with intention tremor, gait ataxia, and eventually dementia.
• Dx: DNA testing for defects in the FMR1 gene with either Southern blot or PCR. FMR1 molecular analysis confirms

Question 51

VON HIPPEL-LINDAU (VHL) SYNDROME

• _____inheritance?
• Pt: Various benign and malignant tumors of the eyes, CNS, kidneys, pancreas, adrenal glands, and reproductive glands
  
  • Most classic presentation is a ______ in adolescence or a_____ by 10yo.
  • Renal cysts are common.
  • Renal cell carcinoma presents in the 40s
• Dx: Depends on one of the following:
  
  • 1) Finding >2 hemangioblastomas in the CNS (particularly cerebellum) or retina
  • 2) Finding 1 single hemangioblastoma plus 1 of the following
    
    • Pheochromocytoma
    • Endolymphatic sac tumors
    • Cysts in the kidney/pancreas
    • Renal cell carcinoma
    • Cystadenomas and neuroendocrine tumors of the pancreas
  • 3) Having a 1st degree relative with VHL and any 1 manifestations listed above

Answer 51

VON HIPPEL-LINDAU (VHL) SYNDROME

• AD
• Pt: Various benign and malignant tumors of the eyes, CNS, kidneys, pancreas, adrenal glands, and reproductive glands
  
  • Most classic presentation is a cerebellar hemangioblastoma in adolescence or a retinal angioma by 10yo.
  • Renal cysts are common.
  • Renal cell carcinoma presents in the 40s
• Dx: Depends on one of the following:
  
  • 1) Finding >2 hemangioblastomas in the CNS (particularly cerebellum) or retina
  • 2) Finding 1 single hemangioblastoma plus 1 of the following
    
    • Pheochromocytoma
    • Endolymphatic sac tumors
    • Cysts in the kidney/pancreas
    • Renal cell carcinoma
    • Cystadenomas and neuroendocrine tumors of the pancreas
  • 3) Having a 1st degree relative with VHL and any 1 manifestations listed above

Question 52

Hereditary Hemorrhagic Telangiectasia (HHT) (aka ______ syndrome)
- ____inheritance?

• Pt: The extent of HHT is variable.
  
  • ____ in the brain, lungs, liver, GI tract, pancreas, and spinal cord, and telangiectasias in the skin and mucosa
  • Cutaneous signs: Telangiectases on the skin and mucosa
• Often have __ and ___ starting in childhood; telangiectasias may not appear until adolescence or early childhood.
  
  • Although headaches and epistaxis are common, family hx can raise concern for HHT
• Management:
  
  • No cure.
  • Refer for genetics evaluation.

Answer 52

Hereditary Hemorrhagic Telangiectasia (HHT) (aka Osler-Weber-Rendu syndrome)
- AD

• Pt: The extent of HHT is variable.
  
  • Arteriovenous malformations (AVMs) in the brain, lungs, liver, GI tract, pancreas, and spinal cord, and telangiectasias in the skin and mucosa
  • Cutaneous signs: Telangiectases on the skin and mucosa
• Often have headaches and epistaxis starting in childhood; telangiectasias may not appear until adolescence or early childhood.
  
  • Although headaches and epistaxis are common, family hx can raise concern for HHT
• Management:
  
  • No cure.
  • Refer for genetics evaluation.

Question 53

Tuberous Sclerosis
- Path: Genetic, _____inheritance? disorder resulting from mutations of ___ (hamartin) (on chromosome 9) or ___ genes (tuberin)

• Pt:
  
  • Skin
    
    • ____ spots (hypopigmented macules), which illuminate under a Wood’s lamp, is the most common presentation in 90% of cases
    • Facial ____ (red spots in malar distribution often mistaken for acne)
    • ____ patch (irregular rough/leathery raised plaque on skin of lower back or trunk; skin-colored or occasionally pigmented; smooth or crinkled)
    • ____ fibroma (painful)
  • CNS
    
    • Giant cell ____
    • ____ - Infantile spasms, afebrile seizures, complex febrile
  • Heart
    
    • Cardiac ____ (50%) - will regress over time. Can monitor if asymptomatic
  • Kidneys
    
    • _____ (80% of pts) - Renal lesion.
• Diagnostic criteria: 2 major features or 1 major + >2 minor features
  
  • Major features
    
    • Angiofibromas (>3) or fibrous cephalic plaque
    • Cardiac rhabdomyoma
    • Cortical dysplasias (eg tubers)
    • Hypomelanotic macules (>3 that are >5mm)
    • Lymphagioleiomyomatosis
    • Multiple retinal nodular hamartomas
    • Renal angiomyolipoma
    • Shagreen patch
    • Subependymal giant cell astrocytoma
    • Subependymal nodules
    • Ungual fibromas (>2)
  • Minor features
    
    • “Confetti” skin lesions: numerous 1-3mm hypopigmented macules often present on arms or legs
    • Dental enamel pits (>3)
    • Intraoral fibromas (>2)
    • Multiple renal cysts
    • Nonrenal hamartomas
    • Retinal achromic patch
• Management
  
  • For skin: Topical mechanistic target of ______ (like ___ or ____) can improve appearance of facial angiofibromas, ungal fibromas, and hypomelanotic macules
  • For infantile spasms: In setting of tuberous sclerosis, tx is usually with anticonvulsant ____.
  • ____ (mechanistic target of rapamycin) inhibitors (sirolimus, everolimus) are often used in the tx of complications: Shrink brain and renal lesions (subependymal giant cell astrocytomas, pulmonary involvement, renal angiomyolipomas, lymphangioleiomyomatosis, symptomatic cardiac rhabdomyomas) (although FDA approved to only treat brain lesions)

Answer 53

Tuberous Sclerosis
- Path: Genetic, AD disorder resulting from mutations of TSC1 (hamartin) (on chromosome 9) or TSC2 genes (tuberin)

• Pt:
  
  • Skin
    
    • Ash-leaf spots (hypopigmented macules), which illuminate under a Wood’s lamp, is the most common presentation in 90% of cases
    • Facial angiofibromas (red spots in malar distribution often mistaken for acne)
    • Shagreen patch (irregular rough/leathery raised plaque on skin of lower back or trunk; skin-colored or occasionally pigmented; smooth or crinkled)
    • Periungal fibroma (painful)
  • CNS
    
    • Giant cell astrocytoma
    • Seizures - Infantile spasms, afebrile seizures, complex febrile
  • Heart
    
    • Cardiac Rhabdomyoma (50%) - will regress over time. Can monitor if asymptomatic
  • Kidneys
    
    • Angiomyolipoma (80% of pts) - Renal lesion.
• Diagnostic criteria: 2 major features or 1 major + >2 minor features
  
  • Major features
    
    • Angiofibromas (>3) or fibrous cephalic plaque
    • Cardiac rhabdomyoma
    • Cortical dysplasias (eg tubers)
    • Hypomelanotic macules (>3 that are >5mm)
    • Lymphagioleiomyomatosis
    • Multiple retinal nodular hamartomas
    • Renal angiomyolipoma
    • Shagreen patch
    • Subependymal giant cell astrocytoma
    • Subependymal nodules
    • Ungual fibromas (>2)
  • Minor features
    
    • “Confetti” skin lesions: numerous 1-3mm hypopigmented macules often present on arms or legs
    • Dental enamel pits (>3)
    • Intraoral fibromas (>2)
    • Multiple renal cysts
    • Nonrenal hamartomas
    • Retinal achromic patch
• Management
  
  • For skin: Topical mechanistic target of rapamycin inhibitor (like sirolimus or rapamycin) can improve appearance of facial angiofibromas, ungal fibromas, and hypomelanotic macules
  • For infantile spasms: In setting of tuberous sclerosis, tx is usually with anticonvulsant vigabatrin.
  • Oral mTOR (mechanistic target of rapamycin) inhibitors (sirolimus, everolimus) are often used in the tx of complications: Shrink brain and renal lesions (subependymal giant cell astrocytomas, pulmonary involvement, renal angiomyolipomas, lymphangioleiomyomatosis, symptomatic cardiac rhabdomyomas) (although FDA approved to only treat brain lesions)

Question 54

Sturge-Weber Syndrome (encephalotrigeminal angiomastosis)
- One of phakomatoses

• Path: Sporadic neurocutaneous disorder caused by a mutation in GNAQ that results in abnormal cell proliferation.
• Pt: Triad includes facial ____, _____, and ____
  
  • Systemic manifestations: seizures, intellectual disability (mental retardation), paresis, cerebral calcifications
  • Skull x-rays, taken after age 2yo, reveal gyriform____ that resemble a ___.
  • 10-20% of these patients have an ipsilateral leptomeningeal angioma
• Dx: Clinical, requires involvement in at least 2 of 3 areas: Skin (port-wine stain), brain (leptomeningeal angiomatosis that may cause seizures, stroke, and intellectual disability), and eyes (glaucoma).
• Tx:
  
  • No definitive treatment is available.
  • Aimed at controlling seizures and decreased intraocular pressure.

Answer 54

Sturge-Weber Syndrome (encephalotrigeminal angiomastosis)
- One of phakomatoses

• Path: Sporadic neurocutaneous disorder caused by a mutation in GNAQ that results in abnormal cell proliferation.
• Pt: Triad includes facial port-wine stain, intracranial angiomata, and glaucoma
  
  • Systemic manifestations: seizures, intellectual disability (mental retardation), paresis, cerebral calcifications
  • Skull x-rays, taken after age 2yo, reveal gyriform intracranial calcifications that resemble a tramline.
  • 10-20% of these patients have an ipsilateral leptomeningeal angioma
• Dx: Clinical, requires involvement in at least 2 of 3 areas: Skin (port-wine stain), brain (leptomeningeal angiomatosis that may cause seizures, stroke, and intellectual disability), and eyes (glaucoma).
• Tx:
  
  • No definitive treatment is available.
  • Aimed at controlling seizures and decreased intraocular pressure.

Question 55

Neurofibromatosis Type 1

• When inherited, ____inheritance? disorder
• Pt:
  
  • Most common - ______ spots (CALMs) (brown macules with irregular border) and multiple neurofibromas (benign peripheral nerve sheath tumors in skin)
• Associations:
  
  • Pheochromocytomas are known to occur in patients with NF-1.
• Diagnosis: >2 or more of 7 criteria:
  
  • > =___ cafe au lait spots >___mm prepubertal OR >15mm/1.5cm after puberty
  • > 1 Plexiform neurofibromas OR >2 dermal neurofibromas (benign)
  • Skin fold (axillary or inguinal) freckling - Crowe sign - small, grouped, freckle-like cafe-au-lait macules 1-4mm
  • Osseous lesion
  • Optic glioma
  • > 2 Iris Lesch nodules /Iris hamartomas- do not affect vision, usually >6yo
  • Affected 1st degree relative (Autosomal Dominant)
• Work up: Surveillance for complications.
  
  • Medical genetics consultation
  • Regular BP monitoring for HTN (renal artery stenosis)
  • Annual ______ evaluation for optic pathway glioma, important due to risk of progressive vision loss. If eye examination is abnormal, _____ must be performed to determine tumor size and extent of intracranial extension.

Answer 55

Neurofibromatosis Type 1

• When inherited, AD disorder
• Pt:
  
  • Most common - Cafe au lait spots (CALMs) (brown macules with irregular border) and multiple neurofibromas (benign peripheral nerve sheath tumors in skin)
• Associations:
  
  • Pheochromocytomas are known to occur in patients with NF-1.
• Diagnosis: >2 or more of 7 criteria:
  
  • > =6 cafe au lait spots >5mm prepubertal OR >15mm/1.5cm after puberty
  • > 1 Plexiform neurofibromas OR >2 dermal neurofibromas (benign)
  • Skin fold (axillary or inguinal) freckling - Crowe sign - small, grouped, freckle-like cafe-au-lait macules 1-4mm
  • Osseous lesion
  • Optic glioma
  • > 2 Iris Lesch nodules /Iris hamartomas- do not affect vision, usually >6yo
  • Affected 1st degree relative (Autosomal Dominant)
• Work up: Surveillance for complications.
  
  • Medical genetics consultation
  • Regular BP monitoring for HTN (renal artery stenosis)
  • Annual ophthalmologic evaluation for optic pathway glioma, important due to risk of progressive vision loss. If eye examination is abnormal, MRI of brain and orbits must be performed to determine tumor size and extent of intracranial extension.

Question 56

HUNTINGTON DISEASE
- ____inheritance?, trinucleotide repeat disorder (_____) that leads to progressive motor disability, cognitive decline and psychiatric disturbances.

• Average age at onset is 35-44 years, with a survival of 15-18 years after onset of symptoms.
• Pt:
  
  • ____ symptoms: Hypokinesia, chorea, rigidity, ataxia, dystonia
  • _____ disturbances: Agitation, anxiety, depression, apathy, disinhibition, delusions, hallucinations.
  • Suicidal ideation is common in individuals with HD
  • Cognitive decline is progressive, resulting in pts’ inability to care for themselves, speak, swallow, or walk.
• Management:
  
  • There is no cure, only symptomatic management.

Answer 56

HUNTINGTON DISEASE
- Autosomal-dominant, trinucleotide repeat disorder (CAG) that leads to progressive motor disability, cognitive decline and psychiatric disturbances.

• Average age at onset is 35-44 years, with a survival of 15-18 years after onset of symptoms.
• Pt:
  
  • Motor symptoms: Hypokinesia, chorea, rigidity, ataxia, dystonia
  • Psychiatric disturbances: Agitation, anxiety, depression, apathy, disinhibition, delusions, hallucinations.
  • Suicidal ideation is common in individuals with HD
  • Cognitive decline is progressive, resulting in pts’ inability to care for themselves, speak, swallow, or walk.
• Management:
  
  • There is no cure, only symptomatic management.

Question 57

___ - ___ gene for Fragile X
___ - __ gene on chromosome __ for Huntington disease
___ repeats - ___ gene on chromosome __ for type 1 myotonic dystrophy
___ repeats - __ gene on chromosome __ for Friedreich ataxia

Answer 57

CGG - FMR1 gene for Fragile X (cat gato gato)
CAG - HTT gene on chromosome 4 for Huntington disease (cage; cat apple gorilla)
CTG repeats - DMPK gene on chromosome 19 for type 1 myotonic dystrophy
GAA repeats - FXN gene on chromosome 9 for Friedreich ataxia

Question 58

CGG - ___
CAG -____
CTG repeats - ____
GAA repeats - ____

Answer 58

CGG - FMR1 gene for Fragile X (cat gato gato)
CAG - HTT gene on chromosome 4 for Huntington disease (cage; cat apple gorilla)
CTG repeats - DMPK gene on chromosome 19 for type 1 myotonic dystrophy
GAA repeats - FXN gene on chromosome 9 for Friedreich ataxia

Question 59

JAG1 -20p12 - ___ syndrome
SMN on chromosome 5q13 - ___
GNAS1 - ___

Answer 59

JAG1 - 20p12 - Alagille syndrome
SMN on chromosome 5q13 - SMA
GNAS1 - McCune-Albright

Question 60

___ - ____ - Alagille syndrome
___ on chromosome ____ - SMA
___ - McCune-Albright

Answer 60

JAG1 - 20p12- Alagille syndrome
SMN on chromosome 5q13 - SMA
GNAS1 - McCune-Albright

Question 61

t__;__ translocation - Ewing’s
__:__ translation - trisomy 21___- ALL
___ - philadelphia chromosome; CML
___ - acute promyelocytic leukemia (APML).

Answer 61

t11;22 translocation - Ewing’s
14:21 translation - trisomy 21
12;21- ALL
t(9;11) - philadelphia chromosome; CML
t(15;17) - acute promyelocytic leukemia (APML).

Question 62

t11;22 translocation - \_\_\_
14:21 translation - \_\_\_
12;21- \_\_\_
t(9;11) - \_\_\_
t(15;17) \_\_\_\_

Answer 62

t11;22 translocation - Ewing’s
14:21 translation - trisomy 21
12;21- ALL
t(9;11) - philadelphia chromosome; CML
t(15;17) - acute promyelocytic leukemia (APML).

Question 63

15q11-13 - \_\_\_
7q11.23 - \_\_\_ 
11p13 - \_\_\_
22q11.2 \_\_\_
11p15 - \_\_\_\_

Answer 63

15q11-13  Angelman / Prader willi
7q11.23 - Williams 
11p13 - WAGR
22q11.2 DiGeorge
11p15 - Beckwith-Wiedemann syndrome

Question 64

\_\_\_ - Angelman / Prader willi
\_\_\_ - Williams 
\_\_\_ - WAGR
\_\_\_ DiGeorge
\_\_\_\_ - Beckwith-Wiedemann syndrome

Answer 64

15q11-13 - Angelman / Prader willi
7q11.23 - Williams 
11p13 - WAGR
22q11.2 DiGeorge
11p15 - Beckwith-Wiedemann syndrome