Genetics Flashcards
When can amniocentesis be done?
16 weeks
What is used to track intrauterine growth over time?
Fetal US
When are structural anomalies (like myelomeningocele) best detected on US?
Between 12-24 weeks gestation
What maternal problem can be a complicating factor that blunts the accuracy of US findings?
Maternal obesity
What 3 hematologic diseases can be diagnosed prenatally?
Factor 8 deficiency, factor 9 deficiency, sickle cell disease
What is monogenic inheritance?
Genetic disorders caused by a mutation in one gene
What is multifactorial inheritance?
Genetic disorders caused by mutations in multiple genes
What is epigenetics?
Genetic disorders caused by a combination of gene mutations and environmental factors
In which inheritance pattern are males affected and females carriers?
X-linked recessive
If there are any female relatives with a disorder, which inheritance pattern is eliminated?
X-linked recessive
Is male-to-male transmission possible in X-linked recessive disorders?
No
If a question casually mentions a kid who had two uncles with a similar problem, what should you think?
You know that only males are affected…pointing towards an X-linked recessive disorder
Which type of inheritance disorders frequently involve an enzyme deficiency?
X-linked recessive
Name 8 frequently tested X-linked recessive conditions
- Hemophilia A/B: Factor 8/9 enzyme deficiencies
- G6PD Deficiency: Enzyme deficiency
- CGD: Enzyme to break down bacterial cells in neutrophil is defective
- Duchenne Muscular Dystrophy
- Nephrogenic Diabetes Insipidus: Enzyme deficiency
- Retinitis Pigmentosa: Enzyme deficiency
- Androgen Insensitivity (Testicular Feminization): Enzyme defective
- Wiskott Aldrich Syndrome
When will you see a phenotypic female, but genetic male and what is the inheritance pattern of this disorder?
Androgen insensitivity (X-linked recessive)
Mom is known carrier of an X-linked recessive disorder…chances of affected male, female carrier, affected children?
Males: 50% affected, 50% not affected
Females: 50% carriers, 50% not carriers
Children: 25% carriers, 25% disease, 50% normal
For X-linked dominant disorder, Dad has gene on his X chromosome, which kids have disease?
- Only has affected X to give to daughters…all daughters will have disorder
- Only has Y to give to sons…none of his sons will have disorder
For X-linked dominant disorder, Mom has gene on one of her X chromosomes, which kids affected?
50% of her kids will have it and 50% won’t
Are there carriers for an X-linked dominant disease?
No
Which other inheritance pattern is the same as X-linked dominant?
Autosomal dominant…makes it very difficult to distinguish
How are mitochondrial disorders transmitted?
Exclusively through mothers
*Mother and mitochondria both start with an M
Which disorders have no male to male transmission?
X-linked disorders (recessive or dominant)
Name 4 X-linked dominant conditions to consider (remember, not too many of them and they will most likely not ask you to pick this up from question)
- X-linked hypophosphatemic rickets
- Pseudohyperparathyroidism
- Aicardi syndrome
- Alport syndrome
What is the only way a disease can be transmitted from father to son?
Autosomal dominant inheritance
What are 3 characteristics of autosomal dominant disorders?
- Variable expressivity
- Possible reduced penetrance
- High risk for spontaneous mutation with no prior family history
What is the mneumonic for 8 of the autosomal dominant diseases?
TAR MAN
Tuberous Sclerosis
Achondroplasia
Retinoblastoma
Marfan Syndrome
Apert, All porphyrias (occasionally Alport syndrome)
Nail Patella Syndrome, Neurofibromatosis
*Neurofibromatosis can have variable expressivity with a high spontaneous mutation rate
What 2 things are autosomal dominant disorders associated with?
- Variable penetrance
2. Variable expressivity
What is variable penetrance?
When there is variability of whether people with the gene for a given trait actually exhibit it
When can chorionic villus sampling be done?
12 weeks
What is variable expressivity?
Range of signs and symptoms that can occur in different people with the same genetic condition…basically a mixed bag of features can be seen in people with a given syndrome with wide variable expressivity.
What rules out an autosomal recessive disorder?
Vertical transmission through 3 generations
Mneumonic for common autosomal recessive conditions?
Receding because you go to get gas from a guy wearing a hat, but he gives you a wak on the hand with a pickax... Galactosemia Alpha 1-Antitrypsin Deficiency Sickle cell and Thalassemia Hurler syndrome Ataxia Telangiectasia Tay Sachs Disease Wilson Disease Adrenogenital Syndrome (and Alpers Syndrome) Kartagener Syndrome PKU
In an autosomal recessive condition, what percent of unaffected offspring are carriers?
2/3
What is genetic anticipation?
Altered gene is passed down from one generation to next…disorder may begin earlier in life and signs and symptoms become more severe in subsequent generations…in some cases, this happens because there is an increase in the length of the unstable region in the gene
Ex: Myotonic dystrophy
Webbed neck, delayed secondary sexual characteristics, left sided congenital heart defects (bicuspid aortic valve, coarctation of aorta), short 4/5th metacarpal bones, widely spaced nipples, lymphedema of hands and feet
Turner syndrome (Primary Gonadal Dysgenesis)
Is Turner Syndrome associated with advanced maternal age?
No (since it isn’t a trisomy)
What are some features of Turner Syndrome in an adolescent?
Short stature, minimal/no breast development, primary amenorrhea, wide carrying angle of elbows, chronic otitis media, hyperconvex nails, low hairline, small mandible, high arched palate, low set ears
What causes Turner Syndrome?
Full or partial X chromosome deletion (in addition to phenotypical features outlined above)
Can a male get Turner Syndrome?
No, Turner Syndrome can only be diagnosed in a female
What is the most common chromosomal defect discovered in spontaneous abortions, and what is the most common form?
Turner Syndrome, 45XO
What is necessary for definitive diagnosis of Turner Syndrome?
Karyotype…buccal smear is not correct
If you think someone has Turner Syndrome and the initial chromosome analysis is normal, what should you do?
Use a FISH study to look for mosaicism (remember, elevated FSH can also be a feature of Turner Syndrome)
What has been used to treat short stature in Turner Syndrome?
Growth Hormone
What used to be known as “Male Turner Syndrome”?
Noonan Syndrome
Who can get Noonan Syndrome?
Males and females
4 classic features of Noonan?
Pertussis excavatum
Webbed neck
Low set ears
Pulmonic stenosis
*Envision a moon man pulling a web neck and grabbing the moon and placing it on his chest, snugly on the pectus excavatum. The moon changes tide on his chest and pulls down the ears, and also exerts pressure on the heart, resulting in pul”moonic” stenosis
What is the karyotype in Noonan?
Normal…no identifiable genetic patterns, although genetics do play a role
Describe eye issues with Noonan Syndrome
Hypertelorism, downslanting, vivid blue or blue-green irides, epicanthal folds, thick/droopy lids, strabismus/amblyopia
What are the two cardiac defects with Noonan Syndrome?
Pulmonary valve stenosis (number 1) and hypertrophic cardiomyopathy
Deeply grooved philtrum, short and webbed neck, low posterior hairline, unusually-shaped chest with superior pectus carinatum and inferior excavatum, developmental delay or MR of variable degree, joint laxity, cryptorchidism, coarse/curly hair, short stature, inverted triangular facies, low set ears, posteriorly rotated ears, fleshy helices on ears, high frequency SNHL, variable coagulation defects, male: female is 1:1
Noonan Syndrome
What is the inheritance of Marfan syndrome?
Usually autosomal dominant (15% of cases are a new mutation)
*There can be great variation of the morphology among affected family members
Connective tissue disorder associated with skeletal, cardiac, and ophthalmologic manifestations.
Marfan Syndrome
Where is the mutation in Marfan?
Chromosome 15 (fibrillin gene)
What are the skeletal abnormalities with Marfan!
Tall stature, high arched palate, dental crowding, hyperextensible joints, pectus abnormalities, arachnodactyly, disproportionately long extremities compared to the trunk
Is mitral valve prolapse one of the amour criteria?
No
What murmurs will you see with Marfan Syndrome?
Aortic or mitral valve regurgitation
Tall teenager presenting with a spontaneous pneumothorax…?
Marfan Syndrome
What are patients with Marfan syndrome at risk for that can lead to death?
Sudden death associated with aortic rupture…close cardiac followup is important (referral of other family members for genetic testing would be appropriate)
What are the 5 major criteria for diagnosing Marfan?
- Dilatation or dissection of the ascending aorta/aortic root
- Lumbosacral dural ectasia
- Ectopia lentis
- Four skeletal manifestations
- Family or genetic history
How do you tell apart Marfan and Homocystinuria?
The body type is similar for both…but in homocystinuria the lens is usually displaced downwards (Marfan the lens is displaced up)
What 2 things is homocystinuria associated with?
Mental retardation and thrombosis
What is wrong with the eyes in Marfan?
Ectopia lentis (upward and temporal displacement of the lens of the eye)
What type of exams are important for Marfans (for the eyes)?
Serial slit lamp evaluations
What are the only genetic disorders that increase with advancing maternal age?
Trisomies (incidence of all trisomies increases with advancing maternal age)
From what 2 things can trisomy 21 arise?
- Nondisjunction
- Translocation
*No phenotypic differences between the two, but genetic implications quite different
In which cause of trisomy 21 are chromosomal studies of the parents crucial?
Translocation
If you find a carrier parent with a full translocation for trisomy 21, what is the chance of Down syndrome reoccurring?
100% chance (but this is extremely rare)
With a partial translocation for trisomy 21, what is the % chance for Downs recurring and which side carries a higher risk?
Close to 15%…if partial translocation is from Mom, chances of recurrence are higher than if from Dad
What is the risk for recurrence of Downs with nondisjunction?
Risk for recurrence equals overall risk for general population (1%) plus Mom age related risk
What is the age related risk for trisomy 21 with mom at age 22? At age 40?
22: 1/1500
40: 1/90
What is the only truly useful test for detecting conditions of a missing or extra chromosome? (Turner or Downs)
Karyotyping
What chromosomal abnormalities will karyotyping miss?
Small changes in a chromosome
What is the gold standard genetic test for detecting small losses or gains in chromosomes?
Array comparative genomic hybridization (array CGH)
What test is widely used in evaluation of intellectual disability or congenital malformations?
Array comparative genomic hybridization (array CGH)
What do people with balanced translocation look like, and what are their offspring like?
Appear normal, often have offspring with a genetic condition
What do people with unbalanced translocations look like and what do their offspring look like?
Have a genetic condition, always have offspring with a genetic condition
Which age group gives birth to more infants with Down Syndrome?
Mothers in their 20s (more women in their twenties have kids, period)
Which age group is at a greater risk for having a child with Down syndrome?
Women in their 40s are at a greater risk for having babies with Down Syndrome
What is the most common abnormality seen in Down syndrome and what 2 things does this play a role in with the condition?
Hypotonia (seen in 80% of cases)… May play a role in feeding difficulties and constipation
Features of trisomy 21 (most can be identified in newborn period)..
Down Syndrome
Dysplasia of the middle phalanx of the 5th finger
Ouch! Cardiac disease
Wide gap between the 1st and 2nd toe
Neck has excess skin in the back
Spots (Brushfield spots in the eye) Y protruding tongue Nice simian crease (can occur in general population) Duodenal atresia (Hirshsprung disease) Really extensible joints Oncology/leukemia risk Moro reflex is incomplete Ears are small and anomalous
What bone do kids with Down syndrome sometimes have missing?
12th rib (12 is 21 backwards…21 chromosome in place of 12 rib)
What can be wrong with EKG for Down syndrome kids and what causes this?
Axis…AV canal (endocardial cushion defect) throws off axis…might refer to it as “NW axis”
Kids with Down syndrome are at increased risk for what 3 things?
- Leukemia
- Duodenal atresia
- Cardiac disease (AV canal/endocardial cushion defect)
What should you be concerned about when doing a sports physical on a patient with Down syndrome who wants to participate in Special Olympics?
Atlantoaxial instability (kids with Down syndrome at particular risk for this)
Features of trisomy 18 (Edward syndrome)?
Clenched fist, rocker bottom feet, hypoplastic nails, prominent occipital, low set ears, horseshoe kidney, overlapping of the index finger over the 3rd, 4th, or 5th digits
*Picture an 18 year old at a rock concert. He has clenched fists and rocker bottom feet. His fists have been clenched for days so he has hypoplastic nails. He’s been drinking a lot and rocking back and forth and banging his head on the wall. He gets a prominent occiput and low set ears. He’s too busy to go to the bathroom so his kidneys get bent out of shape into horseshoes.
Which genetic disorder gets punched out scalp lesions?
Trisomy 13 (Patau Syndrome)
Features of trisomy 13?
Number 13 is “bad luck”
Brain: Holoprosencephaly, Microcephaly, mid scalp lesions
Airs: Low set ears
Digits: Polydactyly (extra digits)
Leukocytes: Unique nuclear projections in the neutrophils
Uterus: Bicornuate uterus and hypoplastic ovaries
Cleft Lip and Palate: Bilateral
Kidneys: Cystic
Teen who is infertile with small testes, but otherwise normal. Socially awkward with normal intelligence.
Klinefelter syndrome
3 buzz words for Klinefelter syndrome?
- Delayed speech
- Poor self image
- Mild motor delay
Chromosomal issue with Klinefelter syndrome?
47 XXY
Why is genetic testing indicated after the birth of any child with a trisomy?
Because the birth of any trisomy increases the risk of having another child with other anomalies
What are the only 3 trisomies that make it to term?
13, 18, 21
Do trisomies with lower or higher numbers cause more problems?
Lower numbers…since chromosomes with lower numbers are larger than those with higher numbers, the consequences of these trisomies increase as their numbers decrease
*Means that trisomy 21 isn’t as bad as trisomy 18 which isn’t as bad as trisomy 13
Kid with delayed motor and language development, tall, arms and legs longer than expected for height, 4 cafe-au-lait spots between 4-5mm each, loner, calm demeanor…next most appropriate diagnostic step?
Chromosome analysis…history most consistent with Klinefelter syndrome
*Don’t be fooled with neurofibromatosis because of cafe-au-lait spots. 6 or more measuring at least 5mm is consistent with neurofibromatosis. Don’t let long arms and legs make you think Marfan
What are weight, head circumference, and height for Klinefelter syndrome?
Weight and head circumference should be normal. Height can be well above average.
What is the problem with the testicles I’m Klinefelter?
They are small…the German word for small is Klein
What is one treatment option for Klinefelter?
Testosterone supplementation
What happens when chromosomal regions with similar (95-99%) sequences cause misalignment of homologous chromosomes, leading to either deletions or duplications of those similar regions?
Contiguous gene malformations
How are common contiguous gene deletions and duplications best diagnosed?
Fluorescence in situ hybridization (FISH)
You MUST specify the suspected diagnosis
Neonatal hypotonia, failure to thrive as infant, voracious appetite starting about 2-3, obesity, intellectual disability, small testicles, small hands and feet?
Prader-Willi Syndrome
What causes much of the morbidity and mortality in kids with Prader-Willi syndrome?
Complications of obesity…diabetes, sleep apnea, slipped capital femoral epiphysis
How does pseudo hypogonadism present and what is the tip off?
Genitalia are normal sized, but the body is big in comparison…tip off could be significant gynecomastia
When are kids with Angelman syndrome usually diagnosed?
Between 3 and 7
Severe developmental delay, profound speech impairment, ataxia and other movement disorders, behavioral anomalies (frequent laughter, easy excitability, short attention span), acquired microcephaly, seizures
Angelman syndrome
Why are kids with Angelman syndrome called happy puppets?
Combination of laughing and abnormal jerky movements
What type of gene malformation is neurofibromatosis 1?
Contiguous gene malformation
What 2 syndromes represent the gene error 15q11-13
Prader-Willi and Angelman
If you have 2 copies of 15q11-13 from mom (Dad’s section is absent) what syndrome do you have?
Prader-Willi
If you have 2 copies of 15q11-13 from dad (Mom’s copy is missing), what syndrome do you have?
Angelman syndrome
What is it when the ability of a gene to be expressed depends upon the sex of the parent who passed on the gene?
Genomic imprinting
Name 7 important features of Beckwith Wiedemann syndrome?
Hypospadias, hypoglycemia, hemihypertrophy, macroglossia, macrosomia, omphalocele
Elfin facies, wide spaced teeth, upturned nose, mild intellectual disability, cocktail party personality (very friendly)
Williams syndrome (think of Robin Williams)
What electrolyte abnormality do you see in kids with Williams syndrome?
Hypercalcemia
What valve issue do kids with Williams syndrome get?
Supravalvular aortic stenosis
What is another name for 22q11 Deletion Syndrome or Velocardiofacial Syndrome?
DiGeorge Syndrome
Hypoplasia of what structures causes the problems in DiGeorge Syndrome?
Thymic and hypoparathyroid hypoplasia
Hypocalcemia, immune deficiencies, conotruncal cardiac defects (like tetralogy of fallot)
DiGeorge Syndrome
(Thymic and hypoparathyroid hypoplasia cause hypocalcemia and immune deficiencies)
(Mutation is highly correlated with conotruncal cardiac defects…like ToF)
Fetal alcohol syndrome can be diagnosed with or without confirmed maternal alcohol exposure if what 3 criteria are present?
- Characteristic facies
- Deficient brain growth
- Prenatal and/or postnatal growth retardation
FAS = Facies, Abnormal brain, Small
Describe the characteristic facies with fetal alcohol syndrome.
Flat philtrum (thing in middle of upper lip), thin vermillion border of the upper lip, midface hypoplasia, short palpebral fissures
*Picture a child drinking alcohol…from having the bottle in his mouth so often, it forms a mark on the middle of his face (midface hypoplasia) and thins out his upper lip and philtrum
What is the most common preventable cause of intellectual disability?
Fetal alcohol syndrome
*In addition to intellectual disability, kids with FAS can also have behavioral and psychiatric disorders…even in absence of intellectual disability
What are the 2 most common identifiable genetic causes of intellectual disability?
Fragile X syndrome and Down syndrome (these 2 are not preventable)
What are some things maternal smoking results in?
Low birthweight infants, higher miscarriage rates, placental abruption, placental previa, IUGR, prematurity, cleft lip/palate
What is associated with asthma, wheezing, and other respiratory ailments?
Smoking during pregnancy…independent of maternal smoking after delivery
What issue with Mom is associated with SIDS?
Maternal smoking
What abnormal neurobehavior can result from smoking during pregnancy?
Deficits in mental development, language deficits, ADHD, and lower IQ (this can extend into childhood)
Exposure to anticonvulsants is associated with increased risk for what?
Microcephaly, intrauterine growth retardation, anticonvulsant face (broad bridge of nose, small anteverted nostrils, long upper lip), fingernail hypoplasia, cardiac defects, cleft lip, hypospadias with cryptorchidism, clubfoot deformity
Valproic acid exposure leads to deformities of what?
Face
What issues does carbamazepine cause?
Spinal problems and facial deformities (change name to car-bam and picture an auto accident resulting in spinal problems and facial deformities)
Phenytoin results in a specific profile that includes what?
Finger stiffness and severe nail hypoplasia
Cardiac, skeletal, and ophthalmological anomalies may occur
What 2 anticonvulsants can result in neural tube defects?
Carbamazepine and Valproic acid
What supplementation prior to conception can decrease the incidence of neural tube defects by more than 50%?
Folic acid
Which started out bad v. started out well but met a roadblock and now is bad?
Malformation started out bad
Deformation started out well, but met a roadblock and now is bad
What is the clustering of anomalies that can’t be explained by chance?
Association (Examples: CHARGE and VACTER-L)
What is the result of a localized abnormality early in fetal development?
Sequence…
Example would be Potter Syndrome (Oligohydramnios Sequence)…effects all stem from olihohydramnios
Pierre Robin sequence is another example
What is the CHARGE association?
Coloboma/cognitive deficits Heart disease Atresia (choanal) Retarded growth and development GU abnormalities (genital hypoplasia) Ear anomalies (hearing loss)
What is the intelligence level in CHARGE syndrome?
Below normal…think of it as since they are mentally challenged, someone else has to be in CHARGE of them
What is the VACTER-L syndrome?
Vertebral defects Anal atresia Cardiac defects/VSD TE fistula Radial hypoplasia and Renal abnormalities
Limb abnormalities
VACTER-L may be part of what deletion syndrome?
22q11
What association often presents with a single umbilical artery?
VACTER-L
What is the intelligence with VACTER-L association?
Normal
What is the deformation of the skull due to premature fusion of one or more of the sutures?
Craniosynostosis
When does craniosynostosis have to be recognized by?
Before 5 months of age…treatment is more successful when done prior to the period of greatest head growth…craniosynostosis can be easily corrected
What neurological complications are more likely to occur when 2 or more sutures close prematurely?
Hydrocephalus or increased intracranial pressure
What might be confused with craniosynostosis, but has a head CT with normal sutures?
Positional plagiocephaly
What might look abnormal, but is harmless and will improve over time once babies don’t spend so much time lying flat on their backs?
Positional plagiocephaly
What is used to treat positional plagiocephaly?
Just time once baby isn’t on back so much
Can use helmets, but this isn’t the right answer for boards
What causes a small symmetrical head (with respect to suture closure)?
Closure of cranial sutures secondary to slow brain growth
What would present with an asymmetrically shaped head (with respect to suture closure)?
Premature closure of a single cranial suture
What causes a parallelogram head shape (ipsilateral frontal bossing)?
Positional plagiocephaly
What causes a trapezoidal head shape (contralateral frontal bossing)?
Unilateral lamdoid synostosis
What causes dolichocephaly/scaphocephaly (long skinny egg-shaped head)?
Saggital synostosis
What causes brachycephaly (short wide head)?
Bilateral coronal synostosis
What causes trigonocephaly (triangle head)?
Metopic synostosis
What causes cloverleaf skull?
Multiple suture synostosis
What is the cause of olihohydramnios sequence (Potter syndrome)?
Renal agenesis
What is the appearance of an infant with Potter syndrome due to?
Consequences of olihohydramnios
Name the 4 primary features of Potter syndrome
- Typical facies described as “pugilistic”
- Hypoplastic lungs
- Limb malformations (club feet)
- Renal agenesis
Which condition will you see “glove-like” excess skin on the hands and have fetal membranes covered by yellowish nodules (amnion nodosum)?
Potter Syndrome (oligohydramnios sequence)
Genitourinary anomalies are an important part of the workup for which sequence/syndrome?
Potter syndrome
Kids with Potter syndrome ultimately die of what?
Pulmonary complications
Broad thumb and cryptorchidism
Rubinstein-Taybi Syndrome (think Rubinstein Thumby)
*It is difficult to bring down an undescended testicle with a broad based thumb
Which syndrome has thumbs and great toes that are short and broad with eyes that are prominent and widely spaced?
Pfeiffer syndrome
Which syndrome has eyes that are prominent and widely spaced?
Crouzon syndrome
A kid who looks like a cross between Crouzon and Rubinstein-Taybi likely has what syndrome?
Pfeiffer syndrome
Triangle face (small chin) and growth retardation?
Russell Silver Syndrome (these kids are very small)
*Picture a small (growth retarded) wrestler with a triangle face made of silver
What leads to the prune belly appearance in Prune Belly Syndrome?
Lack of abdominal muscle development
What is the pathophysiology of prune belly syndrome?
Starts with bladder outlet obstruction, which leads to oligohydramnios. This results in pulmonary hypoplasia. The testes are also undescended.
Conductive hearing loss, small jaw, ear abnormalities, lower eyelid abnormalities, no intellectual disability
Treacher Collins
*You can’t be a “treacher” with abnormal intelligence
How is Treacher Collins inherited?
Dominant trait…picture a dominating teacher in class
This will occur in several family members (might show a family portrait in which several family members have same dysmorphic features)
One or more family members with a hearing aid could be the tip off to what condition?
Treacher Collins
What movie character do people with achondroplasia look like?
Munchkins from Wizard of Oz
Large heads, very short extremities, rhizomelic shortening, frontal bossing, genu varum (bowlegs), lumbar lordosis (puffed out chest), small foramen magna (can cause nerve root compression), respiratory problems (sleep apnea)
Achondroplasia
What is known as short-limbed dwarfism, especially of the proximal portion of the limb?
Achondroplasia
What is rhizomelic shortening?
Shortening of the proximal portion of the limb
What % of kids with achondroplasia have significant sleep apnea?
Over 3/4 of kids (there are frequent respiratory problems)
What does syndactyly refer to?
The union of two or more fingers or toes…typically only involves a skin connection between the two, but can include fusion of bones
What is permanent deviation of one or more fingers, usually the 5th finger (pinky)?
Clinodactyly
What is the inheritance of achondroplasia?
Autosomal dominant
*Like all autosomal dominant conditions, it has a high rate of spontaneous mutation…this means a child can have it, even when the parents do not
What is the intelligence in achondroplasia?
Normal
Macrocephaly, frontal bossing, midface hypoplasia, proximal shortening of the limbs…condition, inheritance pattern, and most likely cause of sudden death in this infant?
Achondroplasia, autosomal dominant, however > 80% of cases occur as a spontaneous mutation, most common cause of sudden death is cervicomedullary junction compression
*Don’t believe respiratory and cardiac failure as associations and thus cause of sudden death
Male, mild intellectual disability, positive family history of uncles and other males affected, long narrow face, prominent forehead, protruding ears, high-arched palate, strabismus, hyperflexible joints, weird behavior, macroorchidism
Fragile X Syndrome (think of Prince Charles)
What is the chromosome issue in Fragile X Syndrome?
Repeat of CGG trinucleotide
What is the most common known genetic cause of inherited intellectual disability?
Fragile X
What is the overall second most common cause of genetic intellectual disability, after Down Syndrome?
Fragile X
What is the most common known single-gene cause of autism spectrum disorder?
Fragile X
Which syndrome is genetic, but rarely inherited?
Down syndrome
Can a female get Fragile X syndrome?
Fragile X typically presents in boys, but it can manifest in females (unlikely, but worth considering)
For a kid with intellectual disability who you think might have Fragile X, what type of testing…karyotype or DNA testing?
DNA testing…much more sensitive in diagnosing Fragile X (technically asking for Fragile X Mental Retardation, FMR 1, DNA testing)
Girl around 1-2 who has lost developmental milestones, autistic-like behavior, wringing hands, regression of developmental milestones?
Rett Syndrome
*Picture Rhett Butler (Clark Gable) from Gone with the Wind. Picture him walking backwards, wringing his hands, saying “Frankly my dear, I don’t give a damn, which is why I am backing out of the deal.”
What is the progression of Rett Syndrome?
Girls have normal development at first, but around 4 months of age their head growth decelerates. Then enter period where they don’t continue development (stagnation…usually from 6-18 months), followed by a loss of their milestones (regression…usually from 1-4 years). After this, there is usually no further decline. These children usually survive into adulthood, although they may not gain/regain purposeful hand use or functional speech.
Small chins relative to their tongues, cleft palate, micrognathia, posterior positioning of their tongues, glossoptosis, extremity anomalies (syndactyly, clinodactyly, hip and knee anomalies), spinal deformities (kyphosis and scoliosis), CNS involvement (language delay, seizure, developmental delay)
Pierre Robin Sequence
*Margaret Thatcher…picture her singing like a robin
Why do kids with Pierre Robin sequence have glossoptosis?
Because their tongue is relatively large compared to their small chin…not because they have big tongues…this is an important distinction.
What can lead to cor pulmonale in Pierre Robin Sequence?
Upper airway obstruction caused by glossoptosis
