Genetics Flashcards
Risk for Trisomy 21 with Robertsonian Translocation 14:21
Higher risk if inherited from an infant’s mother 10% to 15%, but only 1% to 2% if inherited from the father.
NOT affected by maternal age. That one is T21 resulting from meiotic nondisjunction
Maple Syrup Disease
- well for the first 1 to 2 days after birth, and then experience a rapid progression to an encephalopathic state.
Symptoms typically start with ketonuria, a maple syrup odor, poor feeding, and opisthotonus.
Neonates with classic MSUD will have elevated plasma concentrations of branched-chain amino acids (isoleucine, leucine, and valine) and alloleucine on plasma amino acid analysis.
Miscellaneous descriptions
Biotinidase levels screen for biotinidase deficiency. This disorder presents in young children with the slow evolution of neurologic abnormalities, including seizures, hypotonia, ataxia, developmental delays, vision problems, hearing loss, alopecia, and a skin rash.
Ceruloplasmin levels, in conjunction with copper levels, screen for Menkes disease. This disorder presents with a period of normal development in early infancy, followed by developmental regression, coarse, kinky hair (pili torti), and tortuosity of the carotid arteries and vasculature of the brain.
Mucopolysaccharidoses are identified through lysosomal enzyme screening and urine glycosaminoglycans. These disorders typically present with a slowly progressive coarsening of facial features, joint stiffness, and developmental regression.
Very-long-chain fatty acids screen for peroxisomal disorders, which present with a slow progression of hypotonia, poor feeding, dysmorphic facies, seizures, hepatic dysfunction, retinal dystrophy, and sensorineural hearing loss.
Prader-Willi Syndrome
Hypotonia, Hypogonadism, and poor feeding with FTT in infancy. Facial dysmorphology (bitemporal narrowing, thin upper lip, almond shaped eyes, hypogonadism and cryptorchidism)
Feeding pattern then transitions to excessive eating. Mild-moderate disability Short stature Behavioral difficulties Skin-picking behavior
Imprinted gene on CHR 15 - lacks paternal contributed region, inherited both from mom.
Fragile X
- X-linked autosomal dominant - loss of fxn mutation in FMR1 due to trinucleotide repeats (>200)
- Boys: mod-severe intellectual disability
- Girls: normal, mild ID, learning d/o
- 25% autism
- Facies: long face, protruding ears, prominent forehead, macrocephaly, large testes
Carriers: 55-200 repeats
- Males: tremor/ataxia syndrome
- Females: premature ovarian failure
X-linked dominant disorders can affect both males and females, but males are affected to a much greater degree because they have only one X chromosome. Affected men will pass the abnormal X to all of their daughters and none of their sons. Affected women will pass the affected X to 50% of their offspring of either sex.
Dx: FMR1 molecular analysis
All intellectually disabled pts should have chromosomal microarray and fragile X testing
Rett syndrome
GIRLS only
normal early growth/dev then microcephaly and DECLINE in dev skills, loss of purposeful hand movements, classic hand wringing, acquired microcephalus, and intellectual disability
abnormal regulation of autonomic nervous system leading to
- increased risk of sudden death from prolonged QT
- altered respirations and periods of apnea/hypo and hyperventilation
MECP2 molecular analysis - mutation of this gene on X chromosome
PKU
elevated serum phenylalanine levels
mousy body odor, developmental regression, light skin/hair, eczema, seizures, intellectual disability
What finding in neonate requires referral to genetist?
Congenital deafness
Congenital deafness as an isolated clinical finding warrants referral to a geneticist because up to 60% of cases` of congenital and early-onset hearing loss are caused by genetic factors.
Trisomy 18
Clenched fist with overriding fingers
Rocker bottom feet
Facial - micrognathia, ear anomalies, short palpebral fissures, small face
Hypotonia
Growth deficiency
Kidney anomalies - horseshoe kidneys
Cardiac anomalies
90% die within first month after birth.
Friedreich Ataxia
AR disorder with GAA repeat expansion
Frataxin gene on Chr 9
birth and early developmental milestones are normal
then gait and limb ataxia in childhood
areflexia, LE weakness, dysarthria, dysphagia
abnormal saccades of eyes
Medium Chain Acyl-Coenzyme A Dehydrogenase Deficiency
Elevated C8 with lesser elevations of C6 and C10 acylcarnitine
This enzyme is missing so you can’t oxidize medium and short chain fatty acids into glucose or ketones and there is reduced ureagenesis leading to hyperammonemia
Normal at birth.
3-24 months of age - episodes of hypoketotic hypoglycemia, vomiting, lethargy, usually triggered by minor illness
Liver dysfxn, Seizure, Coma, Death
Chart of lab abnormalities and met disorders
file:///Users/vicky/Downloads/C249.pdf
Hemihypertrophy is associated with what cancers?
Beckwith-Wiedemann
- macroglossia, global macrosomia, hemihypertrophy
- hepatoblastoma - AFP levels q3mo until 4 yrs
- nephroblastoma (Wilms) - ABd US q4 mo until 7-8
NOT associated with neuroblastoma
Proprionic Acidemia
Presents in neonates, with a brief symptom free period that progresses to feeding problems, vomiting, seizures, coma, and eventually death
Labs:
- metabolic acidosis with a high anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias.
- elevated C3 (propionylcarnitine)
- urine organic acids: elevated 3-hydroxypropionate level and the presence of methylcitrate, tiglylglycine, and priopionylglycine
How to work up inborn error of metabolism
When a physician suspects an IEM, a basic metabolic workup should be undertaken, which typically includes:
A serum analysis for: Acylcarnitine panel Amino acids Ammonia Blood glucose Carnitine profile Electrolytes Lactate Pyruvate
Urinalysis for:
organic acids
ketones
It is very important to test for ketonuria because the absence or presence of ketonuria clues the diagnosis of the various types of metabolic disorders. Results can be obtained in an expedient manner, allowing for appropriate interventions to be initiated quickly. Genetic sequencing is appropriate, but the results would not be back in time to make life-saving decisions.
DiGeorge Syndrome -> hypoca -> what EKG changes
Prolonged QTc or ST intervals
Dilated Ao root is associated with what
Marfan’s
Alagille Syndrome
Autosomal Dominant = 20p12
Presents within first 4-6 months of life
Cholestatic jaundice, HSM, Pruritis (due to elevated bile acids)
Biopsy: Paucity of intrahepatic bile ducts
Elevated cholesterol, TAG, phospholipids.
ADEK deficiency
Prolonged PT and PTT time
Skeletal: Butterfly vertebrae, abnormalities of ribs/hands, shortening of ulna/radius/phalanges
CV: Pulm atresia, PPS, PDA
Increased risk of HCC as they age
Caffey Disease
Infantile Cortical Hyperostosis Proliferating bone disease - affects infants - irritability, fever, soft tissue swelling (without signs of infection) bc there is underlying cortical hyperostosis/thickening of the bone - MANDIBLE is most often affected. - Labs: leukocytosis, ESR, alk phos high
Autosom Dom or Sporadic
Dilated Ao root is associated with what
Marfan’s
NF1
Sporadic or AD mutation of NF1 gene
2 of the 7 criteria
- cafe au lait 6 or more >5mm prepubertal, > 15mm post
- axillary or inguinal freckling
- neurofibromas
- lisch nodules (hamartomas in iris)
- optic gliomas
- sphenoid dysplasia
- unilateral anterolateral angulation (bowing) of the tibia leading to thinning of the cortex and pathologic fracture (long bone pseudoarthrosis)
- 1st degree relative with NF1
Assoc with learning disorders, ADHD, speech disorders.
- hyperintense areas in the basal ganglia and cerebellum thought to represent localized areas of demyelination
CHARGE
Autosomal Dominant = CHD7 gene
Coloboma of the retina Heart abnormalities Atresia of the choanae Retarded growth and mental development Genital abnormalities in males (micropenis, cryto) Ear abnormalities, including deafness.
Low intelligence
VACTERL
You only need THREE of the below:
Vertebral Anal Atresia Cardiac/VSD TE fistual Renal/Radial Limb
Normal intelligence
Marfan’s vs. Homocystinuria
Patients with Marfan syndrome have a normal IQ (IQ up) and have upwardly displaced lenses.
Patients with homocystinuria have intellectual disabilities (IQ down) and have downwardly displaced lenses.
X-linked disorder transmission
Whether recessive or dominant, there is NO MALE TO MALE TRANSMISSION.
What is the only inheritance pattern that allows father to son transmission?
Autosomal Dominant!
Other features
- both sexes equally affected
- both sexes transmit to offspring
- present in all generations
- every child has an affected parent
Cornelia de Lange
Facial features + Hirsuitism
Limbs - hypoplastic with contractures
Cognitive impairment
FTT
Genital anomalies include cryptorchidism and hypospadias in males and small labia majora and bicornuate uterus in females.
Cardiac, gastrointestinal, ophthalmologic, and renal anomalies may also occur.
NF2
Autosomal Dominant - NF2 gene (22q1.11)
Bilateral vestibular schwannomas
Unilateral vestibular schwannoma + 2 of the following: meningioma, schwannoma, neurofibroma, glioma,
posterior subcapsular lens opacity -> cataract
hearing loss, visual disturbances, tinnitus, cranial nerve abnormalities, gait disturbances, and/or headache.
What tests are recommended as first line to eval developmental delay and intellectual disability of unknown etiology?
Fragile X testing and Microarray!
Microarray can gross chr deletions/duplications as well as MICROdeletions and duplications (unlike karyotype)
NOT
Karyotype = detects sex chr disorders, trisomies, chr rearrangements, gross deletions and duplications
FISH = specific chr aberrations such as for T21, DiGeorge, Cri Du Chat
Neural Tube Inheritance Risk
General population < 1%
Recurrence risk for NTD in future preg with parents unaffected and
1 affected sibling = 5% **
If 2 affected siblings = 10-12%
Folic acid 400-800 1 month prior and 3 months into.
4000 if had a child with a NTD
47 XYY syndrome and 47 XXX syndrome
Both have NORMAL intelligence…
and sexual development and fertility
- taller than normal
- speech and language delay, learning disability
- no facial dysmorphologies
Occurs due to random cell division error during sperm cell formation.
Trisomy 13
Trisomy 13 is typically diagnosed based on physical examination findings noted at birth; laboratory confirmation is via karyotype or fluorescent in situ hybridization analysis for trisomies.
Trisomy 13 syndrome features include microcephaly, microphthalmia, low-set ears, CLEFT LIP and/or palate, HOLOPROSENCEPHALY, CUTIS APLASIA, POLYDACTYLY, clenched hands, rocker bottom feet, cryptorchidism, renal anomalies (cystic kidneys), and cardiac malformations.ALso with bicornate uterus and hypoplastic ovaries.
Most infants with trisomy 13 die in the first year after birth because of complex congenital malformations. Surviving infants will have severe intellectual disability.
CAPS = different from T18
Noonan is associated with…
Bleeding diatheses - most frequently Factor 11 deficiency!
Excessive bruising; recurrent epistaxis; prolonged bleeding following injury, childbirth, or surgery; and menorrhagia are common complaints.
Other features include short stature, congenital heart defects (most commonly, pulmonary valve stenosis), pectus excavatum, webbed neck, low-set ears, hypertelorism, and lymphedema.
Next step when you suspect autism.
Referral for IEP!!
Not administering a screening test bc obviously they would screen positive already -.-
Intellectual disability
Most likely to be due to Fragile X unless they state other symptoms for other syndromes.
In young boys, the classic dysmorphic features are subtle.
Will often see ASD behaviors in fragile X.
Apert Syndrome
Mitten-Hand Deformity Craniosynostosis Maxillary Hypoplasia and dysmorphic facies Low IQ Cardiac/Renal
Mowat-Wilson Syndrome
Deletions in chromosome 2
Associated with Hirschsprung disease
Intellectual disability
Dysmorphic facies
CHD and GU abnl
Marfan’s - Criteria
GHENT criteria
2 of any major criteria
- ectopia lentis (anterior)
- aortic dilation or dissection
- family history
Tuberous Sclerosis
Auto Dom
CNS: Seizures esp infantile spasms; intellectual disability; dev delay. Intracranial hamartomas
Skin: Ash-leaf spots, facial angiofibromas, shagreen patches, periungual and ungual fibromas
Cardiac: rhabdomyosarcomas
Renal: hamartomas, angiolipomas and cortical tubers
Liver: hamartomas and cortical tubers
Waardenburg Syndrome
Mutation in PAX3 gene on chromosome 2
Sensorineural hearing loss Heterochromia Hair hypopigmentation (white forelock) Displacement of medial canthi *Cutaneous depigmentation (patterned areas of depigmentation with sharply defined, irregular borders and scattered 'patchy" hyperpigmented macules
Klippel-Feil anomaly
segmentation defect of the cervical vertebrae.
The most common defect is fusion of C2–C3
Sturge Weber
Anomalous vascular development during early cerebral vascularization
- dilation of ipsi ventricle, calcification, cerebral atrophy
- port-wine stain (upper face/eyelid)
- focal seizures (side contral to port wine stain)
- intellectual disability
- glaucoma: increase intraocular pressure in eye ipsi to stain
Brushfield spots
Trisomy 21 (increased risk of celiac)
“whitish spots in a ringlike configuration at the surface of the iris”
“rings of iris hypoplasia with surrounding areas of normally pigmented iris stroma”
Can be found in 25% of normal kids, esp those with blue eyes
Treacher Collins
Midface and Mandibular Dysmorphology with Craniofacial defects
- hypoplasia
- choanal atresia
- cleft palate
- lower eyelids hypoplastic with NO EYELASHES
- outer and middle ear malformations (inner ear is okay) so conductive hearing loss and hearing aids are needed
What syndrome associated with cleft palate, micrognathia, glossoptosis, and airway obstruction?
This is the Pierre Robin Sequence
Associated with Stickler syndrome: which also has - eye sx - auditory - articular abnormalities
DiGeorge - CATCH 22
Angelman Syndrome
Genetic Imprinting caused by inactivation of maternal chromosomes of chr 15
- happy puppet - laughing, flapping hands, excited
- developmental delay
- seizure
- facial features - flat occiput, large tongue, wide mouth, wide spaced teeth.
Myotubular Myopathy
X-linked
Maturational arrest of fetal muscle
- Hypotonia, decreased muscle mass, diffuse weakness
- Feeding difficulties: difficulty sucking and swallowing due to generalized muscle weakness
- Resp distress
CK is normal; Muscle bx is diagnostic
intrautero: polyhydramnios due to difficulty swallowing amniotic fluid
Williams
Sporadic. Microdeletion 7q11.23
- Cocktail personality
- elfin facies
- learning disabilities, blow average IQ
- Supravalcular Ao Stenosis
- Idiopathic HyperCA of infancy
Arthrogryposis
Multiple joint contractures
Ehlers Danlos
Defects in collagen synthesis
Mitral valve prolapse
Joint hypermobility
Hyperelasticity of skin (doughy)
Tissue fragility: Easy bruisability and poor wound healing**
Holt Oram
Heart-Hand syndrome
Heart: ASD, VSD, heart block
Hand: radius, thumb, carpal bones
Omphalocele
Trisomy 13**
Trisomy 18
Beckwith-Wiedemann
VS. Gastroschisis usually not associated with congenital or chromosomal abnormalities.
Poland Sequence
unilateral absence or hypoplasia of the medial (sternal) portion of the pectoralis major muscle
ipsilateral anomalies include
- hypoplasia or absence of the breast, nipple, and subcutaneous fat
- a shortened upper extremity associated with syndactyly. -
- abnormalities of ribs, ulna, and/or radius are commonly identified on plain radiographs
