Genetic Syndromes Flashcards
Test for Angelman
15q11 methylation study
Kallmann syndrome
hypogonadotropic hypogonadism
anosmia
clef lip/palate or color blindness
These syndromes are associated with Pierre Robin Sequence
Stickler syndrome
22q11 deletion syndromes
Immune deficiency with delayed eruption of primary teeth
Job syndrome. Recurrent skin abscesses, pneumatoceles, elevated IgE, coarse facies, eczema, delayed eruption of primary teeth.
Bilateral acoustic neuromas are seen in
Neurofibromatosis type 2
Erlenmeyer flask deformity of femur
Gaucher disease
AR, lipid storage disease (glucocerebroside)
seizures, splenomegaly, bleeding disorder, anemia
bone pain, osteopenia
Inheritance pattern of PKU
autosomal recessive
MELAS
mitochondrial disorder
Myoclonic epilepsy
Lactic acidosis
Stroke-like episodes
Immune deficiency with partial albinism
Chediak-Higashi syndrome: recurrent sinupulmonary infections, peripheral neuropathy, giant granules on peripheral smear, partial oculocutaneous albinism
Congenital neutropenia syndromes:
Chediak-Higashi (albinism) Dyskeratosis congenita Severe congenital neutropenia Fanconi anemia Schwachman-Diamond syndrome (pancreatic insufficiency) Cartilage-hair hypoplasia Barth syndrome (cardiomyopathy)
Ectopia lentis, thromboses, marfanoid habitus
Homocystinuria (elevated methionine)
11p15
Beckwith-Wiedemann: hemihypertrophy, macroglossia, macrosomia
Down-syndrome-like facies, large forehead,
hepatomegaly
profound hypotonia
liver dysfunction
Zellweger syndrome (peroxisomal disease)
Mutation in long arm of 17
NF1
Disorder of copper uptake
Menke’s. X-linked. Full cheeks, sagging jowls/lips. Sparse hair/eyebrows with little pigmentation. Neurologic degeneration. Subdural hematomas and retinal hemorrhages not associated with trauma.
Achondroplasia inheritance pattern
autosomal dominant
or de novo mutation
If 2 parents with achondroplasia have a child, risk of having a kid with achondroplasia is 2/3 because AA is lethal.
Duplicated distal thumb is seen in this syndrome
Schwachman-Diamond syndrome (neutropenia, exocrine pancreatic insufficiency, skeletal anomalies)
Congenital intestinal anomaly associated with T21
Duodenal atresia
Kids with Beckwith-Wiedemann are at risk of these tumos
Wilms tumor - screen with complete abd US q3 months until age 7-8 yrs
Hepatoblastoma- Screen with AFP q3 months until age 4
(embryonal solid tumors)
Genetics of Incontinentia pigmenti
X-linked dominant (lethal in males)
1. inflammatory vesicles/bullae trunk/ext
(neonate)
2. irregular linear verruclous lesions on ext/hands/feet
3. swirly brown/blue pigmentation fade by adolescence
4. streaks of atrophy and hypopigmentation
PHACE Syndrome
- Posterior fossa defects
- Hemangiomas
- Arterial anomalies (usually brain)
- Cardiovascular
- Eye anomalies
Alagille Syndrome
– jaundice; FEW bile ducts, no gallbladder
– butterfly vertebrae
– heart murmur (PPS)
– hypertelorism
CONJUGATED hyperbili
Dx with liver biopsy (paucity of bile ducts)
Most common fatty acid oxidation disorder
MCAD deficiency
Medium chain acyl-coenzyme A dehydrogenase
Symptoms of Freidrich Ataxia
limb ataxia (childhood) Areflexia Weakness Saccadic eye movements Dysarthria Dysphagia
What is Sprengel deformity?
elevation and rotation of the scapula
Associated with Klippel-Feil (fusion of cervical vertebrae)
Which metabolic disorder can cause retinal hemorrhages and subdural hematoma/be mistaken for child abuse?
Glutaric acidemia type 1 (AR)
can have macrocephaly, frontal and cortical atrophy, increased extra-axial space; dystonia and hypotonia when sick
Sturge-Weber
vascular malformation on face- port wine stain V1 distribution - esp upper lid(can also involve V2/V3). Present at birth- does not change.
- seizures
- glaucoma (early ophtho eval)
What is Stickler syndrome?
affects connective tissue
- Pierre Robin Sequence
- VISION ISSUES (myopia, cataracts, retinal detachment, vitreous anomalies)
- hearing loss
- articular (early OA, hypermobility)
Patients with either of these genetic disorders are at increased risk of spontaneous pneumothorax
Marfan syndrome
Ehlers Danlos
Connective tissue disorders
What is myotonic dystrophy?
– adolescent onset
– delayed relaxation of muscle after contraction
– limb/facial weakness
– drooping face
– tapping thenar eminence -> dimpling
– GI dysmotility
NORMAL CK
When does Rett syndrome start to really show?
between age 1-4 loss of purposeful hand skills-- repeated hand wringing loss of language/social interaction gaze aversion Acquired microcephaly
Absence of radius
Dislocation of carpus
Rudimentary thumb
Holt-Oram syndrome
Syndrome with increased risk of hypercalcemia
Williams syndrome (friendly, abnormal facies, supravalvular aortic stenosis, stellate iris)
Leigh disease
mitochondrial disorder involving many complexes.
Necrotizing changes in BG and midbrain, hypotonia, FTT, loss of respiratory centers,
MCAD deficiency – labs
elevated C8 in plasma acylcarnitine profile
elevated urine acylglycines
hypoglycemia
This substance is elevated in the serum in Ataxia-Telangiectasia
Alpha fetoprotein
Genetic mutation associated with Rett syndrome
MECP2 mutation on X chromosome, usually spontaneous
Omphalocele commonly seen in which genetic sx
trisomy 13, Beckwith-Wiedemann, trisomy 18
What is the significance of transient myeloproliferative disorder in newborns with T21?
increased risk of leukemia later in life (10-30%)
What are early signs of Rett syndrome?
stage I - 6-18 months, very subtle
delays in gross motor, hypotonia, hand wringing
Inheritance pattern of myotonic dystrophy
Autosomal dominant
What is the defect in maple syrup urine disease?
catabolism of branched-chain amino acids (valine, leucine, isoleucine)
missing branched-crain keto acid decarboxylase enzyme
When does Friedrich ataxia present?
adolescence– progressive ataxia in all extremities, LE weakness, diminished DTRs
What is Klippel Trenaunay syndrome?
vascular disorder
port wine stains
overgrowth of bones and tissues
ONE LIMB
Fragile X
> 200 CGG repeats, loss of function of FMR1. X-linked autosomal dominant. Anticipation. Moderate ID in males. Females can have mild symptoms. dx - fragile X DNA molecular analysis
Lisch nodules
NF1.
Lisch nodules are hamartomas in the iris
Tuberous Sclerosis
-- seizures in 1st yr of life (infantile spasms, partial, gen tonic-clonic) -- cardiac rhabdomyomas -- ash-leaf spots -- facial angiofibromas -- Shagreen patches (lumbosacral region) -- periungual/ungual fibromas -- intellectual disability -- renal angiomyolipoma
Kallmann syndrome
- hypogonadotropic hypogonadism
- decreased sense of smell
- midfacial defects (cleft lip/palate)
- renal agenesis
- congenital heart disease
Heart defect seen in Noonan Syndrome
pulmonary valve stenosis
What is PTEN hamartoma tumor syndrome?
hemihyperplasia (overgrowth)
tumors
macrocephaly
Includes disorders like Cowden syndrome (increased breast/uterine cancer)
TAR syndrome
Thrombocytopenia
Absent bilateral radii
Horseshoe kidney
can have congenital heart disease, micrognathia, kidney abnormalities
Aside from cutaneous abnormalities, what are other findings in incontinentia pigmenti?
delayed dentition pegged/conical teeth alopecia nail changes Seizures
Tyrosinemia type 1
– RTA
– rickets
– FTT
– liver dysfunction, hepatomegaly
Diagnosis: Urine succinylacetone
When does ataxia telangiectasia present?
symptoms start in toddlerhood– abnormal eye movements, ocular telangiectasias
fused cervical vertebrae is seen in:
Klippel-Feil syndrome
Holt-Oram Syndrome
- ASD
- heart block
- absent radii
TAR syndrome
Thrombocytopenia -Absent Radii
AR. Bilateral absent radii and can have hypoplasia of ulna/humeri/shoulder girdle.
Can also have heart defects. BM with absent or decreased megakaryocytes.
THUMBS ARE NORMAL
Angelman Syndrome - genetics
Imprinting chromosome 15
Symptoms of Angelman syndrome
Gait ataxia
Lack of expressive language
Microcephaly
Seizures
Heart defect in Noonan Syndrome
pulmonic valve stenosis
Ataxia-Telangiectasia
Ataxia
Telangiectasias
Recurrent infections
Elevated AFP
Rocker bottom feet
microcephaly
cleft lip/palate
cutis aplasia
Trisomy 13 Patau
can also have neural tube defects, cardiac issues, omphalocele, polydactyly
Lethargy during periods of fasting, and hypoglycemia are seen in this category of diseases.
Fatty Acid Oxidation disorders (e.g. MCAD deficiency)
Kids with Apert syndrome may have this hand deformity
mitten hand (fusion of middle fingers) **a craniosynostosis syndrome also with brain malformations, low IQ
Cystic fibrosis: sweat chloride levels are usually higher than
60 mEq/L
Hepatomegaly, nephromegaly, hypoglycemia with chubby cheeks and thin extremities is a classic presentation for:
Glycogen storage disease type 1 (von Gierke)
*also have hyperuricemia, lactic acidosis, hyperlipidemia
Smith-Magenis syndrome
moderate ID
Facial features: heavy brows, coarse features
Unusual behaviors – self-hugging, putting foreign objects into body, self-injurious behaviors
Circadian rhythm problems
Coarse facial features, corneal clouding, umbilical hernia, dysostosis multiplex, HSM, frequent URIs….
MPS type 1- Hurler syndrome (do not have hypoglycemia). Neurodegenerative. lysosomal storage disease. AR. Coarse facial features start to show around 1 year of age
Genetics of fragile X
trinucleotide repeat disorer
>200 CGG repeats on FMR1 gene
Can affect males and females
Complications of Freidrich Ataxia
Cardiomyopathy
Diabetes mellitus
Bladder dysfunction
Progressive ataxia, weakness, dysphagia
Upward lens subluxation is seen in
Marfan syndrome (autosomal dominant)
Elevated very long chain fatty acids
Zellweger syndrome - AR - disorder of peroxisomal biogenesis. HEPATIC/RENAL dysfunction
- large ant fontanelle
- cataracts
- epicanthal folds
- broad nasal bridge
- epiphyseal stippling
Potter sequence
flattened nose/micrognathia/low set ears limb abnormalities due to OLIGOHYDRAMNIOS bilateral renal agenesis/cystic dysplasia pulmonary hypoplasia
How does Pompe disease present?
(glycogen storage disease)
Marked hypotonia and cardiomegaly in infancy (around 1 month– normal at birth). Short PR interval, massive QRS complexes. Normal glucose.
Alpha-glucosidase deficiency. Accumulation of glycogen in muscle, liver, heart, kidney, sm muscle, nerve
Inheritance pattern of hypophosphatemic rickets?
X-linked DOMINANT
excess phosphate loss thru kidneys.
NORMAL PTH level
Presentation of untreated galactosemia
hepatomegaly, liver dysfunction cataracts MR FTT gram negative sepsis (e coli!)
cause of death in Rett syndrome
cardiac arrhythmia/prolonged QTc
baseline may have autonomic dysfunction
Buildup of glucocerebroside is seen in :
Gaucher disease
builds up in brain, liver, lungs, spleen
LIPID ENGORGED MACROPHAGES IN BONE MARROW - pancytopenia
Individuals with Fanconi anemia have increased risk of developing this malignancy
AML (15% risk)
Optic gliomas are seen in
NF1
CHARGE syndrome
Coloboma of retina Heart Atresia of choanae Retarded growth and dev Genital abnormalities (micropenis, cryptorchidism) Ear abnormalities
Must have at least 4. CHD7 gene.
Laurence-Moon-Biedl syndrome/Bardet-Biedl syndrome
obesity hypogonadism retinitis pigmentosa polydactyly genital hypoplasia intellectual disability Autosomal recessive
Imprinted (deleted/inactivated) maternal chromosome 15
Angelman syndome (flappy hands, happy puppet, seizure, flattened occiput, protruding tongue, developmental delay)
Best test to confirm propionic acidemia
urine organic acids (elevated methylcitrate, triglyglycine, propionylglycine)
elevated 3-hydroxypropionate
Cornelia de Lange syndrome
IUGR, FTT mod-severe ID microcephaly, long eyelashes hypoplastic LIMBS bicornuate uterus/cryptorchidism HIRSUTISM
Features of fragile X
Long face Prominent jaw Macro-orchidism Gaze aversion, autistic behaviors, expressive language disorder, sensory sensitivity hyperactivity, hand biting Intellectual disability
Genetics of Noonan Syndrome
autosomal dominant. Mutation on chromosome 12. Normal karyotype. Increased risk of bleeding diathesis, similar features to Turner syndrome
What are the Ghent criteria?
clinical dx of Marfan ( need 2 of the major criteria)
- ectopia lentis
- aortic root dilation or dissection
- family history
What category of diseases is diagnosed with an acylcarnitine profile?
Fatty Acid Oxidation disorders (e.g. MCAD deficiency)
AR disorder of cholesterol metabolism
Smith-Lemli-Opitz Deficiency of dehydrocholesterol reductase. Defect in sonic hedgehog gene. - increase in cholesterol - microcephaly, narrow bifrontal diameter, wide eyes - cleft palate, micrognathia - 2/3 toe syndactyly -CLENCHED HANDS - hypospadias, ambig genitalia
Treatment of MCAD deficiency (fatty acid oxidation disorder)
low-fat diet
lots of carbohydrates at bedtime to avoid hypoglycemia
Presentation of MCAD deficiency
normal birth
present after 3 months with hypoketotic hypoglycemia, vomiting, lethargy
SEIZURES, HEPATOMEGALY, LIVER DYSFUNCTION
Avoid fasting!!
**FAMILY history of sudden death before age 2
Supravalvular aortic stenosis is seen in
Williams syndrome
elastin gene on chrom 7q11
elfin facies, engaging personalities
How does PKU present?
absence of Phe hydroxylase. Phe accumulated
- MUSTY urine
- seizure, delayed milestones
- eczema
- light skin, blond hair, blue eyes
GAA repeats
Freidrich Ataxia
Chromosome 9 - frataxin gene
Autosomal RECESSIVE
Differences between Marfan and Homocystinuria
Homocystinuria is AR has elevated METHIONINE, and at risk of vascular thrombi
Menke’s disease
Failure to absorb copper in the gut –> copper deficiency –> mitochondrial impairment. X-linked (Males)
Presents in infancy: loss of milestones, seizures, MR, tortuous cerebral arteries, kinky hair, hypotonia. Low serum Cu and ceruloplasmin.
What is the defect in Marfan syndrome?
Elastin fibers weakened due to abnromal synthesis of fibrillin protein
musty urine
PKU
What is elevated in maple syrup urine disease?
L-alloisoleucine
Trt: BCAA restriction (leucine, isoleucine, valine)
autosomal recessive
Inheritance pattern of Gardner syndrome
autosomal dominant.
Pre-malignant intestinal polyps, extra teeth, osteomas. Trt = surgery
Screening test for Lesch-Nyhan syndrome
Urinary Urate to Creatinine ratio (>2 is abnormal)
heterochromia of the irises can be seen in:
Waardenburg syndrome (white forelock, hirschsprungs, hearing loss, light eyes)
What are features of AR PKD (polycystic kidney disease)?
Presents in childhood
Chronic kidney disease
Hepatic fibrosis
What is nail-patella syndrome?
Autosomal dominant.
Ortho (e.g. hypoplastic patellae, dislocations), dystrophic nails.
RENAL DISEASE (proteinuria, hematuria –> ESRD)
Sensorineural hearing loss
Most common inheritance pattern in Alport syndrome
X-linked recessive, but can also be others
Inheritance pattern of Wilson disease
Autosomal Recessive
Osler-Weber-Rendu syndrome
Autosomal dominant
Telangiectasias
Vascular malformations
Epistaxis
What is the mucopolysaccharidosis that is X-linked?
Hunter syndrome. Accumulation of GAGs.
MSK defects, short stature, coarse facial features, HSM, communicating hydrocephalus, thickened cardiac valve leaflets, prominent forehead, hypertelorism.
What is the mucopolysaccharidosis that is X-linked?
Hunter syndrome
tall stature, learning disabilities, lens subluxation
Homocystinuria
Upper limb abnormalities + ASD/VSD + cardiac conduction defects seen in this syndrome
Holt-Oram syndrome
autosomal dominant
may see fused or missing digits,
Symptoms of Friedrich Ataxia
AR. Ataxia, LE weakness, pes cavus, diminished DTRs, scoliosis, hypertrophic cardiomyopathy, dysarthria
