Genetic Disorders and inborn errors of metabolism - source BRS Pediatrics

Question 1

Marfan Syndrome

Answer 1

AD - Chr 15 - fibrillin
Connective tissue disorder

Skeletal: tall stature, elongated extremities, long fingers (arachnodactyly), joint laxity, pectus excavatum, scoliosis or kyphosis. Decreased upper to lower segment ratio (U/L) - lower segment distance from symphysis pubis to heel, upper segment height minus lower segment)

Ocular findings: upward lens subluxation, retinal detachment

CV finding: aortic root dilation +/- aortic dissection, MV prolapse, aortic regurgitation

R/o homocystinuria - same clinical features

Question 2

Prader-Willi Syndrome

Answer 2

paternal del 15.11q

Craniofacial: almond-shaped eyes, down-turned fishlike mouth

Growth: FTT first year of life -> obesity d/t hyperphagia later in childhood, risk OSA. Short stature with small hands and feet

Neurologic: hypotonia (more pronounced in newborn period, poor sucking), MR, learning disabilities, behavior problems

Hypogonadism - small penis, small testes, or cryptorchidism

Dx: FISH

Adult risks: cardiac disease, T2DM, psychiatric illnesses

Question 3

Angelman syndrome

Answer 3

Maternal del 15.11q
“happy puppet”

Neurologic: jerky arm movements, ataxia, paroxysms of inappropriate laughter, MR is severe with significant speech delay

Craniofacial: small wide head, large mouth with widely spaced teeth, tongue protrusion, prognathia. Most blond hair, pale blue deep-set eyes

Dx: FISH

Question 4

Noonan syndrome

Answer 4

AD or sporadic, Chr 12

Skeletal: short stature, shield chest

Craniofacial: short webbed neck and low hairline, hypertelorism (wide spaced eyes), epicanthal skin folds, downslanting palpebral fissures, low set ears

CV: Right sided heart lesions - MC pulmonary valve stenosis

Neurologic: MR in 25%

Dx: based on clinical features. Similar to Turner’s Sn presentation, with exception of Turner’s have left-sided heart lesions, and males can get it too.

Question 5

DiGeorge Syndrome

Answer 5

del 22q11
“CATCH-22” - Cardiac, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia, chr 22

Defect of structures derived from 3rd and 4th pharyngeal pouches

Craniofacial: short palpebral fissures, small chin, ear anomalies

CV: aortic arch anomalies, VSD, tetralogy of Fallot

Thymus and parathyroid hypoplasia -> cell-mediated immunodeficiency and severe hypocalcemia (risk for seizures)

Dx: FISH

Question 6

Velocardiofacial syndrome

Answer 6

del 22q11

Craniofacial: cleft palate, wide prominent nose with a squared nasal root, short chin, fish-shaped mouth

CV: VSD, right-sided aortic arch

Neurologic: neonatal hypotonia, learning disabilities, perseverative behaviors

Dx: FISH

Question 7

Ehlers-Danlos syndrome

Answer 7

AD - defective type V collagen

MSK: hyperextensible joints with tendency toward joint dislocation and scoliosis

Dermatologic: soft, velvety textured, loose fragile skin. Minor lacerations -> large wounds that heal poorly with broad, atrophic, tissue paper-thin scars

CV: MV prolapse, aortic root dilation, fragile blood vessels -> ease of bruising

GI: constipation, rectal prolapse, hernias - risk GI bleeds d/t blood vessel fragility

Question 8

Osteogenesis Imperfecta (OI) - type 1

Answer 8

mutation -> abnormal type I collagen

Blue sclerae

Skeletal: fragile bones, frequent fractures, genu valgum (knock-knees), scoliosis or kyphosis, joint laxity, osteoporosis or osteopenia

Yellow or gray-blue teeth

Easy bruisability

Dx: clinical features, decreased type I collagen synthesis in fibroblasts

Complications: early conductive hearing loss, skeletal deformities d/t fractures

Question 9

VACTERL (VATER) association

Answer 9

V-vertebral defects
A- anal atresia, aka imperforate anus
C- cardiac anomalies - MC VSD
TE- tracheoesophageal fistula
R- Renal and genital defects
L- Limb defects - radial hypoplasia, syndactyly, polydactyly

Question 10

CHARGE association

Answer 10

C-colobomas (absence or defect of ocular tissue), usually retina, impaired vision common
H-heart defects - MC tetralogy of Fallot
A- atresia of nasal choanae
R- retardation of growth and cognition
G-gential anomalies - genital hypoplasia
E- ear anomalies - cup shaped ears, hearing loss

Question 11

Williams Syndrome

Answer 11

AD, Del Chr 7 - gene for elastin
“cocktail party personality” -

Elfin facies - short palpebral fissures, flat nasal bridge, round cheeks

MR and loquacious personality

Supravalvular aortic stenosis

Idiopathic hypercalcemia in infancy

Connective tissue abnormalities - hoarse voice, hernias

Dx: FISH

Question 12

Cornelia de Lange (Brachmann-de Lange) syndrome

Answer 12

AD or sporadic

SGA, FTT

Craniofacial: single eyebrow (synophrys), long, curling eyelashes, microcephaly, thin, down-turned upper lip, micrognathia

Infantile hypertonia

MR

Small hands and feet

Cardiac defects

Behavioral: autistic features, lack of facial expression, self destructive tendencies

Dx: clinical features

Question 13

Russell-Silver Syndrome

Answer 13

Sporadic

SGA

Craniofacial: small triangular face, prominent forehead, down-turned mouth, head appears large but normal circumference.

Skeletal: short stature, limb asymmetry

Cafe-au-lait spots

Excessive sweating

Dx: clinical features

Question 14

Pierre Robin Syndrome

Answer 14

Micrognathia, cleft lip and palate, large protruding tongue

Dx: clinical features

Complications: recurrent OM and upper airway obstruction that often requires tracheostomy

Question 15

Cri du chat syndrome

Answer 15

partial del of Chr 5p

slow growth, microcephaly, MR, hypertelorism, downslanting palpebral features, catlike cry

Question 16

Down Syndrome Clinical Features

Answer 16

Craniofacial: brachycephaly, epicanthal skin folds, upslanting palpebral fissures, brushfield spots (speckled irides), protruding tongue

hypotonia

MR

MSK: clinodactyly, single palmar creases, wide space between first and second toes

GI: duodenal atresia, Hirschsprung’s dz, omphalocele, pyloric stenosis

CV: endocardial cushion defects

Question 17

Down Syndrome Complications and screenings

Answer 17

AA cervical spine instability - flexion-extension cervical spine XR assessed by 3-5 yo

Leukemia - 20x more common

Celiac disease - screen at 2 yrs - total IgA and IgA anti-endomysium Ab

Early Alzheimer’s disease

OSA

Conductive hearing loss - screen hearing every 1-2 years

Hypothyroidism - annual TSH screen

Cataracts, glaucoma, refractive erros - annual ophthalmologic exam

Question 18

Trisomy 18 (Edwards)

Answer 18

3x more in females

Neurologic: MR, hypertonia with scissoring of lower extremities

Delicate, small facial features

MSK: clenched hands with overlapping digits, dorsiflexed big toes, rocker bottom feet

95% die within first year of life

Question 19

Trisomy 13 (Patau)

Answer 19

Midline defects of face and forebrain

Neurologic: holoprosencephaly, microcephaly, seizures, severe MR

Ocular: microphthalmia, retinal dysplasia, colobomas, rarely a single eye

Cleft lip and palate

Prognosis poor, death within first month of life

Question 20

Turner syndrome

Answer 20

XO, 1:2000

Short stature
Webbed neck, low posterior hairline
Shield chest, broadly spaced nipples, scoliosis or kyphosis

Swelling of dorsum of hands and feet - congenital lymphedema, present at birth

Ovarian dysgenesis - delayed puberty.

CV: Left sided heart lesions: coarctation of aorta, bicuspid aortic valve, hypoplastic left heart

Hypothyroidism

Question 21

Fragile X Syndrome

Answer 21

CGG repeats on X chromosome - anticipation
more severe in males, females may have MR
MC inherited cause of MR

Mild to severe MR
Craniofacial: large ears, macrocephaly, thickened nasal bridge, blue irides

Large testes develop during puberty

Behavioral: emotional instability, autistic features, ADHD

Question 22

Klinefelter Syndrome

Answer 22

MC male hypogonadism and infertility
XXY - risk with advancing maternal age
1:500

Tall stature with long extremities

Hypogonadism - small penis and testes, delayed puberty d/t lack of testerone, infertility

Gynecomastia

Variable intelligence

Behavioral: antisocial behavior, excessive shyness or aggression - noted before physical findings

Question 23

Rhizomelia

Answer 23

proximal long bone abnormalities - short humerus and femur

Question 24

Mesomelia

Answer 24

medial long bone abnormalities - short ulna and tibia

Question 25

Acromelia

Answer 25

distal abnormalities - small hands and feet

Question 26

Spondylodysplasias

Answer 26

abnormalities of the spine w/ or w/o limb abnormalities

Question 27

Achondroplasia

Answer 27

AD or sporadic - mutation FGF3 receptor gene
Incidence increases with advancing paternal age
MC skeletal dysplasia

Craniofacial: megalencephaly (large brain), foramen magnum stenosis, frontal bossing, midface hypoplasia, low nasal bridge

Skeletal: lumbar kyphosis in infancy evolves into lumbar lordosis later, rhizomelic limb shortening, bowed legs, joint hyperextensivility, trident-shaped hands

Recurrent OM with conductive hearing loss

Dx: clinical features, XR of limbs

Complications:
1) foramen stenosis -> hydrocephalus or cord compression. head circumference monitored closely. Head sweating and dilated facial veins signs of cord compression. Sudden infant death d/t cord compression

2) OSA and respiratory compromise from foramen magnum narrowing and upper airway obstruction
3) orthopedic problems - severe bowed legs, back pain

Question 28

Potter syndrome

Answer 28

severe oligohydramnios -> lung hypoplasia, fetal compression with limb abnormalities, facial features (Potter facies)

Severe oliohydramnios caused by: chronic amniotic fluid leak or intrauterine renal failure d/t b/l renal agenesis, polycystic kidneys, or obstructive uropathy

Question 29

Amniotic band syndrome (amnion rupture sequence)

Answer 29

rupture of amniotic sac
Fluid leak leads to intrauterine constraint, small strands from amnion may wrap around the fetus -> limb scarring and amputation

Question 30

Fetal alcohol syndrome

Answer 30

mom chronically drinks or binges

SGA, FTT
microcephaly, long smooth philtrum with thin, smooth upper lip
MR
ADHD
CV: VSD most common

Question 31

Fetal phenytoin syndrome

Answer 31

mild to moderate MR, Cardiac defects, growth retardation, nail and digit abnormalities

Wide anterior fontanelle, thick hair with low hairline

Question 32

Homocystinuria

Answer 32

AR - cystathionine synthase deficiency

Marfanoid body habitus w/o arachnodactyly
DOWNward lens subluxation (Marfan’s is up)

Hypercoagulable state - increased risk of stroke, MI, DVT

CV: MV or AV regurgitation, aortic dilation absent

Scoliosis and large, stiff joints

Developmental delay, mild MR, psychiatric illness

Dx: increased methionine in urine and plasma or positive urinary cyanided nitroprusside test

tx: methionine restricted diet, aspirin to decrease risk of VTE, folic acid and B6 supplementation

Question 33

Transient tyrosinemia of the newborn

Answer 33

premature infants on high protein diet
first 2 weeks of life
poor feeding or lethargy - or asx

Dx: elevated serum tyrosine and phenylalanine levels

Tx: decrease protein intake during acute episode, Vit C to help eliminate tyrosine

Prognosis: self limited disease, resolve within 1 mo

Question 34

Cystinuria

Answer 34

AR
Defect in renal reabsorption of cystine, lysine, arginine, ornithine -> renal stones

UTI, dysuria, abdominal or back pain, urgency, urinary frequency

Question 35

Hartnup disease

Answer 35

AR
Defect in transport of neutral amino acids

most asx, some intermittent ataxia, photosensitive rash, MR, emotional lability

Question 36

Transient hyperammonemia of the newborn

Answer 36

self limited
premature infants initial 24-48 hrs

respiratory distress, alkalosis, vomiting, lethargy rapidly progressing to coma

Aggressive treatment of hyperammonemia to prevent neurologic sequelae

Question 37

Ornithine transcarbamylase deficiency

Answer 37

MC urea cycle defect
X linked recessive

begin at onset of protein ingestion
Vomiting, lethargy leading to coma

Females: mild disease present in childhood with cyclic vomiting and intermittent ataxia

Dx: elevated urine orotic acid, decreased serum citrulline and increased ornithine, liver bx

Tx: low protein diet, manage hyperammonemia, liver transplant may be necessary

Prognosis: depends on neurologic sequelae of any hyperammonemic episode, recurrent episodes with illness common

Question 38

Galactosemia

Answer 38

AR - galactose-1-phophate uridyltransferase deficiency
Newbord with hepatomegaly and hypoglycemia

After newborn feeds a cow’s milk based formula or breastfeeds for the first time (both contain galactose)

Vomiting, diarrhea, FTT

Hepatic dysfunction with hepatomegaly

Cataracts with oil-droplet appearance

Renal tubular acidosis

Dx: nonglucose-reducing substance in urine, confirm with enzyme defiency in RBC, prenatal/newborn screening

Tx: galactose-free diet (soy, elemental formula)

Prognosis: good with normal intelligence if treated early. delayed dx -> MR, risk of early infancy death from E. coli sepsis
Females suffer ovarian failure.

Question 39

Hereditary fructose intolerance

Answer 39

fructose-1-phosphate aldolase B deficiency
begins infancy after introduced fruit juice

severe hypoglycemia, vomiting, diarrhea, FTT, seizures

Avoid fructose, sucrose, sorbitol

Question 40

Von Gierke’s disease (GSD type 1)

Answer 40

AR, glucose-6-phosphatase deficiency

persistent hypoglycemia, hepatomegaly, metabolic acidosis, hypertriglyceridemia, enlarged kidneys

Tx: frequent feeding of high-complex carbohydrate diet.

High risk for hepatocellular carcinoma

Question 41

Pompe’s disease (GSD type 2)

Answer 41

alpha-glucosidase deficiency
within first 2 weeks of life

flaccid weakness, poor feeding, progressive cardiomegaly, hepatomegaly, acidosis

Question 42

Kearns-Sayre syndrome

Answer 42

mitochondrial disorder

ophthalmoplegia, pigmentary degeneration of retina
Hearing loss
heart block
neurologic degeneration

Question 43

MELAS

Answer 43

Mitochondrial Encephalopathy, Lactic Acidosis, Strokelike episodes

Question 44

Tay-Sachs disease

Answer 44

AR - hexosaminidase A deficiency
Ashkenazi jews

Infantile onset: decreasing eye contact, hypotonia, mild motor weakness, increased startle d/t hyperacusis

• macrocephaly
• Cherry-red macula
• Progressive blindness, seizures, several developmental delay

Juvenile or adult-onset: after 2 yo or early adulthood. Ataxia, dysarthria, choreoathetosis, cherry-red macula absent

Dx: decreased hexosaminidase A activity in leukocytes or fibroblasts

Prognosis: infantile untreatable, death by 4. Juvenile/adult - poor prognosis, degeneration into chronic debilitated state

Question 45

Gaucher’s disease

Answer 45

AR - glucocerebrosidase deficiency

HSM, thrombocytopenia, Erlenmeyer flask-shape to distal femur.

If sxs in infancy, early mortality by 4 yo

Tx: enzyme replacement

Question 46

Niemann-Pick disease

Answer 46

sphingomyelinase deficiency
presents by 6 mo

progressive neurodegeneration, ataxia, seizures, HSM, cherry-red macula

death by 4

Question 47

Metachromatic leukodystrophy

Answer 47

arylsulfatase A deficiency

ataxia, seizures, progressive MR

Death by 10-20 yo

Question 48

dysostosis multiplex

Answer 48

thickened cranium
J-shaped sella turcica
malformed, ovoid or beaklike vertebrae
short and thickened clavicles
oar-shaped ribs

Question 49

Hurler syndrome

Answer 49

alpha-L-iduronidase deficiency
Most severe mucopolysaccharidosis- lysosomal storage disorder

Begin after 1 yo - developmental delay, HSM, kyphosis

progressively coarsened facial features, frontal bossing, prominent sagittal and metopic sutures, wide nasal bridge, thickening of the nasopharyngeal tissues, hydrocephalus, corneal clouding, progressively stiff and contracted joints

Dx: dermatan and heparan sulfates in urine, decreased alpha-L-iduronidase enzyme activity in leukocytes or fibroblasts

Tx: early bone marrow transplant to prevent neurodegeneration

Prognosis: poor, death by 10-15 yo

Question 50

Hunter syndrome

Answer 50

X-linked recessive - corneal clouding absent
- lysosomal storage disorder

HSM, hearing loss, progressively stiff and contracted joints, small papules over shoulder scapula, and lower back, dysostosis multiplex

Dx: dermatan and heparan sulfates in urine, decreased alpha-L-iduronidase enzyme activity in leukocytes or fibroblasts

Prognosis: no treatment available, die by 20

Question 51

Sanfilippo syndrome

Answer 51

AR - lysosomal storage disorder

rapid and severe mental and motor retardation

Question 52

Morquio Syndrome

Answer 52

lysosomal storage disorder
MR absent

Severe scoliosis -> cor pulmonale

death by 40

Question 53

Acute intermittent porphyria

Answer 53

episodic and precipitated by drugs (etOH, sulfa drugs, OCP), hormonal surges (pregnancy or menses), or poor nutrition

Neurologic: personality changes, emotional lability, parethesias, weakness (not following expected neural pathways, accused of malingering)

GI: colicky abdominal pain, vomiting, constipation - mimics acute abdomen

Autonomic instability - tachycardia, htn, sweating, fever

Dark burgundy-colored urine

Dx: increased serum and urine porphobilinogen

Tx: IV glucose, correct electrolyte abnormalities, avoid fasting and precipitating drugs

Question 54

Wilson’s disease

Answer 54

AR - defect in copper excretion - deposits liver -> brain, eyes, heart
hepatolenticular degeneration
develops 2-50 yo

Kayser-Fleischer rings - copper deposition in Descemet’s membrane

Neurologic: behavior changes, dystonia, dysarthria, tremor, ataxia, seizures

Hepatic dysfunction

Dx: decreased serum ceruloplasmin, elevated serum and urine copper, copper deposition in hepatocytes on liver bx

Tx: avoid copper-containing foods (nuts, liver, shellfish, chocolate), chelation therapy with oral penicillamine and zinc salts to prevent absorption… possible liver transplant

Question 55

Menkes kinky-hair disease

Answer 55

X linked recessive
abnormal copper transport -> low serum copper

First few months of life

myoclonic seizures, pale kinky friable hair, optic nerve atrophy, severe MR, progressive neurologic degeneration, early death

Dx: typical hair findings, low serum ceruloplasmin and copper

Question 56

Phenylkentonuria

Answer 56

AR

Developmental delay
Infantile hypotonia
Mousy or musty odor
Progressive MR
Eczema
Decreased pigment - light eyes and hair

Mild PKU presents in early childhood w/ developmental delay, hyperactivity

Dx: increased phenylalanine:tyrosine in serum

Tx: phenylalanine-restricted diet

Prognosis: nearly normal intelligence if diet restriction begun less than 1 mo of age

Question 57

Maple syrup urine disease

Answer 57

AR

Progressive vomiting and poor feeding
Lethargy, hypotonia, and coma
Developmental delay
Maple syrup odor in urine
Hypoglycemia and severe acidosis during episodes

Dx: elevated serum and urine branched-chain amino acids

Tx: dietary protein restriction

Prognosis: protein restriction within 2 weeks of life may avert neurologic damage

Question 58

Tyrosinemia Type 1

Answer 58

AR

episodes of peripheral neuropathy
Chronic liver disease
Odor of rotten fish or cabbage odor
Renal tubular dysfunction

Dx: succinylacetone in urine

Tx: dietary restriction of phenylalanine, tyrosine, NTBC
Liver transplant

Prognosis: death by 1 yo if begins in infancy, increased risk of hepatocellular carcinoma and cirrhosis