- Severe mucocutaneous bleeding in 1st 3 years of life - Normal PT/PTT, delayed bleeding time - Normal platelet # and morphology

Glanzmann's Thrombasthenia: - AR - GIIb/IIIa deficiency - Rx: platelet transfusion

- Severe mucocutaneous bleeding in 1st 3 years of life - Giant platelets +/- thrombocytopenia

Bernard-Soulier Syndrome: - AR - GP1b, V, IX defect - can't bind vWF

- White forelock - SNHL - Abn pigmentation _ Hand anomalies

Waardenberg Syndrome - Type 3 - + Hirschsprung disease - Genes: PAX3, MITF, EDN3, EDNRB, SOX10 - AD

- Abnormal upper to lower body ratio - Tall stature - Pectus deformity - Scoliosis - Arachnodactyly - High arched palate

MARFAN SYNDROME - Ocular - lens dislocation, myopia - Cardiac - aortic root dilation, risk of Ao rupture, mitral valve prolapse - Spinal dural ectasia - Gene: Fibrillin on chromosome 15 - Marfan 2 and Loeys-Dietz syndrome have mutations in gene for TGF beta receptors 1 and 2 - AD

- Progressive symmetric myopathy - Proximal weakness>distall weakness - Calf hypertrophy - Gower manuever - Symptoms prior to 5 years of age - Unable to walk by age 13 - Carrier females may develop cardiomyopathy

DUCHENNE MUSCULAR DYSTROPHY - X-linked recessive - Dystrophin gene on Xp, 65% deletions, 30% point mutations - CK 10x normal - Muscle biopsy - fiber size variation, necrosis, minimal or absent dystrophin staining

- Progressive neurological disorder in girls - Hand wringing, breath holding - Seizures - Males may not survive pregnancy or be very severely affected - Atypical Rett Syndrome may present as autism

RETT SYNDROME - X-linked dominant - Gene: MECP2 at Xq28

Syndromes Flashcards by Khristine Bautista

AV Canal Defect

Trisomy 21

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Bicuspid Ao Valve or Aortic Coarctation

Turner Syndrome

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TOF or Truncus Arteriosus

DiGeorge Syndrome (22q11del)

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Supravalvular Ao Stenosis

William’s Syndrome

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Dilated Aortic Root or Mitral Valve Prolapse

Marfan’s Syndrome

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Limb/thumb Anomalies, ASD +/- VSD

Holt-Oram

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Muscle weakness, ataxia, cardiomyopathy

Friedrich’s Ataxia

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Pulmonic stenosis, webbed neck, short stature

Noonan Syndrome

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Severe mucocutaneous bleeding in 1st 3 years of life
Normal PT/PTT, delayed bleeding time
Normal platelet # and morphology

Glanzmann’s Thrombasthenia:

AR
GIIb/IIIa deficiency
Rx: platelet transfusion

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Severe mucocutaneous bleeding in 1st 3 years of life

- Giant platelets +/- thrombocytopenia

Bernard-Soulier Syndrome:

AR
GP1b, V, IX defect - can’t bind vWF

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Thrombocytopenia

- Absent radius

TAR

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This inheritance typically involves genes encoding structural proteins, transcription factors, plus others

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White forelock
SNHL
Abn pigmentation
_ Hand anomalies

Waardenberg Syndrome

Type 3 - + Hirschsprung disease
Genes: PAX3, MITF, EDN3, EDNRB, SOX10
AD

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Abnormal upper to lower body ratio
Tall stature
Pectus deformity
Scoliosis
Arachnodactyly
High arched palate

MARFAN SYNDROME

Ocular - lens dislocation, myopia
Cardiac - aortic root dilation, risk of Ao rupture, mitral valve prolapse
Spinal dural ectasia
Gene: Fibrillin on chromosome 15
Marfan 2 and Loeys-Dietz syndrome have mutations in gene for TGF beta receptors 1 and 2
AD

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> 6 cafe-au-lait spots (>5mm pre-pubertal, >15mm post-pubertal)
2 + neurofibromas
2+ Lisch nodules
Inguinal or axillary freckling
Optic pathway tumor
Osseous lesion: sphenoid wing dysplasia or thinning of long bone cortex
1st degree relative with NF
Diagnosis by 2 or more of the above findings

NEUROFIBROMATOSIS

- AD

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This inheritance typically involves genes encoding enzymes

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1:12000 newborns
Persistent elevation in phe levels
mutation in phenylalanine hydroxylase gene

PHENYLKETONURIA

- AR

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Lysosomal storage disease (mucopolysaccaridosis)
Coarse facies
Corneal clouding
Organomegaly
Cognitive loss
Mutation in alpha-1 iduronidase gene

HURLER SYNDROME

- AR

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Progressive symmetric myopathy
Proximal weakness>distall weakness
Calf hypertrophy
Gower manuever
Symptoms prior to 5 years of age
Unable to walk by age 13
Carrier females may develop cardiomyopathy

DUCHENNE MUSCULAR DYSTROPHY

X-linked recessive
Dystrophin gene on Xp, 65% deletions, 30% point mutations
CK 10x normal
Muscle biopsy - fiber size variation, necrosis, minimal or absent dystrophin staining

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Lysosomal storage disease
Coarse facies
Hump on back
Short stature
Gibbus
Cognitive loss (variable)
Organomegaly
Clear cornea

HUNTER SYNDROME

- X-linked recessive

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Progressive neurological disorder in girls
Hand wringing, breath holding
Seizures
Males may not survive pregnancy or be very severely affected
Atypical Rett Syndrome may present as autism

RETT SYNDROME

X-linked dominant
Gene: MECP2 at Xq28

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Lactic acidosis
Mutation in gene encoding tRNAs
Myopathy with ragged red fibers
Dilated or hypertrophic cardiomyopathy

MITOCHONDRIAL MYOPATHY AND CARDIOMYOPATHY

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Lactic acidosis
Early onset strokes
Myopathy
Mutation in tRNA genes in mitochondrial genome

MITOCHONDRIAL ENCEPHALOPATHY, LACTIC ACIDOSIS AND STROKE (MELAS)

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Inheritance of cleft lip and palate

Complex inheritance

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Inheritance of neural tube defects

Complex inheritance

- 1:5000 live births - Short stature - Infertility +/- ammenorrhea - Coarctation - Kidney malformations - Hand and foot edema - Neck webbing - Wide carrying angle - Low hair line - Wide spaced nipples

TURNER SYNDROME - X0 * Referral for genetic testing is important to check for presence of Y chromosomal material that increases the risk of gonadal malignancy

- Severe retardation - Cleft lip and palate - FTT - CHD - Microcephaly - Flat nasal bridge with high arched eyebrows

WOLF-HIRSCHHORN SYNDROME | - deletion 4p

- Cat cry - LBW - ID - Microcephaly - Epicanthal folds - CHD

CRI-DU-CHAT | - deletion 5p

- Developmental delay - Dysmorphism - stellate iris, thick lips, puffy eyes, bitemporal narrowing, elfin facies - "cocktail party" personality - HYPERCALCEMIA - supravalvular aortic stenosis

WILLIAMS SYNDROME | - deletion on chromosome 7q11.23

``` C = cardiac A = abnormal face T = thymus hypoplasia/T cell deficiencies C = cleft palate H = hypocalcemia 22 = 22q deletion ```

DIGEORGE SYNDROME | - aka Velocardiofacial Syndrome

A male infant has TOF and a cleft palate. What would be the best genetic test to order?

FISH for 22q11

- ID - Microcephaly - Hirsuitism - Synophrys - Oligodactyly - GERD**

CORNELIA DE LANGE SYNDROME - NIPBL mutation - Chromosome 5p13

- Down slanting palpebral fissures - Malar hypoplasia - Lower eyelid coloboma - Malformed ears with hearing loss

TREACHER COLLINS SYNDROME - mutation in treacle at 5q32 - AD

Most common form of ID in boys

Fragile X

- ID (IQ 30-50) - Language delay - Motor delay - Autistic behaviors - Difficulty with transitions - Anxiety - Tantrums - Hyperactivity - Long face, prominent ears, flat feet, loose joints, soft/smooth skin - Mitral valve prolapse - Strabismus - Large testes after puberty

FRAGILE X SYNDROME | - CGG repeat in FRM1 gene (>200 repeats)

- Neonatal hypotonia, poor feeding - Developmental delay - Almond shaped eyes - Small hands and feet - Obesity and feeding problems - Hypogonadotrophic hypogonadism - DM

PRADER-WILLI SYNDROME - 1/10,000 to 1/25,000 - 70% deletion on chromosome 15q (paternal) - 28% maternal uniparental disomy for chromosome 15 - 2% mutation in imprinting gene

- Severe ID - Laughter outbursts - Ataxia - Large jaw

ANGELMAN SYNDROME - 70% maternal deletion chromosome 15 - 3-5% parental uniparental disomy - 8% imprinting mutation - 8% mutation in UBE3A

Most common CHD in children with Down Syndrome

AV canal is the most common (40-50%)

- Microcephaly - Growth retardation - Long smooth philtrum - Thin upper lip - Down-slanting palpebral fissures - Hirsuitism - Cardiac defects - Developmental delay

FETAL ALCOHOL SYNDROME

- FTT - Microcephaly - Ptosis - Cataract - Small jaw - Cleft palate - Abn genitals/male pseudohermaphroditism - CHD - Severe hypotonia

SMITH-LEMLI-OPTIZ - Metabolic disorder with dysmorphism - Mutations in delta-7-sterol reductase

Conotruncal Heart Defect (transposition, TOF, Interrupted aortic arch, Truncus arteriosus)

FISH for 22q11 deletion

Supravalvular Aortic Stenosis

Williams Syndrome

AV canal defect

Down Syndrome

- Growth deficiency - Microcephaly - Prominent occiput - Small mouth/small jaw - Short sternum - Cardiac anomalies - Cryptorchidism - Overlapped clenched fingers/hypoplastic nails - Rocker bottom feet

TRISOMY 18 - 1:8000 live births - Decreased survival but reports into second decade

- LBW - Microcephaly - Holoprosencephaly - Scalp ulceration - Iris coloboma - Cardiac anomalies - Renal and genital anomalies - Cleft lip and palate - Polydactyly - Rocker bottom feet

TRISOMY 13 - 1:25,000 - Reports of living into second decade

- Crumpled broad long bones - Wormian bones - Narrow chest - Blue sclera

OSTEOGENESIS IMPERFECTA TYPE 2 - mutations in COL1A1 and COL1A2 - death due to inability to ventilate, intracranial hemorrhage

- Most common neonatal skeletal dysplasia - Some forms with cloverleaf skull - Short limb dwarfism - Severe brain malformations

THALANOPHORIC DYSPLASIA | - mutations in FGFR3

- Short stature - Rhizomelia - Vertebral body abnormality - Trident hand - Small foramen magnum

ACHONDROPLASIA - AD - Mutation in FGFR3 - Increased risk for SIDs

Metabolic syndrome that looks like Marfan's Syndrome

Homocystinuria

Syndromes with craniosynostosis

- Apert syndrome - Cruzon syndrome - Pfeiffer syndrome - Jackson-Weiss - Saethre-Chotzen

- Large size - Neonatal hypoglycemia - Macroglossia - Umbilical hernia - Ear lobe grooves

BECKWITH-WIEDEMANN SYNDROME | - 7.5% lifetime risk of tumors - Wilms, Adrenal Cortical Carcinoma, Hepatoblastoma

- Aniridia - ID - Wilms TUmor - Gonadoblastoma

ANIRIDIA-WAGR SYNDROME | - deletion chromosome 11p13

- Enlargement of one side of the body | - Tumors (Wilms, adrenal cortical carcinoma, hepatoblastoma)

HEMIHYPERPLASIA

- Hyperextensibility - Atrophic scars - Delayed walking - Spontaneous gut rupture - Aneurysm - Wound dehicience

EHLERS DANLOS SYNDROME

Radial Ray Anomalies

- TAR - Diamond Blackfan Anemia - Fanconi ANemia - Holt-Oram Syndrome - VATER/VACTERL

- Delayed closure of fontanelle - Skeletal dysplasia - Absent clavicles

CLEIDOCRANIAL DYSOSTOSIS

Clues to Acute Metabolic Disease

1. BP easily maintained 2. Acidosis unresponsive to usual means of respiratory and circulatory support. Ketoacidosis rare in neonate except with metabolic disease 3. Sterile cultures

Association of E. coli sepsis with this metabolic disease

Galactossemia

Seizures 1. Early in life 2. Myoclonus 3. Hiccupping 4. Hypsarrhythmia by EEG

``` Early metabolic etiology Nonketotic hyperglycemia (Born seizing) or beta-alaninemia when these findings are observed together ```

Urine smells like maple syrup, sweet burnt sugar, curry

Maple syrup urine disease (MSUD)

Smells moussey, musty

Phenylketonuria

Smells like sweaty feet

Isovaleric acidemia | Glutaric acidemia, Type II

Smells like cat urine

3-Methylcrotonyl-glycinuria

Smells musty

Tyrosinemia

Smells fruity, sweet

Sparse, pili torti or kinky, steely hair

Menkes Syndrome

Dry, breakable short hair

Argininosuccinic aciduria

Alopecia

Biotinidase deficiency Combined carboxylase deficiency Acrodermatitis enteropathica

Ambiguous genitalia

CAH

Hair and/or skin problems

Biotinidase deficiency Multiple carboxylase deficiency Arginino-succinic aciduria

FAS-like facies | Structural brain abnormalities (agenesis of corpus callosum, cortical cysts)

Pyruvate dehydrogenase deficiency

Macrocephaly

Glutaric Aciduria Type I

Renal cysts, facial dysmorphism

Zellweger Syndrome | Glutaric Aciduria Type II

Cataracts

Galactosemia (ecoli sepsis) | Lowe Syndrome

Lens dislocation | Ectopic Lentis

Homocystinuria-down (kidneys low = down) | Marfan syndrome-up (tall = up)

- Neutropenia | - Metabolic acidemia

Organic acidemias

- Neutropenia - Hepatomegaly - Hypoglycemia - Bleeding diathesis

Glycogen storage disease, Type 1B

- Neutropenia - Apneic/bradycardic episodes - +/- Seizure

Nonketotic hyperglycemia

Cofactors - Neonatal seizures

Pyridoxine (B6)

Cofactors - Biotinidase deficiency (alopecia)

Biotin

What is the mode of inheritance of most metabolic disorders

AR - 25% recurrence risk

1/760 Mennonite population 1. NEONATAL: poor feeding, apnea, ketoacidosis, seizures, hypoglycemia 2. Infants/Adults: ataxia, FTT, +/- acidosis, progressive 3. Childhood/adulthood: Intermittent ataxia, ketoacidosis during infection or protein rich meals 4. Infant/adult: milder, ataxic attacks to psychomotor delay (thiamine responsive)

MSUD - Defect in the branched chain alpha-ketoacid dehydrogenase enzyme - ELEVATED LEUCINE, ISOLEUCINE, and VALINE ALLOISOLEUCINE is pathognomonic - THIAMINE = Cofactor Rx: Restriction of branched chain AA, thiamine

Present in neonatal period with ELEVATED AMMONIA and CATASTROPHIC ILLNESS

Urea Cycle Defects | AR except for OTC deficiency which is X-linked

This urea cycle defect presents with ataxia, not elevated ammonia

Arginase deficiency

Rx for urea cycle disorders

- Low protein diet - Urea cycle intermediate when appropriate - Medications to remove toxic ammonia via alternative pathways (phenylacetate, phenylbutyrate, benzoate) - Outcome: virtually all ID

Present in neonatal period with NEONATAL CRASH, KETOACIDOSIS, HYPOGLYCEMIA, HYPERAMMONEMIA, NEUTROPENIA

Organic Acidemias - Propionic acidemia - defect in propionyl CoA carboxylase; biotin cofactor; Rx - diet, biotin, carnitine - Methylmalonic acidemia - defect in methylmalonyl CoA mutase; Rx - diet, B12, carnitine - Biotin disorders - defect in addition of biotin to 4 apocarboxylases or in biotin recycling; biotin currative

``` Hypoglycemia Reye like illness SIDs 4-24mos of age Hypoketotic hypoglycemia ```

Medium Chain Acyl CoA Dehydrogenase Deficiency Rx - low fat diet; avoid fasting; carnitine; glucose during intercurrent illnesses

1. Prenatal/neonatal onset of intractable seizures, HICCUPS 2. Due to disorder in glycine cleavage enzyme 3. Elevated glycine in serum and/or CSF amino acids

Nonketotic hyperglycinemia

- Abnormal hair and facies - Hypopigmentation - Arterial tortuosity/rupture and thrombosis - Intractable seizures with progressive CNS deterioration - Hypothermia - Osteoporosis - Low serum Copper

Menkes Disease | - X-linked P-type ATPase cation transporter

- Dislocated lenses (down) - Marfanoid habitus - ID

Homocystinuria - Dx: plasma homocystine levels - Cystathionine B-synthase deficiency - AR - 50% pyridoxine responsive

- Liver failure - Renal tubular dysfunction - Cabbage-like odor - French Canadians

Tyrosinemia Type 1 - AR - Rx: dietary restriction, liver transplantation; NTBC

- Corneal dystrophy - Erosions/keratosis of palms and soles - ID

Tyrosinemia Type 2 - AR - Succinylacetone - Rx: low phe, low tyr diet curative

Effects of maternal PKU

- Teratogenic effects - Miscarriage - Microcephaly - ID (>90%) - IUGR (40%) - Cleft palate - Dysmorphic facies PREVENTED BY INSTITUTION OF DIET PRIOR TO CONCEPTION

- Hepatomegaly - Hypoglycemia - Cherubic or doll-like facies - Growth impairment

Hepatic Glycogen Storage Diseases Rx: - Cornstarch - Nocturnal enteral feeding

- GSD - Nephromegaly - Kidney disease - Lactic acidemia - Hyperuricemia - allopurinol - Hypertriglyceridemia

Glucose 6-phosphatase deficiency | von Gierke disease

- GSD - Mucosal ulcerations - Neutropenia - Neutrophil dysfunction

T1 ER glucose 6-phosphate transporter deficiency

- GSD - skeletal and/or cardiomyopathy, progressive - Hyperlipidemia - Elevated transaminases

Debrancher enzyme deficiency | Cori or Forbes disease

- GSD - Severe FTT - Progressive cirrhosis - Hypoglycemia

Branching enzyme deficiency (Amylopectinosis) | Andersen disease

- Massive cardiomegaly - Macroglossia - Hepatomegaly - Progressive muscle weakness - Hypotonia

alpha-GLucosidase deficiency | Pompe disease

- Muscle pain - Exercise intolerance - Progressive weakness - Rhabdomyolysis and myoglobinuria - No increase in blood lactate with exercise

Muscle phosphorylase deficiency | McArdle disease

- Hypoglycemia - Hyperventilation - Ketoacidosis - Lactic acidemia - Irritability, somnolence, coma and apnea - Moderate hepatomegaly - Fruit juice introduces

Fructose 1,6-Bisphosphatase Deficiency

- Choreoathetosis - Compulsive self-mutilation and ID - Hyperuricemia leads to gouty arthritis in adulthood

Lesch-Nyan Syndrome (Hypoxanthine guanine phosphoribosyltransferase deficiency) X-LINKED RECESSIVE

- Normal development until 4-5months - Cherry red macula - Myoclonic seizures - Hyperacusis - Motor weakness - Progressive spasticity - Hyperreflexia, blindness, deafness - Macrocephaly

GM2 Gangliosidosis - Tay Sachs and Sandhoff

- Most common lysosomal storage disorder - Defect of beta-glucosidase - HSM - Pancytopenia, bone pain - Hydrops fetalis, neurological involvement - Rapid deterioration and death

Gaucher disease

Syndromes Flashcards

(104 cards)