Syndromes Flashcards
AV Canal Defect
Trisomy 21
Bicuspid Ao Valve or Aortic Coarctation
Turner Syndrome
TOF or Truncus Arteriosus
DiGeorge Syndrome (22q11del)
Supravalvular Ao Stenosis
William’s Syndrome
Dilated Aortic Root or Mitral Valve Prolapse
Marfan’s Syndrome
Limb/thumb Anomalies, ASD +/- VSD
Holt-Oram
Muscle weakness, ataxia, cardiomyopathy
Friedrich’s Ataxia
Pulmonic stenosis, webbed neck, short stature
Noonan Syndrome
- 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
- Thrombocytopenia
- Absent radius
TAR
This inheritance typically involves genes encoding structural proteins, transcription factors, plus others
AD
- 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
- > 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
This inheritance typically involves genes encoding enzymes
AR
- 1:12000 newborns
- Persistent elevation in phe levels
- mutation in phenylalanine hydroxylase gene
PHENYLKETONURIA
- AR
- Lysosomal storage disease (mucopolysaccaridosis)
- Coarse facies
- Corneal clouding
- Organomegaly
- Cognitive loss
- Mutation in alpha-1 iduronidase gene
HURLER SYNDROME
- AR
- 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
- Lysosomal storage disease
- Coarse facies
- Hump on back
- Short stature
- Gibbus
- Cognitive loss (variable)
- Organomegaly
- Clear cornea
HUNTER SYNDROME
- X-linked recessive
- 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
- Lactic acidosis
- Mutation in gene encoding tRNAs
- Myopathy with ragged red fibers
- Dilated or hypertrophic cardiomyopathy
MITOCHONDRIAL MYOPATHY AND CARDIOMYOPATHY
- Lactic acidosis
- Early onset strokes
- Myopathy
- Mutation in tRNA genes in mitochondrial genome
MITOCHONDRIAL ENCEPHALOPATHY, LACTIC ACIDOSIS AND STROKE (MELAS)
Inheritance of cleft lip and palate
Complex inheritance
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
- BP easily maintained
- Acidosis unresponsive to usual means of respiratory and circulatory support. Ketoacidosis rare in neonate except with metabolic disease
- Sterile cultures
Association of E. coli sepsis with this metabolic disease
Galactossemia
Seizures
- Early in life
- Myoclonus
- Hiccupping
- 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
DM
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
- NEONATAL: poor feeding, apnea, ketoacidosis, seizures, hypoglycemia
- Infants/Adults: ataxia, FTT, +/- acidosis, progressive
- Childhood/adulthood: Intermittent ataxia, ketoacidosis during infection or protein rich meals
- 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
- Prenatal/neonatal onset of intractable seizures, HICCUPS
- Due to disorder in glycine cleavage enzyme
- 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
