Syndromes and diseases

Question 1

Costello syndrome

Answer 1

• Is a RASopathy
• Also called faciocutaneoskeletal syndrome or FCS syndrome
• Caused by any of at least five different mutations in the HRAS gene on chromosome 11
• It is characterized by delayed development and intellectual disabilities, distinctive facial features,
  unusually flexible joints, and loose folds of extra skin, especially on the hands and feet
• Heart abnormalities are common, including a very fast heartbeat (tachycardia), structural heart
  defects, and overgrowth of the heart muscle (hypertrophic cardiomyopathy)

Question 2

Cardiofasiocutaneous syndrome (CFC syndrome)

Answer 2

• Mutations that cause CFC are found in the KRAS, BRAF, MEK1 and MEK2 genes
• Costello and Noonan syndrome are similar to CFC
• It is characterized by the following:
• Distinctive facial appearance
• Unusually sparse, brittle, curly scalp hair
• A range of skin abnormalities from dermatitis to thick, scaly skin over the entire body
• Heart malformations
• Delayed growth
• Foot abnormalities (extra toe or fusion of two or more toes)

Question 3

Noonan syndrome

Answer 3

• Is a type of RASopathy
• May present with mildly unusual facial features, short height, congenital heart disease
  (Pulmonary valvular stenosis (50–60%), bleeding problems, and skeletal malformations
• Complications of NS may include leukemia
• Males appear to be affected more often than females
• Can be due to PTPN11 mutation

Question 4

Crouzon syndrome

Answer 4

-Autosomal dominant genetic disorder known as a branchial arch syndrome
- A defining characteristic is craniosynostosis, which results in an abnormal head shape
- Clinical findings include:
- Widely spaced eyes, short-broad head, hearing loss, bulging eyes, beaked nose, low-set
ears, strabismus, protruding chin, and short humerus and femur
- Caused by a mutation in the fibroblast growth factor receptor 2 (FGFR2), located on
chromosome 10.

Question 5

Muenke syndrome

Answer 5

• Also known as FGFR3-related cranisynostosis
• Autosomal dominant genetic disorder
• Clinical findings include:
• Widely spaced eyes, enlarged head, hearing loss, flat cheeks, and low-set ears

Question 6

Apert syndrome

Answer 6

-Probably due to FGFR2 mutation
- May be an autosomal dominant disorder
- Clinical features include:
- Widely spaced eyes, prominent forehead, flat skull posterior, bulging eyes, low-set ears, flat or
concave face, short thumb, and webbed fingers

Question 7

Saetre-Chotze syndrome

Answer 7

-Due to TWIST1 gene defect
- Clinical features include:
- Widely spaced eyes, low hairline, drooping eyes, interdigital webbing, deformed ears, crossed
eyes, and downward sloping palpebral fissures

Question 8

Neurofibromatosis

Answer 8

• A group of three conditions in which tumors grow in the nervous system. The three types are
  NF1, NF2, and schwannomatosis
• Autosomal dominant disorder
• Conditions in which tumors grow in the nervous system (generally non-cancerous)
• NF1:
• In NF1 symptoms include light brown spots on the skin, freckles in the armpit and groin, small
  bumps within nerves, and scoliosis.
• Mutation or deletion of one copy (or allele) of the NF-1 gene is sufficient for the development
  of NF-1
• NF2:
• There may be hearing loss, cataracts at a young age, balance problems, flesh colored skin
  flaps, and muscle wasting.
• NF 2 is caused by inactivating mutations in the NF2 gene
  -Schwannomatosis:
  -Characterized by chronic pain and common neurological symptoms (numbness, weakness, tingling, headaches)

Question 9

Cystic fibrosis

Answer 9

• Due to mutation in CFTR gene -> defects in CFTR protein
• Commonest cause of suppurative lung disease in caucasians
• Autosomal recessive disease
• Clinical features include:
• Respiratory complications/infections
• Exocrine pancreatic insufficiency
• Male infertility
• Finger clubbing
• Combination of both the following are used to treat people with cystic fibrosis who have the
  F508del mutation in the CFTR:
• Ivacaftor:
• A CFTR potentiator (meaning it increases the probability that the defective channel will be
  open and allow chloride ions pass through the channel pore)
• Lumacaftor:
• Acts as a chaperone during protein folding and increases the number of CFTR proteins that
  are trafficked to the cell surface

Question 10

Fragile X syndrome (FraX)

Answer 10

• Fragile X syndrome does not follow the usual pattern of X-linked dominant inheritance, and
  some scholars have suggested discontinuing labeling X-linked disorders as dominant or
  recessive
• Symptoms often include mild to moderate intellectual disability. The average IQ in males is
  under 55 (but the slides say 41)
• Physical features may include a long and narrow face, large ears, flexible fingers, and large
  testicles
• Typically due to an expansion of the CGG triplet repeat within the Fragile X mental retardation 1
  (FMR1) gene on the X chromosome:
• 55-200 CGG repeat = premutation
• > 200 CGG repeat = full mutation
• Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative
  disorder most frequently seen in male premutation carriers of Fragile X syndrome (FXS) over the
  age of 50
• About 20% of women who are carriers for the fragile X premutation are affected by fragile Xrelated primary ovarian insufficiency (FXPOI), which is defined as menopause before the age of
  40
• Full mutations do not happen de novo
• Women with premutation above 90 or with a full mutation -> always expand to full mutation in
  the next generation

Question 11

Duchenne’s muscular dystrophy

Answer 11

• X-linked recessive disorder caused by a mutation in the gene for the protein dystrophin
• Progressive symmetrical muscle weakness (proximal > distal) often with calf hypertrophy
• Symptoms present before five years of age
• Wheelchair dependency before 13 years of age
• Elevated creatine kinase
• Individuals with dystrophinopathy should avoid botulinum toxin injections
• Individuals with DMD have been reported to have severe reactions to anesthesia (malignant
  hyperthermia-like) that did not meet the criteria for true malignant hyperthermia
• Therapy under investigation:
• Gene repair (CRISPR)
• Ataluren
• Eteplirsen

Question 12

Becker’s muscular dystrophy

Answer 12

• X-linked recessive disorder caused by a mutation in the gene for the protein dystrophin
• Progressive symmetrical muscle weakness (proximal > distal) often with calf hypertrophy
• Weakness of quadriceps femurs is in some cases the only sign
• Wheelchair dependancy after 16 years of age; although some individuals remain ambulatory into
  their 30s and in rare cases into their 40s and beyond
• Preservation of neck flexor muscle strength (differentiates BMD from DMD)
• Elevated creatine kinase
• Individuals with dystrophinopathy should avoid botulinum toxin injections

Question 13

Triploidy

Answer 13

• Usually identified after pregnancy loss. Great majority of triploid conceptions are lost in first
  trimester
• Etiology:
• Digynic:
• Two maternal sets and one paternal (69, XXX or 69, XXY)
• Severe IUGR, large head, oligohydramnios, small placenta
• Diandric
• Two paternal sets and one maternal (69, XXX, 69, XXY or 69, XYY)
• IUGR with structural abnormalities, high maternal serum HCG, big placenta,
  oligohydroamnios
• Other features:
• Toe syndactyly
• Congenital heart defects
• Big anterior fontanelle

Question 14

Down syndrome

Answer 14

• Trisomy 21
• Clinical features:
• Round, epicanthic folds, small ears, protruding tongue, flat occiput, small ears
• Congenital heart defects (AVSD, VSD, PDA, tetralogy)
• Simian crease
• Intellectual disability (IQ of 50)
• Hypothyroidism
• Higher risk of Alzheimers disease < 40 years of age
• Increased risk of cancer (leukemia)
• Vision problems
• Etiology:
• Classical trisomy - nondisjunction (95%)
• 47, XX +21 or 47, XY +21
• Risk of recurrence in the second pregnancy is about 1%

Question 15

Edward’s syndrome

Answer 15

• Trisomy 18
• Clinical features:
• Small birth weight, growth retardation
• Weak cry
• Overriding fingers
• Rocker-bottom feet
• Low set ears
• Congenital heart defect in 90%
• Spina bifida
• Facial clefts
• Short life expectancy: 4 days (due to cardiopulmonary arrest)
• Etiology:
• Classical trisomy 47, XX +18 or 47, XY +18
• Mosaicism
• Risk of recurrence is low (0.55%)

Question 16

Patau syndrome

Answer 16

• Trisomy 13
• Clinical features:
• CNS defects (holoprosencephaly in 70%)
• Growth retardation
• Microphtalmia/anophtalmia (70%)
• Scalp defects (cutis aplasia)
• Cleft lip/palate
• Cardiac malformations (80%)
• Severe/profound mental retardation)
• Etiology:
• Classical trisomy 47, XX +13 or 47, XY +13
• Mosaicism
• Risk of recurrence is low (0.5%)

Question 17

Turner syndrome

Answer 17

• 1:500 female births
• 45, X
• 80% of the X chromosome in 45,X are of maternal origin
• Girls could be normal in phenotype - without dysmorphic features
• Dysmorphic features:
• Short stature
• Broad webbed neck
• Ptosis
• Low hairline
• Fetal edema
• Normal IQ or 10-15 points lower than the normal range
• Main problem is infertility!
• Gonadal dysgenesis
• Diagnosis:
• Karyotyping

Question 18

Klinefelter’s syndrome

Answer 18

• 1:800 male births
• An older mother may have an increased risk of a child with Klinefelter’s syndrome
• Etioloogy:
• 47, XXY (80%)
• Mosaicism (46, XY/47, XXY) (15%)
• 48, XXYY
• 48, XXXY
• 49, XXXXY
• Clinical features:
• Baby appears normal at birth
• Risk of undescended testes (1/3)
• Tall stature
• Increased risk for gynecomastia
• Infertility risk of 95%
• Increased risk for diabetes and cardiovascular diseases
• IQ decreased by 10-15%
• Higher risk fo autism (10%) and ADHD (36%)

Question 19

XYY syndrome

Answer 19

• 1:1000 male births
• Not linked to advanced paternal age
• IQ mainly in the normal range
• Increased incidence of delayed speech (70%)
• Behavioural problems
• Normal fertility
• Testosterone levels in the normal range
• Rare:
• Micropenis
• Cryptorchidism

Question 20

XXX/48 XXXX syndromes

Answer 20

• Could be without malformations
• Tall women
• Fertility is not disrupted
• IQ mainly in 85-90 range, or lower
• Problems in school with learning
• 1:1000 female births

Question 21

Sex chromosome mosaicism

Answer 21

• 46, XX/46, XY in prenatal testing:
• Due to maternal cell contamination or vanishing twins -> 2 genetically dissimilar gametes
• High probability of fetes being normal male (46, XY)
• USS is used to confirm normal male genitalia
• 45, X/45, XY
• Wide spectrum of phenotypes
• Could be:
• Turner syndrome
• Mixed gonadal dysgenesis
• Male pseudohermaphroditism
• Phenotypically normal male

Question 22

DiGeorge syndrome

Answer 22

• 22q11.2 microdeletion syndrome
• Normal or mild learning problems (62%)
• Moderate or severe learning problems (18%)
• IQ generally ranges from 70-90
• Psychiatric disorders in 10% of cases
• Motor milestones are delayed
• Postnatal onset of short stature in 36%
• Cleft palate
• Conductive hearing loss secondary to the cleft palate
• Limbs are slender and hypotonic with hyper extensible hands and fingers (63%)
• Cardiac defects are present in 85%, most common being VSD (62%), right aortic arch (52%),
  tetralogy of Fallot (21%)

Question 23

1p36 deletion syndrome

Answer 23

-Intellectual disability, severe in the majority of cases
- Speech more severely affected than motor development
- Behaviour difficulties
- Hyperphagia
- Microcephaly
- Cardiac structural defects in 71%, including PDA, VSD, ASD
- CNS defects including enlarged lateral ventricles, cortical atrophy, diffuse brain atrophy,
hypotonia and seizures with onset between 4 days and 3 years
- Micropenis, cryptorchidism, hypospadias, renal anomalies
- Hearing loss

Question 24

Prader-Willi syndrome

Answer 24

-About 74% of cases occur when part of the father’s chromosome 15 is deleted. In another 25%
of cases, the person has two copies of chromosome 15 from their mother and none from their
father
- Normal birth length, but mean adult heigh in males is 155 cm and in females 148 cm
- Obesity: Excessive appetite and increased weight beginning at a median age of 2 years
- Hair, eyes and skin: Blond to light brown hair with blue eyes and fair skin that is sun-sensitive
- Intellectual disability is mild (IQ of about 60 to 70)
- Speech articulation problems
- Small hands and feet
- Small genitalia and hypogonadism
- High pain threshold

Question 25

Angelman syndrome

Answer 25

• Due to a lack of function of part of chromosome 15 inherited from a person’s mother. Mostly due
  to a deletion or mutation of the UBE3A gene on that chromosome. Occasionally, it is due to
  inheriting two copies of chromosome 15 from a person’s father and none from their mother
• Blond hair (65%)
• Pale blue eyes (85%)
• Large mouth with tongue protrusion and widely spaced teeth
• Ataxia and jerky arm movements resembling a puppet gait (100%)
• Severe intellectual disability with marked delay in attainment of motor milestones (100%)
• Movement or balance disorder (100%)
• Absent speech or fewer than six words (100%)
• Easily excitable personality
• Seizures

Question 26

Indications for karyotyping

Answer 26

• Women with amenorrhea and couples with infertility of habitual abortion
• Pregnancy in an elderly woman (>35 years) (fetal chromosome analysis)
• Stillbirths and neonatal deaths
• Problems in early growth
• First degree relatives of a known or suspected case of chromosome abnormality
• Neoplasia

Question 27

Two methods of karyotyping

Answer 27

• Classical cytogenic karyotyping
  
  • Giemsa or G-banding karyotype analysis
  • Light microscope
  • Uses any cell capable of growth and devision
  • Band resolution and detection limit
  • Maximum detection: 5 Mb
• Molecular karyotypying
  
  • aCGH (array Comparative Genomic Hybridization)
  • Fluorescence scanner
  • Uses any sample adequate for DNA extraction
  • High resolution
  • Can only be used for unbalanced chromosomal
    alterations (duplications, deletions,
    monosomy, trisomy etc.)

Question 28

Preimplantation genetic screening/diagnosis

Answer 28

• Procedures performed during in vitro fertilisation before implantation
• Can be used to select embryos without genetic disorders
• Methods:
• PCR
• Next generation sequencing
• FISH
• aCGH
• Indications:
• Woman’s age > 35 years
• Recurrent miscarriages
• Non-effective in vitro fertilization in the past
• A child with chromosomal aberrations in previous pregnancy

Question 29

Fetal ultrasound

Answer 29

• Basic diagnostic test in pregnancy
• Should be performed in all pregnant women at least three times:
• Between 11th and 14th week of pregnancy
• Between 18th and 22nd week of pregnancy
• Between 28th and 32nd week of pregnancy
• Used for initial assessment of fatal anatomy and aneuploidy markers
• First trimester screening markers:
• Fetal heart rate
• Normal: 100-160 bpm
• Bradycardia in trisomy 18 and triploidy
• Tachycardia in trisomy 13 and Turner syndrome
• Increased nuchal translucency scan
• Increased in trisomy 21
• Absent or hypoplastic nasal bone
• Absent in trisomy 21
• Tricuspid regurgitation
• in 55% of foetuses in trisomy 21 and 30% of foetuses with trisomy 18 and 13
• Disappears in most foetuses with trisomy and healthy foetuses in second trimester
• Fetal ductus venous flow assessment
• Abnormal in 65% of foetuses with trisomy 21
• Abnormal in 55% of foetuses with trisomy 13 and 18

Question 30

Indications for fetal MRI

Answer 30

• Congenital brain anomalies
• Screening foetuses with a family risk for brain anomalies (tuberous sclerosis etc)
• Vascular abnormalities of the brain

Question 31

Double test

Answer 31

• Between 10th and 13th week of pregnancy
• Measures the following:
• Pregnancy Associated Plasma Protein A (PAPP-A)
• free beta human chorionic gonadotropin (B-hCG)
• In trisomy 21, PAPP-A is decreased and B-hCG is increased
• In trisomy 18 and 13, both are decreased

Question 32

Triple test

Answer 32

• Between 14th and 20th week of prengnacy
• Measures the following:
• Alpha-fetoprotein (AFP)
• Beta-hCG
• Unconjugated estriol (UE3)
• In trisomy 21, AFP and unconjugated estriol are decreased and beta-hCG is increased
• In trisomy 18, all are decreased
• In neural tube defects, AFP is increased and the rest is normal

Question 33

Cell-free foetal DNA in maternal blood

Answer 33

• cffDNA appears after 7th week of pregnancy
• Non-invasive fetal trisomy test (NIFTY test) can be performed between 10th and 24th week of
  pregnancy with the usage of Next Generation sequencing (NGS)
• Estimates risk of trisomy 21, 18 and 13, sex chromosome aneuploidies and some micro deletion
  syndromes
• Sensitivity is above 99%

Question 34

Invasive prenatal diagnosis

Answer 34

• Used to exclude or confirm fatal genetic disease
• Techniques:
• Chorionic villus sampling (CVS)
• Sampling chorionic villus and karyotyping it
• Done between 11th and 13th week of pregnancy
• Risk of miscarriage (0.5-1%)
• Risk of infection and amniotic fluid leakage
• Amniocentesis
• Performed between 15th and 17th week of pregnancy
• Small amount of amniotic fluid which contains fatal tissues in sampled and the fetal DNA is
  examined for genetic abnormalities
• 0.1% risk of miscarriage
• Risk of preterm labour
• Risk of respiratory distress
• Risk of alloimmunisation of the mother
• Percutaneus umbilical cord blood sampling (PUBS)
• Performed above 20th week of pregnancy
• Examines blood from fetal umbilical cord
• Carries a significant risk of complications (1-1.5% risk of miscarriage)
• Fetoscopy
• Endoscopic procedure during pregnancy that allows access to the fetus, amniotic cavity,
  umbilical cord and the fetal side of the placenta
• Allows medical interventions such as a biopsy or laser occlusion of abnormal blood vessels
  or the treatment of spina bifida

Question 35

Unusual smell of body fluids

Answer 35

• Can be typical for some metabolic diseases, examples:
• Mousy -> phenylketonuria
• Maple sirup -> maple sirup urine disease
• Sweaty feet -> isovaleric aciduria

Question 36

Phenylketonuria

Answer 36

• Autosomal recessive disease that primarily affects the brain
• Occurs in 1:10000 persons
• It is the result of a defect in the hydroxylation of phenylalanine to form tyrosine
• Symptoms:
• Affected infants are normal at birth
• Severe mental retardation (IQ <30) when left untreated; life-long treatment is required
• Treatment:
• Diet with very low protein + supplement of a phenylalanine-free amino acid mixture
• Treatment with BH4
• Maternal PKU
• Need for strict dietary treatment of mother because of risk of maternal PKU syndrome (secere
  brain damage and heart defects in the foetus without PKU

Question 37

Hyperammonemia

Answer 37

• Failure of the liver to clear plasma ammonia
• Can be caused by:
• Mechanical portal vein obstruction
• Liver failure due to hepatitis
• Inborn errors of metabolism involving the synthesis of urea (inherited hyperammonemia)
• Clinical manifestations:
• Severe neonatal hyperammonemia (> micromol/L)
• Poor feeding, hypotonia, apnea, hypothermia, vomiting, seizures, coma, death
• Urea cycle defects usually occur in 2nd day of life because milk contains protein
• Treatment:
• Reduction of dietary protein
• Removal of ammonia (hemodialysis)
• Sodium benzoate or phenyl acetate
• Arginine

Question 38

Organic acidemias

Answer 38

• Propionic acidemia, metylmalonic acidemia, isovaleric acidemia (citric acid cycle)
• Overload of metabolic acids to be excreted
• Laboratory manifestations:
• Hypoglycemia
• Metabolic acidosis with elevation of ketone bodies
• Neutropenia, thrombocytopenia
• Abnormal blood amino acids
• Treatment:
• Acute management:
• Stop all protein intake
• Being IV D10 at 8-10 mg/kg/min
• Being IV carnitine
• Treat hyperammonemia, acidosis, “trigger”
• Start calorie source (intralipid)
• Blood exchange transfusion/dialysis
• Long term management:
• Specific amino acid restricted diet
• Carnitine supplementation, B12, folate

Question 39

Fatty acid oxidation defect

Answer 39

• Symptoms after fasting as fatty acid oxidation increases during fasting or during infections
• Fatty acids are used in:
• Liver: ketogenesis
• Heart: important fuel
• Muscle: fuel for chronic use
• Symptoms:
• Liver: Reye-like syndrome (vomiting, personality changes, confusion, seizures, and loss of
  consciousness)
• Heart: Cardiomyopathy - arrhythmias
• Muscle: rhabdomyolysis - myopathy

Question 40

Medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency)

Answer 40

• Mostly manifests in infancy up to 2 years
• Can always appear during times of metabolic stress
• Triggering factors:
• Fasting
• Infections
• Symptoms:
• Reye-like syndrome
• Hypoglycemia
• Heart: Arrythmia, sudden death
• Sudden infant death syndrome (SIDS)
• Autopsy: fatty liver, heart, brain edema
• Treatment:
• Avoid fasting
• Prompt treatment of infections
• IV glucose
• L-carnitine

Question 41

Galactosemia

Answer 41

• Glassic galactosemia: galactose-1-phosphate uridyltransferase deficiency
• Increased blood and urine galactose
• Liver failure and renal tubular function disorder after milk feeding with rapid improvement on
  galactose-free diet
• Cataracts (toxic influence of galactitol)
• Mild brain damage despite treatment

Question 42

Lysosomal storage diseases

Answer 42

A group of inherited diseases resulting from decreased activity of specific lysosomal enzymes
- Enzyme deficiency -> storage of specific macromolecules that are “cellular waste”
- Cumulative frequency: 1:5000-7000
- Pathogenesis:
- M degraded macromolecules -> progressive accumulation of these in lysosomes in various
tissues and organs -> progressive deformation of cartilages and of the skeleton ->
enlargement of organs (liver, spleen) -> damaging of heart valves, blood vessels, bone
marrow, skin, eyes, brain, nerves
- Symptoms depend on organ specificity of storage and on severity of the enzymatic block
- Treatment:
- Enzyme replacement therapy!
- Bone marrow transplantation
- Substrate reduction therapy

Question 43

Enzyme replacement therapy

Answer 43

Administration of an active artificially manufactured enzyme

• What can we treat?
• Alglucerase (now replaced my imigucerase) -> Gaucher disease
• Agalsidase alfa -> Fabry disease
• Aglucosidase alfa -> Pompe disease
• Enzyme infusion weekly or every two weeks
• Works best with Gaucher disease so far
• Treatment is not effective within the brain
• Costs are extremely high

Question 44

Sanger sequencing

Answer 44

Gold standard in DNA testing for point mutations

• Uses polymerase chain reaction (PCR)
• Sanger sequencing:
  1. DNA sample
  2. PCR amplification
  3. Sequencing PCR
  4. Signal detection
  5. Data analysis and interpretation

Question 45

Congenital anomaly

Answer 45

• Is an anomaly that affects a body part or physiologic function and is present at birth
• The process is affected by genetic, environmental or both factors
• Frequency:
• Major congenital anomalies
• Isolated (3%)
• Multiple congenital anomalies (0.7%)
• Minor congenital anomalies (14%)

Question 46

Malformations

Answer 46

• Caused by an abnormal development of the organ/tissue, that is abnormal from the beginning
• Caused by genetic or environmental factors
• Etiology is usually multifactorial
• Types:
• Hypoplasia (underdevelopment or incomplete development of a tissue or organ)
• Incomplete closure (e.g. neural tube defects, cleft palate)
• Incomplete separation (e.g. syndactyly)

Question 47

Deformations

Answer 47

• Caused by an abnormal physical force that damages healthy organ/tissue
• Usually develop during the third trimester of pregnancy
• Have a tendency to spontaneous correction when physical force passes
• Correcting treatment gives good results
• Examples:
• Congenital hip dysplasia
• Congenital clubfoot

Question 48

Disruptions

Answer 48

• Caused by a destructive process that affects an organ/tissue that had started to develop
  normally
• Amniotic band syndrome:
• Cuased by entrapment of fetal parts (usually a limb or digits) in fibrous amniotic bands while i
  utero
• May result in constriction rings around the digitis, arms and legs, swelling of the extremities
  distal to the point of constriction (congenital lymphedema) or amputation of digits, arms and
  legs (congenital amputation)

Question 49

Dysplasias

Answer 49

• Caused by an abnormal organization of the cells in the organ/tissue
• Almost all dysplasia are monogenic diseases

Question 50

Multiple congenital anomalies:

Answer 50

• Syndromes
• Complex of phenotypic traits that are typical for defined clinical diagnosis
• Examples:
• Down syndrome
• DiGeorge syndrome
• Achondroplasia
• Fetal alcohol syndrome
• Sequences
• Multiple anomalies that result from the pathologic cascade caused by a primary insult
• Examples:
• Potter sequence (renal agenesis -> oligohydroamnios -> pulmonary hypoplasia -> RDS etc)
• Pierre-Robin sequence (micrognathia -> cleft palate and glossoptosis -> airway obstruction)
• Associations
• Selected congenital anomalies that tend to develop all together in an association
• VACTERL:
• V - Vertebral anomalies
• A - Anorectal anomalies
• C - Cardiovascular anomalies
• T - Tracheoesophageal fistula
• E - Esophageal atresia
• R - Renal anomalies
• L - Limb defects

Question 51

Teratogenesis

Answer 51

• Teratogene is an agent that is able to affect normal ontogenetic development and leads to a
  congenital anomaly
• Mutagene is an agent that is able to affect the genetic information on the level of DNA or on the
  level of chromosomes. Mutagenes cause mutations
• Teratogens cause congenital noamlaies. Some mutagens are also teratogens. However, not all
  teratogens are mutagens

Question 52

Three main groups of teratogens

Answer 52

• Physical
• X-rays (mind you, common diagnostic doses are not dangerous)
• Ionizing radiation (e.g. gamma radiation)
• High temperature (sauna, fever)
• Mechanical factors (amniotic bands, oligohydramnion)
• Chemical
• Chemical substances used in industry or agriculture
• Alcohol (cause of Fetal alcohol syndrome)
• Products of cigarette smoking
• Other drugs, doping
• Cytostatics and some other groups of medicaments (antiepileptics, antibiotics, warfarine,
  ACE-inhibitors
• Biological
• Teratogenic effect is species-dependent and the dose-dependent
• A substance could be teratogenic in only a specific week of the pregnancy
• The teratogenic effect might be restricted to the development of a specific organ/tissue
• During the time of blastogenesis, the damage caused by teratogens cause no anomalies
• The time of organogenesis (3rd to 12th week of pregnancy) is the most critical period when it
  comes to teratogens

Question 53

Drugs with proven teratogenic effects (alot)

Answer 53

Alcohol
- Facial dysmorphy, brain growth retardation, congenital anomalies of the heart
- Warfarine
- Chondrodysplasia punctata, risk of abortion
- Retinoids
- Anomalies like DiGeorge syndrome, anomalies of CNS, anomalies of the internal ear
- Aminopterine + Methotrexate
- Anomalies of cranium and skeleton, anencephaly
- Thalidomide
- abnormal development of long bones, phocomelia, polydactyly, syndactyly, oligodactyly and
other malformations
- Phenytoin
- Congenital anomalies of the heart, failure of the CNS closure, cleft palate
- Trimetadione
- Congenital anomalies of the heart, anomalies of the urogenital system, mental retardation
- Valproate
- Facial dysmorphy, defects of the CNS
- Lithium
- Anomalies of the heart, Ebstein’s anomaly
- Amfetamine
- Congenital anomalies of the heart, exencephaly, biliary atresia
- Diazepam
- Cleft lip and cleft palate
- ACE-inhibitors
- Hypoplasia of the skull, renal dysgenesis
- Corticosteroids
- Cleft palate, renal atrophy
- Androgens
- Masculinization of the external genitalia
- Progesteron
- Virilization, anomalies of the heart, anomalies of the CNS, defects of the extremities,
esophageal atresia

Question 54

Biological teratogens

Answer 54

Torch:
- T-Toxoplasma
- O-Other viruses
- R-Rubella virus
- C-Cytomegalovirus
- H-Herpesvirus
Diseases of the mother:
- Diabetes mellitus
- Phenylketonuria

Question 55

Oncogenetics

Answer 55

• Cancer affects approximately one person in three during their lifetime
• The great majority of cancers are sporadic occurrences related to the gradual accumulation of
  somatic mutations with age and exposure to carcinogenic factors in the environment such as
  cigarette smoke, UV radiation, X-ray
• Majority of familial cancer susceptibility syndromes follow an autosomal dominant pattern of
  inheritance. Transformation to cancer usually requires a balletic mutation at the cellular level.
• Oncogenesis is a multistep process including:
• Mutation of cellular genes
• Clonal selection
• Aggressive growth

Question 56

Mutations (somatic or germinal)

Answer 56

• Mutation in a proto-oncogene (normal genes that can be mutated to become oncogenes)
• Can be activated through:
• Viral transduction/insertion
• Point mutation
• Gene amplification
• Chromosomal translocation
• The mutation results in either:
• An increase in the amount of normal gene product
• Production of an abnormal gene product
• Mutation in a tumor supressor gene (encode proteins that suppress tumor formation)
• If there is loss of function of the tumor suppressor genes due to mutation on both alleles
  (Knudson’s two-hit hypothesis), there will be uncontrolled cell growth that can result in cancer
• Mutation in a gene responsible for DNA repair
• A loss of function mutation on one or on both alleles leads to an increased number of
  mutations in proto-oncogenes or tumor suppressor genes -> cancer

Question 57

Examples of oncogenes in human malignancies

Answer 57

• K-RAS
• • Point mutation
• • Colorectal cancer
• N-MYC
• • Amplification
• • Neuroblastoma
• BCR-ABL
• -Translocation
• -CML/ALL
• RET
• • Rearrangement
• • Thyroid carcinoma

Question 58

Examples of tumor suppressor genes in human malignancies

Answer 58

• BRCA1
• • Breast cancer
• Rb1
• • Retinoblastoma
• p53
• • Li-Fraumeni syndrome
• WT1
• • Wilm’s tumor
• NF2
• • Neurofibromatosis

Question 59

Examples of DNA repair genes involved in human malignancies

Answer 59

• ATM
• • Ataia-teleangiectasia
• • Autosomal recessive
• XPA, XPB, XPC, XPD and other genes
• • Xeroderma pigmentosum
• • Autosomal recessive
• MLH1, MSH2, MSH6, PMS2
• • Hereditary non-polyposis colorectal cancer (Lynch syndrome)
• • Autosomal dominant

Question 60

Breast cancer

Answer 60

• High population prevalence (lifetime risk for women: 10-12%)
• Familial incidence (only accounts for 3-4%)
• • Early onset (<40 years)
• • Frequently presents with bilateral tumors
• • Ovarian cancer in the family
• Genetic background:
• • Dominantly inherited mutations in BRCA1 and BRCA2

Question 61

Colorectal cancer

Answer 61

• Third most common cancer in males (after lung and prostate cancers) and second most
  common (after breast cancer) in females)
• <1% of cases develop the disease <45 years
• Genetic susceptibility accounts for 5% of cases
  – Familial adenomatous polyposis
  – Lynch syndrome

Question 62

Familial adenomatous polyposis

Answer 62

• Due to autosomal dominant inheritance of germline mutations in the APC gene (15-20% of
  cases arise de novo)
• Almost complete penetrance
• Prophylactic colectomy in affected individuals between the ages of 16 and 20 to minimise the
  risk of cancer

Question 63

Lynch syndrome

Answer 63

• Autosomal dominant mutation of DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2
• Main features:
• • Colorectal cancer (lifetime risk 80% in males and 40% in females)
• • Endometrial cancer (lifetime risk 50%)

Question 64

Ataxia-teleangiectasia

Answer 64

• Cerebellar ataxia
• Telangiectasia (dilated blood vessels over the sclera of the eye and sun-exposed skin)
• Immunodeficiency (chronic infections)
• High risk for lymph
• High alpha-fetoprotein levels in blood

Question 65

Li-Fraumeni syndrome

Answer 65

• Rare autosomal dominant disorder with a wide spectrum of neoplasia occurring in children and
  young adults
• Breast cancer, soft tissue sarcomas, osteosarcoma, brain tumors, daren-cortical cancer, Wilms
  tumor and phyllodes tumor are very typical
• Due to p53 mutation

Question 66

MEN1

Answer 66

• Autosomal dominant disorder due to mutations in the tumour suppressor gene MEN1
• Development of symptoms at all ages
• Occurence of tumors:
• Parathyroid (95%)
• Pancreatic islet (40%)
• Anterior pituitary (30%)
• High penetrance

Question 67

MEN2

Answer 67

• All MEN2 subtypes are inherited in an autosomal dominant manner and caused by occurrence of
  a gain-of-function pathogenic variant of the RET proto-oncogene
• MEN2A
• 70-80% of MEN2 cases
• Medullary thyroid carcinoma (early adulthood)
• Pheochromocytoma
• Parathyroid adenoma/hyperplasia
• FMTC
• 10-20% of MEN2 cases
• Familial medullary thyroid carcinoma (middle age)
• MEN2B
• 5% of MEN2 cases
• Medullary thyroid carcinoma (early childhood)
• Pheochromocytoma
• Mucosal neuromas
• Ganglioneuromatosis of the GI tract
• “Marfanoid” habitus (constellation of symptoms resembling those of Marfan syndrome)

Question 68

Intellectual disability

Answer 68

• 1-2.5% have an IQ <70 and 0.3-0.5% have and IQ <50
• Cytogenic and clinical diagnoses in mild mental retardation (IQ range of 50-70)
• Idiopathic (80%)
• Down’s syndrome (5.7%)
• Fragile X syndrome (4.6%)
• Malformation or genetic syndrome (3.4%)
• Cytogenic and clinical causes of severe mental retardation (IQ <50)
• Idiopathic (30-50%)
• Chromosomal, including Down’s syndrome (4-28%)
• Malformation or genetic syndrome (10-20%)
• CNS anomalies (7-17%)
• Environmental causes, prematurity (5-13%)
• CNS anomalies (7-17%)
• Fragile X syndrome (2-6%)

Question 69

Dementia

Answer 69

• Affects memory, speech, perception, and mood
• Risk of developing dementia increases with age
• Most common dementia over the age of 40 is Alzheimer’s disease. Other common causes
  include vascular dementia, Lewy body dementia, frontotemporal dementia and Parkinson’s
  disease
• Alzheimer’s disease has a prevalence of:
• 1-2% among those aged 65-69 years
• 40-50% among those 95 years of age and over
• Familial Alzheimer’s disease has three identified causative genes
• Beta-amyloid precursor protein on chromosome 21
• Presenilin 1 (PSEN1) on chromosome 14
• Presenilin 2 (PSEN2) on chromosome 1

Question 70

Beckwith-Wiedemann syndrome

Answer 70

• Loss of methylation on the maternal chromosome at imprinting center 2 (IC2) 50%
• Paternal uniparental disomy for chromosome 11p15 (20%)
• Gain of methylation on the maternal chromosome at imprinting center 1 (IC1) 5%
• Deletions or duplication in the region 11p15
• Point mutations of CDKN1C (40% of familial cases and 5-10% of cases with no family history)
• Major findings:
• Macrosomia (weight and length >97th centile)
• Macroglossia
• Hemihyperplasia (asymmetric overgrowth of one or more regions of the body)
• Omphalocele or umbilical hernia
• Embryonal tumor (e.g. Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma)
• Visceromegaly (liver, spleen, kidneys, adrenal glands, pancreas)
• Cleft palate
• Cardiomyopathy
• Positive family history

Question 71

Silver-Russel syndrome

Answer 71

• Hypomethylation of the paternal imprinting center 1 (IC1) of chromosome 11p15.5 (35-50%)
• Maternal uniparental disomy for chromosome 7 (UPD7) 10%
• Idiopathic
• Major findings:
• Intrauterine growth retardation
• Short stature
• Relative macrocephaly
• Fifth-finger clinodactyly
• Triangular face
• Hemohypotrophy

Question 72

Wolf-Hirschhorn syndrome

Answer 72

• Deletion of the region 4p16.3
• Major findings:
• Intrauterine growth retardation
• Postnatal growth retardation
• Hypotonia
• Developmental delay/intellectual disability
• Seizures
• Skeletal anomalies
• Congenital heart defects
• “Greek warrior helmet” appearance of the nose
• High anterior hairline
• Micrognathia

Question 73

Achondroplasia

Answer 73

• Mutation in FGF3 gene
• Signs and symptoms:
• Disproportionate dwarfism
• Rhizomelic shortening
• Varus (bowleg) or valgus (knock knee) deformities)

Question 74

Pfeiffer syndrome

Answer 74

• Strongly associated with mutations of the fibroblast growth factor receptor 1 (FGFR1) on
  chromosome 8 or the fibroblast growth factor receptor 2 (FGFR2) gene on chromosome 10.
• Widely spaced eyes, underdeveloped jaw, beaked nose, hearing loss, and bulging eyes
• About 50 percent of children with Pfeiffer syndrome have hearing loss; dental problems are also
  common