Genetics Flashcards
CHROMOSOME
Partial trisomy 10q
various renal anomalies
abnormal facies
microcephaly
limb, cardiac
Trisomy 8
Mostly mosaic, usually lethal in utero
Deep creases in palms/soles
Campotodactyly (flexion of PROX I/P joints)
Deep set eyes, cupped ears
ID
Trisomy 13
MIDLINE abnormalities
Cardiac VSD > PDA
Cutis aplasia
Polydactyly, narrow hyperconvex fingernails
Cleft lip, cleft palate, SMALL EYES, colobomas
Sloping forehead
GI - umb or inguinal hernia
GU - cryptorchidism, abnormal scrotum
Neuro - microcephaly, HOLOPROSENCEPHALY, seizures
Other - persistance fetal hemoglobin, increased neutrophils with nuclear projections
95% spont abortions, 90% die within 1st year
PATAU
Trisomy 18
Edward syndrome
F»_space; M
Cardiac - VSD, PDA > bicuspid AV, pulm stenosis
Extremities - overlapping 2nd over 3rd or 5th over 4th fingers, CLENCHED HAND, hypoplastic nails, rockerbottom feet
Facial - micrognathia, small mouth, small eyes, small palpebral fissures, occipital prominence
GI - umb or inguinal hernia
GU - cryptorchidism
Neuro - hypertonia after NB period, narrow biparietal diameter, ID
Single umb artery, IUGR, short sternum
majority spont abortions; 50% mortality 1st year of life
Trisomy 21
extra chromosome mostly maternal, due to nondisjunction
50% CV - endocardial cushion defect > VSD > PDA
Endo - hypothyroid
Extremities - wide gap between 1st and 2nd toes, hyperflexibility of joints, clinodactyly, transverse palmar crease
Facial - upslanting palpebral fissures, flat nasal bridge
BRushfield spots, inner epicanthal folds
Large protruding tongue
Short neck, redundant posterior folds
GI - DA, HD
GU - hypogonadism, most females infertile, most males too
CNS - hypotonia, m ild microcephaly, ID
Pelvic dysplasia, OSA, transient myeloproliferative disorder, leukemia, Alzheimer’s
SPORADIC or ASSOCIATIONS
Brown pigmentation
Fibrous dysplasia of bones
Hyperparathyroidism
Hyperthyroidism
Pit adenomas
Precocious puberty
McCune Albright
sporadic
also considered neurocutaneous
Coast of Main hyperpigmented along lines of Blashko, Mutation in GNAS1
VACTERL
vertebral
anal atresia
cardiac
TEF
renal
limb
1/2 with renal agenesis, some with renal dysplasia
Eagle-Barrett syndrome
hypoplasia of abdominal muscle,
cryptorchidism
prostatic hypoplasia
MEGAURETERS - hydronephrosis, dysplastic kidneys
atonic bladder
Caudal regression syndrome
sacral and lumbar hypoplasia
disruption of distal spinal cord
neurogenic bladder
VUR
hydronephrosis, renal agenesis
Zellweger syndrome
Cerebrohepatorenal
- hepatomegaly
- GLAUCOMA
- brain anomalies
- cortical renal CYSTS
Jeune syndrome
Thoracic asphyxiating dystrophy
- small thoracic cage
- short ribs
- abnormal costochondral junctions
- CYSTIC tubular dysplasia, glomerulosclerosis, hydronephrosis
Meckel-Gruber syndrome
ENCEPHALOCELE
microcephaly
polydactyly
cryptorchidism
POLYCYSTIC or DYSPLASTIC kidneys
Pentalogy of Cantrell
Pentalogy of Cantrell (POC) is a collection of five congenital midline birth anomalies heart, pericardium, diaphragm, sternum, and abdominal wall.
It is also referred to as thoracoabdominal ectopia cordis, a condition where the heart is covered by an omphalocele-like membrane. Ectopia cordis (EC) is often found in fetuses with POC.
Infants usually have multiple cardiac malformations with ventricular septal defect, and tetralogy of Fallot being the most common. POC may also carry genetic associations with trisomy 13, 18, 21, and Turner syndrome. The initial management addresses the lack of skin overlying the heart and abdominal cavity.
OEIS complex
The OEIS complex comprises a combination of defects including omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects. It may represent the most severe manifestation of a spectrum of birth defects, the exstrophy-epispadias sequence.
AUTOSOMAL DOMINANT
Tuberous sclerosis
AD - chr 9, 16
PCKD, renal angiomyolipomata
Fibrous angiomatous lesions
RHABDOMYOSARCOMA
ASHLEAF MACULES
Hypopigmented macules
Intracranial calcifications
seizures
2+/8 features
Cafe au lait spots (6+)
Lisch nodules
First relative with this disease
Axillary or groin freckling
Neurofibroma
Optic glioma
Plexiform neurofibroma
Skeletal dysplasia
Neurofibromatosis 1
AD
Most common NB presentation = cafe au lait spots (increase with age, usually 100% by 4 yo)
NF 2 - bilateral acoustic or central neurofibromatosis
Nail-patella syndrome
hereditary osteo-onychodysplasia
hypoplastic nails
hypoplastic / absent patella
proteinuria, nephritis syndrome
Achondroplasia
80% from new mutations – mutation in transmembrane domain of fibroblast growth factors receptor 3 gene
Relative glucose intolerance
TRIDENT hands (fingers nearly equal length, 3rd, 4th separation)
Short limbs (esp prox long bones)
Depressed nasal bridge, frontal bossing
Megalocephaly, mild hypotonia, small foramen magnum (may lead to hydrocephalus)
Caudal narrowing of spinal cord - can cause sx later
Normal intelligence
Apert
Acrocephalosyndactyly
sporadic disorder with AD inheritance pattern
mutation in fibroblast growth factor receptor 2 gene
Fusion of SKULL, HANDS, FEET bones
HYPERTELORISM, MIDFACE hypoplasia
abnormally shaped skull, large fontanels, flat facies
BROAD distal phalanx of thumb and big toe
Irregular CRANIOSYNOSTOSIS (esp coronal)
VSD, PS, overriding aorta
ID
Increased risk acne, fusion cervical vertebrae
Crouzon
Craniofacial dysastosis
AD
Variable expression
Mutation in fibroblast growth factor 2 gene (diff mutations than Apert)
MAX HYPOPLASIA, SHALLOW orbits, ocular PROPTOSIS, curved parrot beak nose
premature CRANIOSYNOSTOSIS (esp coronal, lambdoid, sagittal)
LESS mental deficiency
decreased visual acuity, conductive hearing loss
Beckwidth Wiedemann
Usually Sporadic occurence
Loss of methylation of maternal chromosome 11 (50%), PATERNAL uniparental disomy (20%), gain of methylation of mat chromosome 11 (5%)
Face - macroglossia, linear EARlobe fissures, EXOPHTHALMOS, prominent OCCIPUT
GI - omphalocele
Growth - macrosomia, organ hyperplasia (renal, pancreatic, pit), fetal adrenocortical cytomegaly
without mental deficiency, large tongue
Also with nevus capillary malformations
intraabd malignancies esp wilms tumor and hepatoblastoma (by 8 yo), limb hyperplasia, hypoglycemia (HCT responsive)
Outcomes - delayed neonatal adaptation, feeding issues, may need sleep study; tumor surveillance q3 mo until 7 yo
infant mortality as high as 21%
Holt Oram
AD
Some 12q2
Hand heart
CV - >50% ASD»_space; VSD, CoA, conduction
Extr - upper limb defects, absent HYPOPLASTIC or ABN THUMBS, narrow shoulders
Marfan
AD, variable expression
Fibrillin 1 gene
CV - dilated aorta, aortic aneurysm, MVP
Extr - arachnodactyly, hyperextensibility, scoliosis
Face - lens subluxation (upward), myopia
INguinal hernia
Other – severe neonatal form w/in 3 mo - CV, MV esp, contractures, high arched palate, hyperextensibility
Mgmt - childhood BB (decrease risk aortic dilatation), yearly ECHO, Abx before dental, no sports contact
Noonan
AD, wide variable expression
12q22
“TURNER LIKE”
CV > 50% Dysplastic pulmonary valve, ASD, CM
Pectus excavatum
Increased carrying angle
Short, WEBBED neck, lost posterior hairline, hypertelorism
Cryptorchidism, small penis
ID
Short stature
Abd in coagulation pathway – increased incidence von willebrand disease, 1/3 thrombocytopenia, in utero cystic hygroma
Osteogenesis Imperfecta
AD, defect in collagen I
I: 25% in 1st year, blue sclera, increased risk fractures, deafness, abn dentition, easy bruising, hypertextensible joints
II: At BIRTH, dark blue sclera, increased fx, SHORT AND BROAD bones, die early infancy resp failure, Wormian bones
III: at BIRTH, increased risk of fx, IUGR, macrocephaly, deafness, severe kyphoscoliosis
IV: normal to grey sclera, increased risk bone deformities
Stickler syndrome
AD, variable expression
Collage type II
hereditary arthro-ophthalmopathy
FLAT facies, midface or mandibular hypoplasia (can be ax Pierre Robin), myopia, chorioretinal degeneration, cataracts, ret detach
Deafness, hypotonia, hyperextensible joints
MYOPIA, SPONDYLOEPIPHYSEAL DYSPLASIA (flat vertebrae w. anterior wedging – affects SPINE and LONG BONES), MVP
Thanotrophic dysplasia
all from new mutations
mutation in tyrosine kinase domain of FGFR3 gene
I: more common, curved long bones, flat vertebral bodies (platyspondyly) - TELEPHONE FEMUR
II: straight femoral bones, taller vertebral bodies, cloverleaf skull
SHORT limbs, BOWED long bones
LARGE cranium (vs body size), LOW nasal bridge, bulging eyes
Temporal lobe dysplasia, hydrocephalus, brain stem hypoplasia, hypotonia, severe DD
narrow thorax
Treacher Collins
AD, variable expression
Mandibulofacial Dysostosis
TCOF1 gene on Chr 5 -> leads to 1st and 2nd branchial arch maldevelopment
Face - LOWER eyelid coloboma, MANDIBULAR hypoplasia, MALAR hypoplasia (maybe cleft in zygomatic bone)
Partial to total absense lower eyelashes
conductive hearing loss, visual loss
normal intelligence
XR: hypoplastic zygomatic arch
Outcome: can develop resp distress from narrow airway (may need mandibular distraction), surgical facial correction after facial growth as older, amblyopia may lead to visual loss
Waardenburg syndrome
I: AD PAX3 gene mutation 2q35 - lateral displacement MEDIAL CANTHI, deafness severe, pigmentary abn
II: AD microphthalmia gene 3p12.3 - normal medial canthi, deafness, severe 50%, pigmentary abn
III: AD - upper limb defects eg bone and mm hypoplasia, contractures, pigmentary, ocular, auditory
IV: AD or AR - like type II. also HIRSCHSPRUNG
non, progressive, profound hearing loss (defect in organ of Corti)
Von Hippel Landau
Chr 3, AD
over-expression of HIF -> tumor overgrowth
Mult tumors esp cerebellum
Hemangiomatas
Pheochromocytomas
MICRODELETIONS
Newborn with hypotonia
Almond shaped eyes
Poor feeding, poor sucking
Bilateral failure of testes to descend
Excessive sleepiness
Prader Willi
Deletion of paternal allele in 15q11 - q13 so gets both copies of this region from mother (maternal uniparental disomy)
Hypotonia
Jerking movements “like a puppet”
Ataxia
Risk seizures
Widely spaced teeth
Large mouth
Deep set eyes
Angelman
Deletion of paternal allele in 15q11 - q13 so gets both copies of this region from FATHER (paternal uniparental disomy)
DiGeorge
de novo
velocardiofacial syndrome = CATCH 22
cardiac (AORTIC ARCH abnormalities, PDA (#1?), ToF, VSD
Abnormal facies - cleft palate, PROMINENT NOSE / BULBOUS, HYPERTELORISM, protuberant ears, micrognathia, SHORT PHILTRUM, SHORT PALP FISSURES
Thymic hypoplasia - cellular immunity deficient
Cleft palate
Hypocalcemia - due to hypoplastic parathyroid glands –> can lead to seizures
GI can have CDH, imperforate anus, esophageal atresia
Rubenstein-Taybi
16p13.3 - mostly sporadic - DELETION
Cardic PDA, VSD, ASD
BROAD thumbs, BROAD first toes, 5th finger clinodactyly, flat feet, joint hypermobility
DOWNWARD slanting palpebral fissures, hypoplastic maxilla, narrow palate, prominent or beaked nose
Hirsuitism, keloids
MICROCEPHALY, POSTNATAL growth deficiency, INCREASED RISK TUMORS
WAGR
11p13 - diff sized deletions with diff phenotypes
Wilms tumor, Aniridia, GU abnormalities, moderate to severe ID (R)
prominent lips, micrognathia
congenital CATARACTS
GU - cryptorchidism
may devp gonadoblastomas, short stature, microcephaly
Williams syndrome
7q11.23 deletion – deletion of elastin gene
CV - supravalvuler subaortic stenosis»_space; PPS, VSD 50 - 70% CV
HYPOPLASTIC NAILS
PROMINENT LIPS, HOARSE VOICE, blue eyes, stellate IRIS pattern, periorbital fullness
low IQ
Renal asymmetri or pelvic kidney
transient hyperCa
X linked DOMINANT
Fragile X syndrome
XL dominant
Loss of function mutation (due to unstable CGG repeats)
most commonly inherited cause of ID
triple repeat mutation with >= 60 CGG repeats
number of methylated repeats ass with severity disease
LONG facies, prominent forehead, LARGE ears
Large testes
ID, 50% females ID and rest LD
autism
cluttered behavioral problems
Hyperextensible joints, mild CT dysplasia
Premutation 50 - 200 (females premature ovarian failure, ID - have some functional gene)
Complete > 200
X linked RECESSIVE
Menkes
Xq13
kinky hair
abnormality of copper transport –> Cu deficiency –> Cu cannot act as cofactor for many enzymes
TWISTED, FRACTUREd lightly pigmented hair, PUDGE face without expression
Progressive cerebral deterioration (1-2 mo age hypertonia, irritable, seizures)
Wormian bones, increased risk fractures (lateral spur on bones)
Dx - abnormal Cu uptake in amniotic fluid cells (prenatal dx)
Death in early infancy
Klinefelter
47XXY
CV - MVP, ToF, ASD
Disproportionately long arms and legs, elbow dysplasia
HYPOGONADISM, HYPOGENITALIA, gynecomastia, infertile (atrophy seminiferous tubules)
behavioral difficulties, LD
Increased risk extragonadal germ cell tumors
Mgmt - testosterone 11 - 12 yrs, consider mastectomy
Turner
45X, 40% mosaic – 45X / 46XX depends on distribution of cells that lack X chromosone, some secondary sex characteristics
chromosome deleted usually PATERNAL so not associated with AMA
in utero - spont abortion
CV 35% CoA, BAV, AS, MVP
Cubitus valgus (increased carrying angle)
Cystic hygroma, excess nuchal folds, webbed posterior neck
gonadal dysgenesis, no secondary sex characteristics, amenorrhea
horseshoe kidney
congenital lymphedema, short stature, broad chest wide nipples
incresaed risk gonadoblastoma
Mgmt - growth hormone, estrogen for secondary sex characteristics, echo q5 yrs (risk dissection)
Most normal intellience, some LD, increased risk osteoporosis, a/i thyroid disease
CHARGE
chromodomain helicase DNA binding gene 7 (CHD 7) on chr 8q12
AD but mostly de novo
Coloboma, heart disease, atresia of choanae, retarded growth, Genital hypoplasia (more common - 50% with this) , Ear anomalies
Dx = all 4 major or 3 major and 3 minor
Major - ear, CN, coloboma, choanal atresia
Minor - DD, cardiac, facial features, FGR, genital hypoplasia, TEF, CLeft lip/palate
note - can also have some hypoCa and immune dysfunction ( has been reported in some)
Cat eye
Extra part of chromosome 22, in quadruplicate or triplicate at 22q11 region
CV TAPVR, persistent SVD
Facial - downslanting palpebral fissures
ANAL ATRESIA
mild ID
COLOBOMA iris
renal agenesis
Cornelia de lange
mutation in 1 of 3 cohesin genes - NIPBL, SMC1L1, SMC3
VSD > ToF
MICROMELIA, ulnar abn
SYNOPHRYS (eyebrowns joined in middle), THIN downturning upper lip, long and curly eyelashes
ID, initial hypertonic, microbrachycephaly
Hirsuitism, low posterior hairline
some have mild phenotype
AUTOSOMAL RECESSIVE
Bone marrow failure (anemia, thrombocytopenia)
Skeletal abnormalities (thoracic dystrophies)
Recurrent infections
Pancreatic insufficiency (FTT, steatorrhea)
Schwachmann Diamond
AR
chromosome 7q11 on SDS gene
- role in ribosomal assembly
risk of myelodysplastic syndromes
Carpenter
AR
50% CV PDA, VSD, ASD, PS
Polydactyly, syndactyly
LATERAL DISPLACEMENT INNER CANTHUS, shallow supraorbital ridges
Brachycephaly, ID
FTT, may be omphalocele
Ellis van Crevald
AR
Chondroectodermal dysplasia
CV 50% SINGLE ATRIUM OR ASD
SHORT DISTAL extremities, polydactyly, nail hypoplasia
narrow thorax, normal intelligence
50% mortality due to cardioresp difficulties (narrow thorax)
Fanconi pancytopenia
increased number of chromosomal breaks in lymphocytes and amniotic fluid cells
DERM - hyperpigmentation (increases with age, esp groin, axilla, trunk)
EXTR - thumb hypoplasia, RADIUS HYPOPLASIA, short stature
Facial - ptosis, nystagmus
GU - Renal and GU 35%, small genitalia
Heme - pancytopenia
ID
IUGR
Dx - breakage study
Outcome - 35% mortality heme abnormalities, increased risk AML
Meckel-Gruber
AR, 17q21
Cardiac - asd, vsd
polydactyly
microphthalmia, cleft palate, micrognathia, ear
OCCIPITAL ENCEPHALOCELE, microcephaly, cerebral and cerebellar hypoplasia, absence CC or septum pellucidum
CYSTIC DYSPLASTIC KIDNEYS
bile duct proliferation, hepatic cysts
Prenatal – elevated AFP if +encephalocele
Outcome depends on severity of illness
Smith-Lemli-Opitz
AR
defect in cholesterol synthesis –> low cholesterol level and elevated 7 dehydroceholesterol
anteverted nostrils, ptosis, cataracts
2nd and 3rd toe syndactyly
moderate ID, tone hypo then hypertonic
IUGR
high mortality 1st year if severe
Thrombocytopenia absent radius
AR
CV ToF, ASD
Worse hematologic in infancy - thrombocytopenia esp precipitated by virus, esp GI, granulocytosis, anemia
ABSENT BILATERAL RADII, have thumbs, ULNAR abnormalities, hip dysplasia
Fryns
AR
GI - CDH, increased risk HD, DA, imperforate anus
Neuro agenesis CC, hydrocephalus, olfactory tract abnormality, optic hypoplasia, neuronal heterotopias
CLOUDY cornea, micropthalmia, COARSE facial features
DIGT and NAIL hypoplasia, renal anomalies
Denys Drash
progressive renal disease
Wilms tumor
male pseudohermaphroditism (per B&M book)
WAGR
Wilms tumor
Aniridia
GU
Mental “Retardation”
Mitochondrial diseases
Glycogen storage diseases
Lysosomal storage diseases
Lysosomal storage diseases
Urea acid cycle
Non ketotic hyperglycemia
Klippel Trenauney Weber syndrome
affects devp of vasculature, soft tissues (skin, mm) and bones
Port-wine stain, hypertrophy of soft tissues and bones, and vein malformations
Townes Brocks
Imperforate anus
Dysplastic ears
Thumb abnormalities
Linear inflammatory vesicles along trunk and extremities (EOS) - birth
Pigmented warts on red base
Whorls on trunk and extremities (1st year)
Hypopigmented linear streaks - childhood
XLD
Incontinentia Pigmenti
Females; b/c lethal in males
Mother with subtle skin findings
Blisters at dermal and epidermal junction – throughout body
Dystrophic nails
Oral and anal mucos involved
- inheritance
- scarring?
Junctional epidermolysis bullosa
AR
Atrophic scarring
May present with pyloric stenosis
Short life span
Intra-epidermal blisters on FACE, HANDS and SCALP
Simplex or Epidermolytic Epidermolysis Bullosa
AD
No scarring, mild clinical course, heal quickly
Intra-dermal blisters
Often alsowith hair loss, anemia, dysphasia,poor growth
Dystrophic / Dermolytic EB
AR or AD
Secondary to type VII collagen decrease
Increased collagenase
Presents with bright erythema on face -> severe bullous eruptions diffusely (FLACCID, easy to RUPTURE)
Fever, irritable, tender skin
Conjunctivitis, nasal congestion
+Nikolsky sign
Crusting around mouth and eyes
Dx
Outcomes
Staph Scalded Skin Sydrome
- mostly due to EXOTOXIN of Staph aureus - group II phage most common
- separation at GRANULAR layer of skin (of epidermis)
CULTURE nasopharynx, conjunctiva, skin and blood – BULLAE not helpful to culture b/c STERILE flid.
Rx abx, fluids -> no scarring, rapid recovery
Waxy scaly, hair loss, scalp
nevus sebaceous jacobbson
Collodion membrane
thickened stratum corneum from amniotic fluid -> swells - > eyelids everted, lips everted -> born -> parchment paper like skin, erythematous -> risk dehydration!
often due to nonbullous congenital ichthyosiform
Cutis marmorata
ass with trisomy 18, 21, hypothyroidism, cornelia de lange
Differences between preterm, term and adult skin
Types of chromosomal translocations
Changes in embryo hemoglobin, fetal hemoglobin and post-natal hemoglobin
Terms describing congenital abnormalities - and examples
paternal uniparental disomy
Apert vs Crouzon
Neurocutaneous genetics
Neurocutaneous genetics
tests
FISH
tri 13
fragile X
pre term vs term skin
“common” chromosome mutations and genetics
same as pop - always a new mutation!
Holt Oram presentation
AD
