Miscellaneous syndromes: Autosomal Dominant Flashcards
Alagille Syndrome: Genetics
Inheritance: Autosomal dominant
Genes: JAG1, NOTCH2
Alagille Syndrome: Major features
Major features:
●Bile duct paucity (histological finding on liver bx)
●Cholestasis (reduction of bile flow)
●Cardiac defects
oStenosis of the pulmonary artery and its branches is most common
oCan manifest from Tetralogy of Fallot
●Butterfly vertebrae and other skeletal anomalies
●Posterior embryotoxon on ophthalmologic exam (displacement of Schwalbe’s line)
●Dysmorphic features (Inverted triangle face)
oDeep-set eyes
oFrontal bossing
oHypertelorism
oPointed chin
oBulbous nose tip
Alzheimer’s Disease (Early Onset): Genetics
Inheritance: Autosomal dominant
Genes: APP, PSEN1, PSEN2
Alzheimer’s Disease (Early Onset): Major features
Major features:
●Onset before age 65 (may be as early as late 30s, though rare)
●Slowly progressive dementia
●CT/MRI/PET findings
oGross cerebral cortical atrophy
oDiffuse cerebral hypometabolism
●Accumulation of beta plaques
●CSF shows increased A beta-amyloid 42 and decreased tauBranchio-oto-renal Syndrome (Melnick-Fraser Syndrome)
Inheritance: Autosomal dominant
Genes: EYA1, SIX1, SIX5
Branchio-oto-renal Syndrome (Melnick-Fraser Syndrome)
Major Feature
Major features: ●Branchial cleft cyst/fistulae ●Sinus tract ●Hearing loss ●Preauricular pits/tags ●Lop ear malformation ●External auditory canal atresia or stenosis ●Middle ear anomalies ●Cochlear hypoplasia ●Renal agenesis, hypoplasia, or dysplasia ●Utero-pelvic junction obstruction ●Hydronephrosis ●Vesicoureteral reflux ●Pelviectasis ●Cleft palate ●Retrognathia ●Facial nerve paralysis
CHARGE Syndrome
Inheritance: Autosomal dominant
Gene: CHD7
Major features: ●Coloboma of the eye/CNS anomalies ●Heart defects ●Atresia of the choanae ●Retardation of growth ●Genitourinary anomalies ●Ear anomalies/deafness
Goldenhar Syndrome
Inheritance: Familial/AD
Gene: Unknown
Major features ●Hemifacial microsomia oIncomplete development of the ear, nose, soft palate, lip, and mandible ●Limb dermoids ●Preauricular skin tags ●Strabismus ●Heart, kidney, and lung underdevelopment/agenesis (typically unilateral) ●Hearing loss (typically unilateral) ●Blindness (typically unilateral)
Greig Cephalopolysyndactyly Syndrome: Genetics
Inheritance: Autosomal dominant
Genes: GLI3, or 7p13 microdeletion
Greig Cephalopolysyndactyly Syndrome: Major features
Major features: ●Macrocephaly ●Hypertelorism ●Limb anomalies oPreaxial polydactyly oPostaxial polydactyly oCutaneous syndactyly (Often of toes 1,3 or fingers 3,4) ●Normal intellectual ability
Hay-Wells Syndrome (AEC Syndrome): Genetics
Inheritance: Autosomal dominant
Gene: TP63
Hay-Wells Syndrome (AEC Syndrome): Major features
Major features:
●Ectodermal dysplasia
●Complete or partial fusion of upper and lower eyelids
●Ectodermal defects
oSparse, wiry hair
oSkin erosions
oPigmentary changes
oNail changes
oAbnormal teeth
oHypohidrosis
oEctrodactyly
●Maxillary hypoplasia
●Microstomia
●Hypospadias
●Cleft lip/palateHolt-Oram Syndrome: Genetics
Inheritance: Autosomal dominant
Gene: TBX5
Holt-Oram Syndrome: Major Features
Major features:
●Limb malformations
oWrist-bone abnormalities, partial or complete absence of forarm bones, missing limbs, limb reduction, underdeveloped bones
●CHDs – ASD is most common in Holt-Oram (75% have a heart problem of some sort)
●Increased susceptibility for cardiac conduction disease
Holt-Oram is a phenocopy of Thalidomide exposure/vice versa
Kabuki Syndrome: Genetics
Inheritance: Autosomal dominant
Genes: KMT2D (MLL2), KDM6A (very rare X-linked, only 6 cases)
Kabuki Syndrome: Major features
Major features: ●Mild-to-moderate intellectual disability ●Developmental delay ●Pleasant, outgoing personality ●CHDs ●Hearing loss ●Skeletal anomalies ●Joint laxity ●Short stature ●Persistent fingerpads ●Seizures ●Normal life expectancy
Progeria: Genetics
Inheritance: Autosomal dominant (de novo)
Gene: LMNA
Progeria: Major features
Major features: ●Failure to thrive ●Scleroderma-like skin lesion ●Growth deficiency ●Full-body alopecia ●Large head with prominent scalp veins ●Wrinkled/aged facial appearance ●Atherosclerosis ●Cardiovascular complications ●Kidney failure ●Loss of vision ●Small, fragile body ●Musculoskeletal deterioration ●Normal intellect ●Severely shortened lifespan – typically teens/twenties
Rubinstein-Taybi Syndrome: Genetics
Inheritance: Autosomal Dominant
Genes: CREBBP, EP300
Rubinstein-Taybi Syndrome: Major features
Major features:
●Moderate to severe intellectual disability
●Developmental delay
●Short stature/poor growth
●Congenital heart defects
●Microcephaly
●Attention/behavioral concerns
●Broad thumbs, broad first toes
●Cryptorchidism
●Dysmorphic features:
oMalocclusion
o“Talon cusps” on teeth
oDownslanting palpebral fissures
oConvex nasal ridge, low hanging columella
o High palate
oGrimacing smileTreacher Collins Syndrome: Genetics
Inheritance: Autosomal dominant
●60/40 de novo/inherited
Genes: TCOF1, POLR1C, POLR1D
Treacher Collins Syndrome:
Major features:
●Normal intellect
●Hypoplasia of the facial bones
oUnderdeveloped mandibular and zygomatic bones
oMandibular hypoplasia
●Airway obstruction/breathing difficulties secondary to mandibular hypoplasia
●Cleft palate
●Conductive hearing loss secondary to internal ear anomalies
●External ear anomalies
●Coloboma
●Strabismus
●Downslanting palpebral fissures
●Vision loss
Surgical correction of mandibular hypoplasia can help to improve symptoms of airway obstruction
Waardenburg Syndrome: Genetics
Inheritance: Autosomal dominant
Genes: PAX3, MITF, WS2B, WS2C, SNAI2, EDNRB, EDN3, SOX10
Waardenburg Syndrome: Major features
Major features:
●White hair forelock
●Hypertelorism due to broad nasal root
●Moderate-to-profound hearing loss (can be congenital)
●Patches of hypopigmented skin
oSome of the genes that cause Waardenburg are involved in formation of melanocytes!
●Heterochromia (Type II)
●Very bright, blue eyes
●Some have Hirschprung’s disease
●Normal intellect
