Miscellaneous syndromes: Autosomal Dominant

Question 1

Alagille Syndrome: Genetics

Answer 1

Inheritance: Autosomal dominant
Genes: JAG1, NOTCH2

Question 2

Alagille Syndrome: Major features

Answer 2

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

Question 3

Alzheimer’s Disease (Early Onset): Genetics

Answer 3

Inheritance: Autosomal dominant
Genes: APP, PSEN1, PSEN2

Question 4

Alzheimer’s Disease (Early Onset): Major features

Answer 4

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 tau

Question 5

Branchio-oto-renal Syndrome (Melnick-Fraser Syndrome)

Answer 5

Inheritance: Autosomal dominant
Genes: EYA1, SIX1, SIX5

Question 6

Branchio-oto-renal Syndrome (Melnick-Fraser Syndrome)

Major Feature

Answer 6

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

Question 7

CHARGE Syndrome

Answer 7

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

Question 8

Goldenhar Syndrome

Answer 8

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)

Question 9

Greig Cephalopolysyndactyly Syndrome: Genetics

Answer 9

Inheritance: Autosomal dominant
Genes: GLI3, or 7p13 microdeletion

Question 10

Greig Cephalopolysyndactyly Syndrome: Major features

Answer 10

Major features:
●Macrocephaly
●Hypertelorism
●Limb anomalies
  oPreaxial polydactyly
  oPostaxial polydactyly
  oCutaneous syndactyly (Often of toes 1,3 or fingers 3,4)
●Normal intellectual ability

Question 11

Hay-Wells Syndrome (AEC Syndrome): Genetics

Answer 11

Inheritance: Autosomal dominant
Gene: TP63

Question 12

Hay-Wells Syndrome (AEC Syndrome): Major features

Answer 12

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/palate

Question 13

Holt-Oram Syndrome: Genetics

Answer 13

Inheritance: Autosomal dominant
Gene: TBX5

Question 14

Holt-Oram Syndrome: Major Features

Answer 14

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

Question 15

Kabuki Syndrome: Genetics

Answer 15

Inheritance: Autosomal dominant
Genes: KMT2D (MLL2), KDM6A (very rare X-linked, only 6 cases)

Question 16

Kabuki Syndrome: Major features

Answer 16

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

Question 17

Progeria: Genetics

Answer 17

Inheritance: Autosomal dominant (de novo)
Gene: LMNA

Question 18

Progeria: Major features

Answer 18

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

Question 19

Rubinstein-Taybi Syndrome: Genetics

Answer 19

Inheritance: Autosomal Dominant
Genes: CREBBP, EP300

Question 20

Rubinstein-Taybi Syndrome: Major features

Answer 20

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 smile

Question 21

Treacher Collins Syndrome: Genetics

Answer 21

Inheritance: Autosomal dominant
●60/40 de novo/inherited
Genes: TCOF1, POLR1C, POLR1D

Question 22

Treacher Collins Syndrome:

Answer 22

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

Question 23

Waardenburg Syndrome: Genetics

Answer 23

Inheritance: Autosomal dominant
Genes: PAX3, MITF, WS2B, WS2C, SNAI2, EDNRB, EDN3, SOX10

Question 24

Waardenburg Syndrome: Major features

Answer 24

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