Miscellaneous Syndrome: X linked

Question 1

Aarskog Syndrome (Aarskog-Scott, Faciogenital Dysplasia)

Answer 1

Inheritance: X-Linked recessive
Gene: FGD1

Question 2

Aarskog Syndrome (Aarskog-Scott, Faciogenital Dysplasia): Featurea

Answer 2

Physical features:

●Hypertelorism
●Downslanting palpebral fissures
●Long philtrum
●Widow’s peak
●Mild-to-moderate short stature during childhood
●Brachydactyly
●5th clinodactyly
●Cutaneous syndactyly
●Single palmar crease
●Shawl scrotum
●Cryptorchidism
●Inguinal hernia
●Pectus deformities
●Webbed neck

Other features:
●Learning difficulties
●Intellectual disability (less common)
●Female “carriers” may be mildly affected

Question 3

X-linked Agammaglobulinemia

Answer 3

Inheritance: X-linked recessive
Gene: BTK

Question 4

X-linked Agammaglobulinemia: Features

Answer 4

Major features:
●Immune deficiency
●Recurrent bacterial infections
●Absence of circulating B cells
●Low serum immunoglobulins
Treatment:
●Gammaglobulin supplementation
●Prophylactic antibiotics

Question 5

Aicardi Syndrome

Answer 5

Inheritance: X-linked dominant
Gene: Unknown

Question 6

Aicardi Syndrome: Features

Answer 6

Major features:
●Complete or partial absence of the corpus callosum
●Seizures (infantile spasms)
●Retinal lacunae
●Increased tumor risk
●Average lifespan 8-9 years

Question 7

Alport Syndrome

Answer 7

Inheritance: Autosomal dominant, autosomal recessive, X-linked recessive
Genes: COL4A3, COL4A4, COL4A5

Question 8

Alport Syndrome: Features

Answer 8

Major features:
●Onset of symptoms in early in childhood/young adult life
●Hematuria and proteinuria
●Glomerulonephritis
●End-stage kidney disease
●Progressive hearing loss
●Leiomyomatosis of the esophagus
oDysphagia
oVomiting
oEpigastric pain
●Eye changes
   oCataracts
   oKerataconus
   oRetinal flecks in the macula
●Aortic dissection (rare)
Treatment:
●ACE inhibitors slow progression of kidney disease
●Dialysis
●Kidney transplant

Question 9

Coffin-Lowry Syndrome

Answer 9

Inheritance: X-linked
Gene: RPS6KA3

Question 10

Coffin-Lowry Syndrome: Features

Answer 10

Major features:
●Short stature
●Severe intellectual disability
●Cardiac anomalies
●Auditory problems
●Dysmorphic features:
oCoarse facies
oFrontal bossing
oHypertelorism
oDownslanting palpebral fissures
oBroad nose
oFull, everted lips
oPectus deformities
oHypodontia
oScoliosis/kyphosis
oBrachydactyly
oMicrognathia
●Female “carriers” may have intellect ranging from normal to severe intellectual disability and may have craniofacial anomalies ranging from mild to severe

Question 11

Coffin-Siris Syndrome

Answer 11

Inheritance: Autosomal recessive, autosomal dominant
Genes: ARID1B, SOX11

Question 12

Coffin-Siris Syndrome

Answer 12

Major features:
●Mild-to-severe ID
●Short thumbs with hyoplastic/absent nails
●Frequent respiratory infections
●Low birth weight/feeding difficulties
●Hypotonia
●Joint laxity
●Delayed bone age
●Microcephaly
●Coarse facial feat

Question 13

Cornelia De Lange Syndrome

Answer 13

Inheritance: Autosomal Dominant, X-linked
Genes: NIPBL, RAD21, SMC3, HDAC8, SMC1A

Question 14

Cornelia De Lange Syndrome: Features

Answer 14

Major features:
●Growth retardation
●Hirsuitism
●Severe-to-profound intellectual disability and developmental delay
●Limb reduction defects
●Craniofacial abnormalities
●Autistic/self-destructive behaviors
●Seizures
●Sensorineural hearing loss
●GERD
●Cryptorchidism
●Ptosis, nystagmus, myopia
●Congenital heart defects
●Vesicoureteral reflux
●Dysmorphic features:
    oMicrobrachycephaly
    oSynopphrys
    oHighly arched eyebrows
    oLong eyelashes
    oLow-set, posteriorly rotated ears with thick helices
    oDepressed/wide nasal bridge
    oLong philtrum
    oHigh-arched/cleft palate
    oMicrognathia
    oShort neck
●Mild CDLS exists
    oMany of the same dysmorphic features
    oLess severe intellectual disability and limb defects

Question 15

Diamond-Blackfan Anemia

Answer 15

Inheritance: Autosomal dominant, X-linked
Genes: GATA1, RPLs and RPSs, TSR2

Question 16

Diamond-Blackfan Anemia: Features

Answer 16

Major features:
●Normocytic or macrocytic anemia with normal platelets and leukocytes
●Increased risk for hematological malignancies and osteogenic sarcoma
●50% are dysmorphic
    oKlippel-Feil anomaly
    oUpper limb and hand deformities
●Genitourinary abnormalities
●CHDs
●Growth delay

Question 17

Hypohidrotic Ectodermal Dysplasia (HED): Genetics

Answer 17

Inheritance: X-linked recessive, (less common: AD, AR)
Genes: EDA, EDAR (AD or AR), EDARADD (AR)

Question 18

Hypohidrotic Ectodermal Dysplasia (HED) Major features

Answer 18

Major features:
●Most common form of ectodermal dysplasia
●Hypohidrosis (reduced ability to sweat)
    oHyperthermia secondary to hypohidrosis
●Hypotrichosis
    oLight-colored hair
●Hypodontia
●Small, pointed teeth/malformed teeth
●Frontal bossing
●Flattened nasal bridge
●Eczema
●Ozena (smelly discharge from the nose :/ )

Question 19

Incontinentia Pigmenti (IP): Genetics

Answer 19

Inheritance: X-linked dominant
Genes: IKBKG

Question 20

Incontinentia Pigmenti (IP): Major features

Answer 20

Major features:
●4 stages
   oSkin blistering (birth – 4months)
   oWart-like rash (several months)
   oSwirling macular hyperpigmentation (6 months – adulthood)
   oLinear hypopogmentation
●Alopecia
●Hypodontia
●Dystrophic nails
●Cognitive delays
●Intellectual disability or learning disability

Question 21

L1 Syndrome (X-Linked Hydrocephalus, MASA Syndrome, SPG1): Genetics

Answer 21

Inheritance: X-linked recessive
Genes: L1CAM

Question 22

X-Linked Hydrocephalus Major features:

Answer 22

X-Linked Hydrocephalus Major features:
●Severe, prental-onset hydrocephalus
●Severe intellectual disability
●Adducted (clasped) thumbs
●Spasticity/brisk reflexes
●Stenosis of the aqueduct of Sylvius

MASA Syndrome Major Features:
●	Mild-to-moderate intellectual disability (Mental retardation)
●Aphasia
●Spastic paraplegia
●Adducted thumbs
●Brain MRI abnormalities

SPG1 Major Features (X-linked complicated hereditary spastic paraplegia 1):
●Mild-to-moderate intellectual disability
●Spastic paraplegia
●Normal MRI

Question 23

Rett Syndrome

Answer 23

Inheritance: X-linked dominant
Gene: MECP2

Major features:
●Typically male lethal
●Normal development followed by psychomotor regression beinning around age 2, which eventually plateaus 
●Partial or complete loss of purposeful hand skills
●Partial or complete loss of spoken language
●Impaired or absent walking ability
●Hand stereotypies
●Severe intellectual disability
●Scoliosis
●Growth retardation
●Small, cold hands and feet
●Sleep disturbances
●Diminished pain response
●Communicate with eyes

Question 24

Septo-Optic Dysplasia (de Morsier syndrome)

Answer 24

Inheritance: Multifactorial, Autosomal recessive, autosomal dominant
Genes: (RARELY DUE TO SINGLE GENE) HESX1

Question 25

Septo-Optic Dysplasia (de Morsier syndrome) Major features

Answer 25

Major features:
●Optic nerve hypoplasia
oNystagmus
oPoor vision
●Pituitary hypoplasia/dysfunction
oGrowth hormone deficiency
oAbsence of hormone production (severe cases)
●Midline brain anomalies
oAbsence or underdevelopment of the cavum septum pellucidum (CSP)
oAbsence or underdevelopment of the corpus callosum
1/3 of patients with SOD have all three major features