Tegay - Sensory Genetics

Why do dermatologic and neurologic disorders overlap so much?

They share a common ectodermic for neuro and surface ectoderm

• Ras/MAPK and PI3K/Akt/mTOR

What syndromes are associated with cafe-au-lait spots?

• NF1 + 2

• Noonan Syndrome

• Russell-Silver Syndrome

• McCune Albright Syndrome

• Legius Syndrome

Neurofibromatosis Type 1

Skin Findings:

• Cafe-Au-Lait (OVERLAP)

• Neurofibromas (skin nodules or plexiform)

• Optic Glioma: Tumors along the optic nerve can lead to blindness

• Lisch Nodules (hamartomas of the Eye)

• Osseus lesion

  • Macrocephaly (OVERLAP)

  • Inguinal Freckling (OVERLAP)

Many clinical findings develop with AGE: infants with NF can be missed

• Cutaneous finding: 95%

• Opticologic findings: Lisch nodule 95%, optic glioma <20%

• Neurodevelopment: IQ close to normal

Autosomal Dominant Neurofibromin Gene Mutation; HIGH PENETRANCE

• 50% inherited

• 50% de novo

Legius Syndrome

CAN MEET CLINICAL DIAGNOSTIC FOR NF1

• Multiple cafe-au-lait

• axillary freckling

• Macrocephaly

BUT NO

• Neurofibromas, Lisch nodules, CNS tumors

Autosomal Dominant SPRED1 gene mutation

Noonan Syndrome

• Multiple Cafe-au-lait Spots

• can meet the NF1 diagnostic features, but not nearly all of them

McCune Albright syndrome

• UNUSUAL Cafe-Au-Lait Spots

  • Irregular Coast of Maine

• Endocrine organ tumors

  • Thyroid

  • Parathyroid

  • Pituitary

  • Acromegaly, premature puberty

ALL LIVING PATIENTS ARE MOSAICS: GNAS 1 gene mutation in germline is LETAHL in utero:

• molecular testing requires biopsy of affected tissue (cannot test patient’s blood)

Neurofibromatosis Type 2 (NF2)

• Cafe-Au-Lait skin spots are present

• Neurofibromatosis NOT PRESENT on the skin

• Instead, you have SCHWANNOMAS

  • Mainly are CNS tumors: Brain, spinal cord, peripheral nerve (REQUIRES CONSTANT MONITORING TO REMOVE MASSES IN THE BRAIN)

  • Vestibular schwannomas: loss of hearing, tinnitus, dizziness

• juvenile onset posterior cataracts

Autosomal dominant NF2, complete penetrance

• 50% inherited

• 50% De Novo

Ash Leaft Spots Sydnromes

• Tuberous Sclerosis

• Piebaldism

• Waardenburg Syndrome

Tuberous Sclerosis

• ASH LEAF SPOTS

Clinical Features

• Cutaneous (Universal): Ash Leaf spots, FACAL FIBROMAS

• CNS Tumors (universal):

• Cardiac: Congenital Rhabdomyomas (tumors in the heart muscle) 50%

• Increased morality from

  • CNS tumors

  • Seizures

  • Renal Disease

Autosomal Dominant TSC1 or TSC2 Gene Mutation

• 80% De Novo

• 20% Inherited

Piebaldism

• Ash Leaf Spots

• ALSO have a striking white forlock

• NO OTHER ISSUES, healthy

Autosomal Dominant KIT gene mutations

• Testing to rule out other conditions ( LIKE WAARDENBURG SYNDROME)

Waardenburg Syndrome

4 Types, with different combinations of

• White forlock (50%)

• Sensorineural hearing loss(80%)

• Iris Heterochromasia: different colored eyes (50%)

• Distal canthorum (the wide spacing of the inner eye canthorum, but not the eye itself

Waardenburg Syndrome type 1

Most common form

• Dystopia Canthorum

• Autosomal Dominant PAX3 mutation

Waardenburg Syndrome type 2

less common,

• No Dystopia Canthorum

• Autosomal Dominant MITF, SNAI2, SOX10

Waardenburg Syndrome type 3

• Rare

• Presents Dystopia Cantorum with limb anomalies

• Autosomal Recessive PAX3 mutation

Waardenburg Syndrome type 4

• rare

• Presents with Dystopia Cantorum and Hirschsprung Disease

• Autosomal Recessive ADNRB, EDN3 and SOX10 mutations

Albinism

• Diffuse Hypopigmentation of Heterogenous Origin

  • Most common form: Oculocutaneous Albinism (OCA)

  • Decreased melanin production in skin, hair, and eyes

  • Multiple forms: OCA1A/B, OCA2, OCA3, OCA4, X-linked Ocular Albinism (ALL AUTOSOMAL RECESSIVE)

Incontentia Pigmenti

• Hypopigmentation pattern: Swirl hyper and hypopigmentation (Starts as a rash

• Neurologic

  • Epilepsy

  • Intellectual disability

• Ectodermal dysplasia

  • Alopecia

  • Delayed tooth eruption

  • rigged or pitting nails

• X-linked Dominant, Females only (Male Lethal)

• IKBKG (NEMO) gene

Hypomelanosis of Ito

• WHIRLED and SWIRLED SKIN PATTERN

  • No history of blistering

• Happens in Males and Females (not lethal in males)

• Usually Post-Meiotic Somatic Mosaicism

  • Chromosomal (usually 9 or 2) or protein mutation in hypopigmented skin

Portwine Stain

• 90% Isolated

• 10% Syndromic

  • Klippel-Treanauny-Weber:

  • Struge-Weber Syndrome: upper face

Sturg-Weber Syndrome

• Port-Wine Stain: Usually Facial

• Failure of regression of vascular plexus in utero of neural tube: regions of brain with stain are affected

  • Epilepsy

  • Stroke

  • underlying bone and soft tissue hypertrophy

• Somatic Mosaicism GNAQ mutations

  • Germline is Lethal In Utero

• ALWAYS SPORADIC: No recurrence Risk

Ectodermal Dysplasia

• Group of conditions (>150 types)

• Common features

  • Sparse or absent air

  • Reduced number/size of tee

  • Can’t sweat (will overheat)

  • Flat nasal bridge

• X-Linked most prevalent (95%)

  • EDA gene mutation

Ichthyosis

• scaly, dry skin disorders

Feature

• ‘waxy’ baby (collodion)

• scaly, flaky skin

Autosomal Recessive Congenital

• 12 ARCI genes

Epidermolysis Bullosa

• group of blistering skin disorders: sloughing off of skin

• 3 categories

  • Simplex: hand, foot, nail blisters

  • Junctional: minimally scarring blisters, alopecia

  • Dystrophic: Severe scarring Col7A1,

Deafness / Hearing Loss

• Diagnosed at birth with auditory testing

• Genetic causes

  • 2/3 isolated

  • 1/3 syndromic

• Genetically heterogeneous

  • GJB2 Gene→ Connexin 26 most often

• Mode of inheritance

  • Autosomal recessive 80% (from carrier parents)

  • Autosomal Dominant 15%

  • X-linked / Mitochondrial 1%

Important autosomal Recessive Causes of hearing Loss

• DFNB1: GJB2/GJV6 ; Prelingual profound hearing loss, some pass screening

• DFNB4: SLC2A4 ; High-frequency hearing loss, post lingually, enlarged vestibular aqueduct, increased thyroid disease

Important autosomal Dominant Causes of hearing Loss

• DFNA3: GJB2/GJB6 ; profound prelingual deafness, some ichthyotic skin rashes

Important Syndromic Causes of Hearing loss

• Alport’s syndrome: XL or AR collagen gene; Hearing loss and progressive renal failure (blood in urine detection),

• Brancho-oto-renal syndrome: AD ; Hearing loss and Preauricular pits

• Jervell-Lange Neilsen syndrome: Long QT syndrome → EKG

• Pendred’s Syndrome: Goiter, vestibular

• Treacher Collins:

• Usher’s Syndrome: 3 types with varying degrees of hearing loss and loss of eyesight

• Waardenburg’s syndrome:

Hearing Loss Investigation

• Clinical tests

  • EKG - Jervell-Lange Neilsen

  • Renal analysis- Alports syndrome

  • MRI - Pendred’s syndrome

• Genetic

  • GJB2/6 main target

  • NGS can also be done now

Colorblindess

• 3 detection pigments: Blue, Green, Red

• 5% of males are color blind

• Most common cause: X-linked recessive

  • OPN1MW: Green Color deficiency → Deuteranomaly

  • OPN1LW: Red Color deficit →Protanomaly

  EXTERMELY RARE FORMS

  • Blue-Yellow deficient: Tritanomaly

  • Complete deficit: Achromatopsia

Retinitis Pigmentosa

• A common genetic cause of degeneration of the RETINA degeneration

  • progressive loss of peripheral vision, then central vision

• Heterogeneous group of Genes (>40)

• Autosomal recessive (50-60%), autosomal dominant (20 - 30%), XLR (10%), Mitochondrial (rare)

Bardet-Biedl Sydnrome

• Syndromic form of Retinitis Pigmentosa

Cardinal features

• -obesity (75%)

• Retinitis pigmentosa (75%)

• Mental retardation >75%

• Hypogonadism>75%

Corneal Dystrophy

• disorders of the Cornea

  • Cataracts

  • Loss of vision

• Many syndromes that cause this (usually metabolic or skin)

  • ex: Fabry’s disease, cystinosis

  • ex: X-Linked Ichthyosis

Optic Nerve Atrophy

• Genetic basis

• Autosomal domain Atrophy

• Lebers Hereditary Optic Neuropathy (LHON)

  • mtDNA NADH Dehydrogenase gene mutations

• Wolfram Syndrome (DIDMOAD)

  • Juvenile onset

  • Autosomal Recessive, WFS!

• Behr Syndrome

  • Childhood onset,

  • Autosomal recessive, cause unknown