Sensory Genetics - Tegay

Why do dermatologic and neuroglic 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 w NF can be missed

• Cutaneous finding: 95%

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

• Neurodelvpment: IQ close to normal

Autosomal Dominant Neurofibromin Gene Mutation; HIGH PENETRANCE

• 50% inherited

• 50% de novo

Legius Syndrome

CAN MEET CLINICAL DIAONGTIC FOR NF1

• Mutiple 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 diaogntic feautres, 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, precious 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 patients 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 chord, peripheral nerve (REQURiES CONSTANT MONTIOING TO REMOVE MASSES IN THE BRAIN)

  • Vestiburalr schawamon: loss of hearing, tenits, dyseualirum

• juvenlie onsent psoterior catercts

Autosomal domainat NF2, comeplte 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 whiteforlock

• NO OTHER ISSUES, healthy

Autosomal Dominant KIT gene mutations

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

Waardenburg Syndrome

4 Types, with different combinations of

• Whiteforlock (50%)

• Sensounaul hearing loss(80%)

• Irsis Hetachromasia: different colored eyes (50%)

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

Waardenburg Syndrome type 1

Most common form

• Dystopia Canthorum

• Autosomal Dominant PAX3 mutation

Waardenburg Syndrome type 2

less common,

• No Dystopia Canthorum

• Autosomal Domiant MITF, SNAI2, SOX10

Waardenburg Syndrome type 3

• Rare

• Presents Dystopia Cantorum and 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 that is mistaken for ( ) )

• 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 SWILRED SKIN PATTERN

  • No history of blistering

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

• Usually Psot-Meiotic Somatic Mosaicism

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

Portwine Stain

• 90% Isolated

• 10% Syndromic

  • Klippel-Treanauny-Weber:

  • Struge-Weber Syndrome: upper face

Strug-Weber Syndrome

• Port-Wine Stain: Usually Facial

• Failure of regression of vascualr 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 hetergeneous

  • GJB2 Gene→ Connexin 26 most often

• Mode of inheritince

  • Autosomal recessive 80% (from carrier parents)

  • Autsomal Domaint 15%

  • X-linked/Mitochondials 1%

• Genetic causes majority of congenital onset hearing loss

  • CJB2 for 21%

  • SLC26A4 (Pendred’s syndrome) 3%

• Older oneset hearing loss other factors

  • MT-RNR1 Gene 1%

Important autosomal Recessive Causes of hearing Loss

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

• DFNB4: SLC2A4 ; High-frequency hearing loss, postlingually, enlarged vestibular aqueduct, increased thyroid diease

Important autosomal Dominant Causes of hearing Loss

• DFNA3: GJB2/GJB6 ; profound prelinguinal deafness, some icthotic 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, vestibualr

• Treacher Collins:

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

• Waardenburg’s syndrome:

Hearing Loss Investigation

• Clnical tests

  • EKG - Jervell-Lange NEislen

  • Renal analysis- Alports dynrome

  • MRI - Pendred’s syndrome

• Genetic

  • GJB2/6 main target

  • NGS can also be done now

Colorblindess

• 3 detection pigments: Blue, Green, Red

• 5% males are color blind

• Most commo ncause: Xlinked recsvvie

  • OPN1MW: Green Color defeciet → Dueteranomaly

  • OPN1LW: Red Color defcit →Protanomaly

  EXTERMELY RARE FORMS

  • Blue-Yello deficent: Tiranomaly

  • Comeplte deficet: Achromaptopsia

Visual Impairment

Retinitis Pigmentosa

• Common genetic cause of degeneration of the RETINA

  • progressive loss of peripheral then central vision

• Heterogenous group of Genes (>40)

Bardet-Biedl Sydnrome

• syndromic form of Retinitis Pigmentosa

Cardinal features

• -obesity (75%)

• rentisis pigmentosa (75%)

• Menatal retardation >75%

• Hypogoandism >75%

Corneal Dystrophy

• disorders of the Corena

  • 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 Dehydrongane gene mutations

• Wolfram Syndrome (DIDMOAD)

  • Juveline onset

  • Autosomal Recessiv, WFS!

• Behr Sydnrome

  • Childhood onset,

  • Autsomal recssiv, cuase unknonw

Mosaicism only Neurofibromatosis syndromes

Conditions ONLY are somatic mosaics: 0% recurrence chance, LETHAL IN UTERO if germline inheritance

• McCune-Albright Syndrome: “Coast of Maine” Cafe-Au-Lait ; GNAS

• Sturge-Webber Syndrome: Portwine Stain, GNAQ

• Hypomelanosis of Ito

Alport’s Syndrome

• Syndromic hearing loss

• Associated with RENAL FAILURE: Hematuria (bloodin the urine)

• X-Linke or Autsomal Recessive

Jarvell and Lange Nielsens Syndrome

• Syndromic Hearing loss cause

• A Heart condition: Long QT syndrome (heart waves)

  • RECOMENDS EKG FOR HEARING LOSS SCREENING

• Autosomal Recessive

Usher’s Syndrome

• Syndromic Hearing loss cause

• also includes RETINITIS PIGMENTOSA

Pendred’s Syndrome

• Syndromic Hearing loss cause

• involves also:

  • Goiter

  • Enlarged Vestibular Aqueduct

• Autosomal Recessive

Deuteranomaly

the most common, affects the green cone photopigment, making certain greens appear redder.

OPN1MW

Protanomaly

affects the red cone photopigment, making certain reds appear greener and less bright

OPN1LW gene