Sensory (Skin, Eye, Ear) - Boards

Cafe-Au-Lait Spots: Differential Diagnosis

The RAS-opathies

• Neurofibromatosis Type 1 (NF1)

• Legius Syndrome (SPRED1)

• Noonan Syndrome (PTPN11, SOS1, RAF1, KRAS, etc.)

• Costello Syndrome (HRAS)

• LEOPARD Syndrome (Noonan with multiple lentigenies)

The NON-Ras-opathies

• ******Neurofibromatosis Type 2 (NF2)*****

  • ***NOT A RAS-OPATHY***

• McCune-Albright Syndrome

• Proteus Syndrome

• Russell-Silver Syndrome

Neurofibromatosis Type 1: Overview

Gene: NF1 (important for turning OFF RAS/MAPK pathway)

• A RASopathy

• Loss of ‘brakes’ for RAS signaling → abnormal cell growth and tumor formation

Inheritance

• Autosomal Dominant

  • De Novo 50%

  • Inherited 50%

• COMPLETE PENETRANCE (by adulthood)

  • 50% meet criteria at age 1

  • 95 % meet criteria by adulthood

• ****HIGHLY variable expressivity****

Clinical Features

• Skin

  • Cafe-Au-Lait (at Least 6)

  • Neurofibromas (at Least 2)

    • Sub-cutaneous (small)

    • Plexiform (large) → painful, large, can become malignant nerve sheath tumors

  • Axillary or Inguinal Freckling (many freckles where there is NO SUNLIGHT)

• Eye

  • Optic Glioma (tumors along the optic nerve)

  • Iris Hamartoma (at least 2) → also call LISHC NODULES

• Bone

  • Osseous Lesions

    • Sphenoid Dysplasia

    • Tibial Pseudarthrosis

• Neurologic

  • Learning disabilities, ADHD

• Cancer Risk

  • Malignant peripheral nerve sheath tumor (MPNST)

  • Breast Cancer

  • Pheochromocytoma

  • Gastrointestinal stromal tumor (GIST)

Neurofibromatosis Type 1 Clinical Diagnostic Criteria

(CRITERIA MODIFER: IF a PARENT is affected → ONLY 1 FEATURE needs to be present)

Must have two of the following

• CAFE-AU-LAIT: AT LEAST 6 Cafe-Au-Lait Spots:

  • pre-pubescent: more than 5mm in size

  • post-pubescent: more than 15mm in size

• NEUROFIBROMAS: AT LEAST

  • 2 Neurofibromas: (external) Cutaneous or Subcutaneous

  • 1 PLEXIFORM Neurofibroma: (internal) form along nerves → Painful and MALIGANT potential (pathognomonic)

• Axillary (Armpit) and Inguinal (Groin) Freckling → Early childhood

• OPTIC GLIOMA: Optic Nerve tumor

• LISCH NODULES (Iris Hamartomas): AT LEAST 2

• OSSEUS LESION

  • Sphenoid wing dysplasia (eye socket/ skull bone)

  • Tibial bowing (curving out of the shin bone)

  • Tibial pseudarthrosis (endstage tibial bowing: broken tibia never heals but remains sperate)

• CONFIRMED PATHOGENIC NF1 VARIANT

Neurofibromatosis Type 2:

Gene: NF2 (controls the proliferation of nerve cells via NONE RAS/MAPK PATHWAYS)

• NOT a RAS-opathy

• Loss of control → uncontrolled proliferation of SCHWANN CELLS and other nervous system cells

Inheritance

• Autosomal Dominant

  • De Novo 50%

  • Inherited 50%

• COMPLETE PENETRANCE (100% by 60yo)

  • but still AGE DEPENDENT

• Variable Expressivity

• ***MOSASCISM COMMON**** → reduced tumors + later onset

  • 20-30% of all cases

  • 50-60% of apparently DE NOVO cases

Clinical Features

***AN ADULT-ONSET CONDITION***

NO SKIN FINDINGS

• Ear

  • ****BILATERAL Vestibular Schwannomas**** (late teens - early 30s yo) → Leads too :

    • progressive sensorineural hearing loss

    • Tinnitus

    • Balance issues

• Eye

  • Cataracts (subcapsular or cortical wedge)

• Central Nervous system

  • Cranial/Spinal Nerve Schwannomas

  • Meningiomas

  • Glioma (not just optic nerve → can be any nerve/brain cell)

  • Ependymomas

  • Neurofibroma

Neurofibromatosis Type 2 Diagnostic Criteria

To meet Clinical Diagnostic Criteria, must have:

• 1 PRIME feature

• 2 MAJOR features

• 1 Major + 2 Minor features

PRIME Features

• Bilateral Vestibular Schwannomas

• Identical NF2 pathogenic variant *in two separate types* of NF2-related tumors

  • *****NOTE: if Variant allele frequency is <50% → MOSAIAC NF2*****

Major Features (Need 2 or 1 + 2 minor)

• UNILATERAL vestibular schwannoma

• One 1st-degree relative with NF2→ ****CANNOT BE A SIBLING****

• At Least Two Meningiomas

• NF2 Pathogenic Variant found in UNAFFECTED TISSUE (i.e. blood sample rather than tumor tissue)

Minor Features

• One Meningiomas (two = 1 major)

• One Ependymoma or Schwannoma (two = 2 minors, not 1 major)***

• Cataracts (the special ones) BEFORE the age of 40yo

LEGIUS syndrome

Gene: SPRED1 (enables NF1 protein to regulate RAS/MAPK pathway effectively)

• RASopathy

• Loss of SPRED→ Longer for RAS pathway to be turned off (but not fully lost) → “On” signal = Skin findings but NOT the Neurofibromas/Nerve tumors/Eye

Inheritance

• Autosomal Dominant

  • De Novo 50%

  • Inherited 50%

• High Penetrance

• Variable Expressivity

Clinical Features

ONLY NF1 Skin findings, NO CNS

No PROVEN increased Cancer Risk

• Skin

  • Cafe-Au-Lait

  • Axillary/Inguinal Freckling

  • Lipomas (occasional)

• Neurology

  • Relative Macrocephaly

  • Learning Disabilities /ADHD

  • Mild Speech/Motor delays

[ NF1 without Tumors ]

Non-NF2 Schwannomatosis

Genes: SMARCB1, LZTR1 (Both tumor-suppressor genes → loss of function = schwannoma formation)

• s

Inheritance

• Autosomal dominant

  • Mostly De Novo

• Reduced Penetrance

• Variable Expressivity

Clinical Features

Onset Adolescence to Adulthood

• Multiple Schwannomas (mainly peripheral or spinal)

  • Painful → chronic pain common

  • nerve compress → weakness/ numbness

  • ****Vestibular uncommon → ONLY UNILATERAL ; bilateral suggest bilateral)

• Meningiomas (less common)

Tuberous Sclerosis

Gene: TSC1, TSC2 ( control mTOR pathway → loss of function = cell proliferation)

Inheritance

• Autosomal Dominant

  • ****DE NOVO 80%****

  • Inherited 20%

Clinical Features

Intelligence affect and Shortened life expectancy

• Skin

  • ****Ash Leaf Spots****

  • Facial Angiofibroma

  • Shagreen Patches

• CNS tumors

  • Cortical Tubers (90%)

  • Subendymal nodules

• Cardiac tumors

  • Congenital Rhabdomyoma→ will REGRESS with age

• Renal

  • Angiomyolipoma

• Ocular

  • Retinal Hamartomas

Management

• “Full Body” imaging (working with each organ system specialist to monitor)

Tuberous Sclerosis Diagnostic Criteria

Require:

• 2 Major Features

• 1 Major Feature + AT LEAST 2 Minor Features

• TSC1 or TSC2 Pathogenic Variant

MAJOR CRITERIA:

Skin

• AT LEAST (3) Hypomelanotic Macules (Piebald patches)

• AT LEAST (3) Angiofibromas (found on face usually)

• AT LEAST (2) Ungual Fibromas (found on edge of nail-beds)

• (1) Shagreen Patch (large, pebbly, dimpled ‘organ peel’ → Lower Back, Neck, Buttocks, Thighs)

CNS

• AT LEAST (2) Subependymal Nodules (SEN)

• *****MULTIPLE Cortical Tubers***** (ITS IN THE DAMN NAME)

• (1) Subepdenymal Giant Cell Astrocytoma (SEGA)

Cardiac

• (1) CONGENTIAL Rhabdomyoma

Renal

• AT LEAST (2) Angiomyolipomas

Eye

• AT LEAST (2) Retinal Nodular Hamartomas

MINOR

Skin

• “Confetti” Skin Lesions (smaller, scattered hypopigmented macules)

Bone

• Sclerotic Bone Lesions

Teeth

• AT LEAST 3 Dental Enamel Pits

• AT LEAST 2 Intraoral Fibromas

Renal

• AT LEAST 2 Renal Cysts

Waardenburg Syndrome

Gene: PAX3 (important for neural crest cell migration)

• Neural cells particularly for: Melanocytes, Inner Ear, GI nervous systems (Hirschsprung disease for Type IV)

  • Type I: Dystopia Canthorum

  • Type II: No Dystopia Canthorum

  • Type III: Type 1 + Upper limb abnormalities (Recessive)

  • Type IV: Hirschsprung Disease

Inheritance

• Autosomal Dominant (most forms)

Clinical Features

Normal intelligence and life expectancy

• Ear

  • *****CONGENITAL sensorineural hearing loss*****

  • Complete or Segmental Heterochromia (one blue one brown eye)

  • ***Dystopia Canthorum (displacment of the canothroum makes eyes seem hypertelmoric)*** → Type I + III

• Hair

  • ****White Forelock****

  • Premature graying

• Skin

  • ****Piebald spots (areas of HYPOPIGMENTATION)****

Hermansky - Pudlak Syndrome (HPS)

Gene: HPS1, HPS3, HPS4, HPS5, HPS6 (important for organ specific- Lysosomes)

• Melanosomes → Pigmentation (skin + eyes)

• Platelet dense granules → Platelet production (blood clotting)

• Lamellar Bodies → SURFACANT production

Inheritance

• Autosomal Recessive

• VERY HIGH in PUERTO RICO

Clinical Features

• Skin/Hair

  • ****Oculocutaneous albinism****

  • White hair

• Eyes

  • Decreased visual acuity

  • Photophobia (Sensitive to Light)

  • Strabismus (Misalignment of the eyes)

• Bleeding

  • Excessive bleeding

  • *****EASY BRUISING****

• Pulmonary

  • Progressive Pulmonary Fibrosis (loss of lung function over time)

Incontinentia Pigmenti

Gene: NEMO (important for controlling apoptosis of ectodermal cells → loss of function = abnormal apoptosis of skin, hair teeth, eyes, CNS)

• “Whirled & Swirled” Skin pattern on Lines of Blaschko

Inheritance

• X LINKED DOMIANT

  • De Novo 80%

  • FEMALE ONLY (Male Lethal)

Clinical Features

Intelligence CAN be affect but with a NORMAL life expectancy

***PROGRESSIVE development of ECTODERMAL DYSPLASIA***

• Skin (progressive development)

  • Hyperpigmentation in a “Swirling” pattern → starts as blisters in infancy

  • Hair loss (in affected areas)

• Eyes

  • Hypodontia (missing teeth)

  • “Peg” Teeth

• Eyes

  • Retinal Vascular Diease: Ischemia (lack of blood), Detachment → VISION LOSS if untreated

• CNS (20-30%) → VARIABLE, can range from absent to severe

  • Intellectual Disability

  • Seizures

  • Stroke-Like Episodes

Hypomelanosis of Ito

Gene: Somatic Mosaic Point Mutation or Chromosomal Abnormality

• “Whirled & Swirled” Skin pattern on Lines of Blaschko

• WIDE range of features

Inheritance

• SPORADIC Post-Meiotic Mosaicism

• MALES and FEMALEs equally (vs Females only for IP)

Clinical features

• Skin

  • Hypopigmented Streaks “Whirled & Swirled” Skin pattern on ****Lines of Blaschko****

• CNS

  • Epilepsy

  • Developmental delay

  • OTHER CONGENTIAL ANOMLAIES

Management

• TEST AFFECTED TISSUE → The Skin in the Pattern

Hypohidrotic Ectodermal Dysplasia

Gene: EDA (Most Common), EDAR, EDARADD, WNT10A (important for development of ectodermal structures)

• a

Inheritance

• X-Linked Recessive (EDA)

Clinical Features

Normal Intelligence

• *****Teeth***** (Hypodontia)

  • Missing teeth

  • Peg/Conical Shaped teeth

• ***Hair*** (Hypotrichosis)

  • Sparse scalp hair (Hypotrichosis)

• *****Sweat Glands***** (Hypohidrosis)

  • Reduced Ability to Sweat

  • Heat Intolerance/ hyperthermia

• Facial

  • Flat Nasal Bridge

Epidermolysis Bullosa

Gene: COL7A1 + Many Genes (associated with important structural proteins for the skin)

• Non-functional structural proteins → Abnormally fragile skin = BLISTERING

• Large group of disorders grouped into three

  • Simplex: blisters at surface of skin; (MILDEST)

  • Junctional: slightly deeper → some scars, hair

  • Dystrophic: Blisters at deepest level → severe scarring (COL7A1)

Inheritance

• Simplex: AR and AD

• Junctional: AR

• Dystrophic: AR and AD

Clinical Features

Increased Risk for

• Simplex: Mildest form, Normal Life Exp.,

  • Blisters on hands and feet, minimal scarring, nails preserved

• Junctional: Range of severity, some life-threatening in infancy

  • Blistering all over body, Scarring, Growth failure, Enamel Hypoplasia

• Dystrophic:

  • SEVERE Scarring, Nail Loss, Pseudosyndactyly (“Mitten Deformities”)

  • ****Cutaneous squamous cell carcinoma****

Hearing Loss / Deafness Differential Diagnosis

• Post-Infections:

  • TORCH

  • Measles, Mumps, Rubella

  • Meningitis

• Environmental:

  • Noise Pollution

  • Trauma

  • ***Hyperbilirubinemia****

• UNKNOWN → 30-40%

Hearing Loss Genetic Etiology

MORE for COGENTIAL HL rather than later in life → Genetic Awnser

• Genetic Cause

  • 50% of Congenital Cases

    • 2/3 Isolated

    • 1/3 Syndromic

• Genetically Heterogenous

  • GKB/Connexin genes often associated (GJB2 Gene → Connexin 26 most often)

• Inheritance

  • Autosomal Recessive: 80%

  • Autosomal Dominant: 15%

  • X-Linked Recessive: 1%

  • Mitochondrial: 1%

GJB2-related hearing loss

Gene: GJB2, GJB6 (a deletion - less common) (coeds for CONNEXIN 26→ important for potassium ion recycling in cochlea after sound stimulation)

• NON-SYNDROMIC Hearing Loss

• 21% of all Congenital Hearing Loss

• Loss of function GJB2 → cochlear hairs become dysfunctional

Inheritance

• Autosomal Recessive

  • ALWAYS INHERITED (from a Carrier Parent)

Clinical Features

• Congenital Sensorineural Hearing Loss

  • Bilateral

  • Usually PROFOUND

  • Normal vestibular function (BALANCE NORMAL)

*****Some Infants Pass New Born Audiology Screening*****

Pendred Syndrome

Gene: SLC26A4 (codes for pendrin: a anion transporter that moves chloride, iodide and bicarbonate)

• 5% of Inherited Hearing loss

• Expressed in

  • Inner ear → maintains ions needed for normal hearing and balance

  • Thyroid → moves iodide into thyroid follicle for hormone synthesis

  • Kidney → maintain acid-base balance (NO KIDNEY DIEASE USUALLY)

• Loss of Pendrin → cochlear development and iodine transport disrupted → hearing loss and thyroid abnormalities

Inheritance

• Autosomal Recessive

  • ALWAYS Inherited (from a carrier parent)

Clinical Features

• Congenital/Early childhood Hearing Loss

  • Progressive

  • Bilateral

  • ***FLUCTUATING***(sudden drops and recovery) - unlike GBJ2 → can be triggered by minor head trauma or infections

• Vestibular Issues (33%)

  • Balance problems

  • shows ***ENLARGED VESTIBULAR AQUEDUCT**** (hallmark sign)

• Thyroid

  • ***GOITER***

  • Usually normal thyroid function is normal → can get mild hypothyrpidsm

Managment

• Hearing aids/Implants

• Life style:

  • avoid contact sports (making HL worse)

  • Avoid activities with PRESSURE CHANGES (life flying or Suba diving)

Usher Syndrome

Gene: MYO7A (Type I), USH2A (Type II - Most Common), CLRN1 (Type III) (codes proteins important for sensory cells: cochlear, vestibular and photoreceptors)

• HEARING, BALANCE, VISION

• Accounts for 50% of inherited Deaf-Blindness

• Three Types

  • Type I: Balance+ DEAF

  • Type II: Moderate HL w/ normal balance

  • Type III: Progressive (vision, hearing, blance)

Inheritance

• Autosomal Recessive

  • ALWAYS INHERITED (from carrier parents)

Clinical Features

• Vision (ALL TYPES LOSS VISION)

  • ****RETINITIS PIGMENTOSA**** (all types) progression to vision loss

• Type I (most severe)

  • Profound congenital Deafness

  • Absent vestibular function → ***DELAYED WALKING***

  • RP is early onset

• Type II (MOST COMMON)

  • Moderate-to-severe SNHL

  • NORMAL BLANCE***

  • RP in adolescence

Stickler Syndrome

Gene: COL2A1 (90%), COL11A1 (10%) (codes for collagens that are important for the Eye and the Ear)

• Connective Tissue disorder causing retinal detachment

Inheritance

• Autosomal Dominant

  • DE NOVO 50%

  • Inherited 50%

Clinical Features

Vary with age of onset

• Eyes

  • Myopia: congenital, severe, progressive

  • ***Retinal Detachment***

  • ***Cataracts: JUVENLIE ONSET****

• Hearing

  • Sensorineural hearing loss (can also be Conductive and Mixed)

  • Progressive

• Craniofacial

  • Pierre Robin Sequence (micrognathia, glosspostis, CLEFT PALATE)

• Skeletal

  • Joint Hypermobility + Degeneration

  • ****EARLY ARTHRITIS***** (by 20-30s yo)

  • Chronic Pain

Jervell and Lange-Nielsen syndrome

Gene: KCNQ1 (90%), KCNE1 (10%) (important for potassium channel function)

• Loss of function → unable to cardiac repolarize and recycle potassium in the inner ear

• Long QT syndrome + Profound Congenial Hearing Loss

Inheritance

• Autosomal Recessive

  • Always Inherited (from carrier parents)

  • Carrier Parents usually normal ECG or have ***Mild QT Prolongation***

Clinical Features

• Congenital Bilateral Profound Sensorineural Hearing Loss

  • Present at Birth

  • Profound

  • No progression or Fluctuation

• Congenital Long QT Syndrome

  • ****Torsades de pointes****

  • Syncope

  • Seizures (from cerebral hypoperfusion)

  • Ventricular fibrillation

  • Sudden cardiac death

Management

• DIAGNOSIS → ****PROLONGED QT INTERVAL****

Leber Congenital Amaurosis

Gene: Many genes (important for rods and cones of the eye) - RPE65

• Loss of function → early degeneration or dysfunction of rods/cones→ severe visual impairment in infancy

• RETINAL DYSTROPHY

Inheritance

• Autosomal Recessive (usually)

  • ALWAYS INHERTIED (from carrier parents)

Clinical Features

• Vision Impairment (at birth)

• Nystagmus (rapid, involuntary eye movement)

• ****Oculodigital Sign****: Children rub, poke or press on their eye

Management

• Testing

  • Electroretinography → VERY ABNORMAL: ABSENT or SEVERLY REDUCED

• Treatment: RPE65 has gene-therapy

Congenital Cataracts (Crystallin-Related Congenital Cataracts)

Gene: Many Genes (important for crystallin which maintain the transparency of the lens)

• Loss of function → Lens opacification (cataract)

• ISOLATED congenital cataracts

Inheritance

• Autosomal Dominant (usually)

  • ***DE NOVO 70%***

  • Inherited 30%

Clinical Features

• Congenital Cataracts

  • present at birth

  • Unilateral or Bilateral

  • leukocoria (abnormal white refelection from retina seen through the pupil)

Management

• Diagnosis → need to rule out potential metabolic conditions (due to how early the eye-sight loss is)

  • ****GALACTOSEMIA****

  • Congenital Rubella

  • Peroxisomal Disorders (Zellweger Spectrum)

Retinitis Pigmentosa

Gene: Many Genes

• Groupe of conditions that have the same retinal deteriorating: From ***Night blindness***→ Peripheral vision loss → central vision loss

Inheritance

• Autosomal Dominant (25%)

• Autosomal Recessive (40%)

• X-linked (15%)

Clinical Features

• Progressive vision loss:

  • Night Blindness First

  • Peripheral Vision Loss

  • Central Vision Loss

Management

• Imagining: very specific → Using Eye Exam

  • Bone-Spicule Pigmentation: clumping of pigment on retina

  • Attenuated (narrowed) Retinal Vessels

  • Waxy Optic Disc Pallor

Retinoblastoma

Gene: RB1 (a tumor suppressor → loss of function = uncontrolled retinal cell proliferation)

• Two-Hit Hypothesis

• Cancer Predisposition Syndrome with HIGH PENETRANCE

Inheritance

• Autosomal Dominant

  • HIGH PENETRANCE (90%)

  • De Novo 80%

  • 1/3 of ALL RETINOBLASTOMA cases are from DE NOVO VARIANTS

Clinical Features

• Eyes

  • Retinoblastoma (before age 5)

    • Germline: Bilateral - <1 yo

    • Sporadic: Unilateral - 1-3 yo

  • Leukocoria (abnormal white reflection from retina seen through the pupil)

• Cancer Risk

  • Pineoblastoma (trilater retinblasotoma) - Childhood

  • ******Osteosarcoma****** - Adulthood

  • Melanoma - Adulthood

  • Leiomyosarcoma - Adulthood

Bardet-Diel Syndrome

Genes: Many genes - BBS1 (25%), BBS10 (20%) (encode for primary cilium → critical for retina, kidney, limb development, gonads)

• Loss of function → impaired intracellular signaling (WNT +SHH) = multisystem dysregulation

• CILIOPATHY

• Tri-Allelic Inheritaince (possibly)

Inheritance

• Autosomal Recessive

  • ALWAYS INHERITED 9from carrier parents)

Clinical Features

• Eyes

  • ****Retinitis Pigmentosa**** (starts after 10yo)

• Growth

  • Truncal Obesity (infancy/early childhood)

• Limbs

  • ***Postaxial Polydactyly***(extra digit is after the 5th toe/finger)

• Neurologic

  • Mild Intellecualt/learning disalbity

  • Autism

• Kidney (leading cause of death)

  • Structural Renal Anomalies

  • Chronic kideny diease → End-Stae renal deiase

• Genetial

  • Hypogondaism

  • Reduced fertility (inferltiy common in men, women usually not full infertile)

Managment

• Needs disalysiss