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![Page 1: 1 Genetic Skin Disorders Basic Dermatology Curriculum Content for this module was developed by The Society for Pediatric Dermatology Last updated March.](https://reader034.fdocuments.in/reader034/viewer/2022051820/56649c9e5503460f9495e1b9/html5/thumbnails/1.jpg)
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Genetic Skin DisordersBasic Dermatology Curriculum
Content for this module was developed
by The Society for Pediatric DermatologyLast updated March 1, 2015
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Module Instructions
The following module contains a number of blue, underlined terms which are hyperlinked to the dermatology glossary, an illustrated interactive guide to clinical dermatology and dermatopathology.
We encourage the learner to read all the hyperlinked information.
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Goals and Objectives
The purpose of this module is to help develop a clinical approach to the evaluation and initial management of patients presenting with genodermatoses
By completing this module, the learner will be able to:• Identify and describe the morphology of skin lesions typical of
tuberous sclerosis, neurofibromatosis type 1, and Sturge-Weber Syndrome
• Summarize the clinical manifestations of these three genodermatoses
• Describe the clinical features and summarize the clinical findings of genetic disorders other than NF1 associated with café au lait macules
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Case One
Claire
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Case One: History
HPI: Claire is a 9 year old girl who presents for well child care with 6 light brown spots (each >5mm) that have grown with her since birth
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Case One: Physical Exam
• Oval uniformly pigmented light brown macules and patches with smooth borders
• Consistent with Café au lait (CAL) macules and patches
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Case One: Question 1
How many CAL macules/patches (>5mm) would prompt referral to a geneticist for evaluation of possible Neurofibromatosis 1 (NF1)?
a. ≥ 2
b. ≥ 3
c. ≥ 4
d. ≥ 6
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Case One: Question 1
Answer: d
How many CAL macules/patches (>5mm) would prompt referral to a geneticist for evaluation of possible NF1?
a. ≥ 2
b. ≥ 3
c. ≥ 4
d. ≥ 6
In Caucasian children, > 3 may prompt evaluationMust also take into account family history and other associated symptoms
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Café au Lait Spots(CALS) Discrete uniformly pigmented macules or patches, varying from light to
dark brown with smooth or irregular borders Histology: increased melanin content with giant melanosomes, no
melanocyte proliferation
In newborns, having at least 1 CALM varies with ethnicity:
18% of African American
3% of Hispanic
0.4% of Chinese
0.3% of Caucasian
> 3 CAL spots are noted in only 0.2-0.3% of school children without a genetic disorder
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Differential Diagnosis of CALS
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Becker’s Nevus: Overlying hypertrichosis in teenager
Congenital melanocytic nevus: May have overlying hypertrichosis
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Differential Diagnosis of CALS
Speckled Lentiginous Nevus(Also referred to as nevus spilus)
.
Segmental Pigmentation Disorder(Also referred to as pigmentary mosaicism)
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Systemic Disorders Associated With CALS Other Than NF1
Neurofibromatosis Type 2 CALS not essential for diagnosis, but may be noted Associated with vestibular schwannomas and other
neoplasms McCune Albright Syndrome
Patches usually large, have irregular borders and are located on sacrum, buttocks, and upper spine
Associated with endocrine abnormities and fibrous dysplasia of bones
Legius Syndrome NF1-like syndrome due to SPRED1 gene mutation
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Case One, Question 3
How is NF1 transmitted from parent to child?a. Autosomal dominant
b. Autosomal recessive
c. X-linked dominant
d. X linked recessive
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Case One, Question 3
Answer: a
How is NF1 transmitted from parent to child?
a. Autosomal dominant
b. Autosomal recessive
c. X-linked dominant
d. X linked recessive
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Ask About Family History
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NF1 is autosomal dominant and there may be a family history of disease Variable expressivity means individuals with the
same mutation can have different phenotypes There are some families with multiple generations
of > 6 CALS without a genetic disorder 50% of mutations are de novo which means these
patients will not have a positive family history
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NF1: The Basics
NF1 is a multisystem disease with predominantly skin and neoplastic manifestations
Mutation in the gene encoding neurofibromin, chrom 17 Affects 1/3500 live newborns Equal gender predominance across ethnicities Associated malignancies:
malignant peripheral nerve sheath tumor (5-10%) optic glioma glioblastoma GI stromal tumor breast cancer leukemia pheochromocytoma rhabdomyosarcoma duodenal carcinoid tumor
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NF1 Diagnostic Criteria
NF1 is diagnosed clinically. Commercial genetic testing investigates truncation of the NF1 gene and detects 50-70% of mutations
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Other Physical Exam Findings to Look for in NF1
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Axillary and groin freckling Present in 85% of patients by 10 years of
age Lisch Nodules: Hamartomas of the iris
Present in 25% of patients by 5 years, 50% by 10 years, 95% by 20
May require slit-lamp to diagnose, especially if few in number and patient is young
Do not affect vision Cutaneous Neurofibroma
Present in 20% of patients by 10 years of age, > 90% in adults
Lead to cosmetic problems, no malignant potential
Move with the skin
Lisch nodules
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Other Neurofibromas
Subcutaneous Neurofibroma (15% of patients) Firm, rubbery, may be painful Skin moves over them
Plexiform Neurofibroma (25% of patients) Soft plaque with overlying hyperpigmentation +/-
hypertrichosis Potential for malignant transformation (pain can be
sign of malignancy) Present at birth, but may be diagnosed later Can involve all skin levels down to bone and viscera May cause compression, distortion, or overgrowth of
structures Spinal Neurofibroma - may have sensory and motor effects
Plexiform neurofibroma
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Back to Case One
Claire
9 year old girl with multiple CALMs
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Case One: History Continued
PMH: no major illnesses or hospitalizations Medications: none Allergies: none Family history: adopted, unknown Social history: lives with parents and brother
age 11. In 3rd grade ROS: occasional headaches, trouble with
math in school21
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Skin Examination Continued
Axillary Freckling
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Ask a thorough Review of Systems Optic gliomas – most common CNS tumor (15%), develops in children < 6 yo
Headaches, visual field defects, proptosis, strabismus, nausea, anorexia, hypothalamic dysfunction, precocious puberty
Only 1/3 develop symptoms – only treated if symptomatic Imaging asymptomatic children is NOT recommended as they rarely progress
Mental retardation is rare (4-8%) Learning disabilities are common (40-60%) Short Stature (33%) Macrocephaly (50%) Skeletal Problems
Scoliosis (10-26%) Tibial dysplasia (2-3%)– manifests as bowing of lower legs increase risk of
fracture and pseudoarthrosis Hypertension (due to renal artery stenosis or pheochromocytoma)
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Follow up and Referrals
Claire has > 6 CALS axillary freckling learning disability headaches
You refer her to ophthalmology and genetics
She undergoes genetic testing and is diagnosed with NF1
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Health Supervision for Children with NF1
Guideline Age
Growth
At every well child check (Neonatal, 2mo, 4mo, 6mo, 9mo, 12mo, 15mo, 18mo, 2-21 years annually)
*Sub-specialty audiology at 1 and 4 years and sub-specialty development and behavior at 4 years
Blood pressure
Skin exam
Bone examination (tibial dysplasia, scoliosis, hypertrophy)
Neurologic examination
Vision screening*
Hearing screening*
Genetic counseling Prenatally and once in adolescence
Phenotype review Prenatally, neonatal, or at time of diagnosis
Ophthalmologist eye exam Annually starting at 12 months
Psychological/social adjustment Every well visit starting at 12 months
School placement/performance Annually starting at 3 years
Sexual and reproductive issues Once in childhood (5-13 years), annually starting at 13 years
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Case Two
Alex
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Case Two: History
• HPI: Alex is a 14 year old male with at least 7 café au lait patches measuring >15mm, relative macrocephaly, axillary freckling and a learning disability
• No history of neurofibromas, bony changes, Lisch nodules or optic gliomas
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Case Two: History Continued
Genetic testing is negative for NF1 gene Further testing reveals: SPRED1 gene mutation Legius Syndrome
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Legius Syndrome
• ‘RAS-opathy’ due to SPRED1 gene mutation
• Patients have CAL spots, freckling, macrocephaly and in some, mild neurocognitive delays
• Single case of AML• No other neoplastic findings commonly
seen in NF-1
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Case Three
Maria
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Case Three: History
HPI: Maria is a 3 year old girl who presents with 4 hypopigmented patches
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Case Three, Question 1
What procedure would you use to further evaluate this patient?
A. Dermoscopy
B. Fungal Culture
C. KOH preparation
D. Wood’s Lamp
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Case Three, Question 1
Answer: D
What procedure would you use to further evaluate this patient?
A. Dermoscopy
B. Fungal Culture
C. KOH preparation
D. Wood’s Lamp – to screen for other hypopigmented lesions including ash leaf spots or confetti hypopigmentation seen in tuberous sclerosis
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Differential Diagnosis of Hypopigmented Macules or Patches
• Tuberous Sclerosis (TS) Tinea Versicolor Vitiligo (early) Post inflammatory hypopigmentation
Due to the number of hypopigmented lesions, this case is concerning for Tuberous Sclerosis and the patient is referred to genetics who confirms the diagnosis of TS with genetic testing
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Tuberous Sclerosis: The Basics
Neurocutaneous disorder due to mutations in TSC1 or TSC2 genes encoding hamartin and tuberin proteins, respectively
Leads to a lack of inhibition of mTOR hamartomas Incidence is 1:6,000 to 1:100,000 Found in all races, equal gender distribution Autosomal dominant transmission
Principal early manifestations Seizures Mental retardation > 3 Hypomelanotic macules (≥ 5mm or more) polygonal or
oval shaped (Ash leaf spots) or small confetti-like hypopigmented macules 35
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Other Skin Findings in TS
Facial angiofibromas are pathognomonic but may not appear until 3rd and 4th year of life
Shagreen patch: connective tissue nevus, skin colored, occurs on back and buttocks
Dental enamel pits Ungual fibromas Intraoral fibromas
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TS: Other Associated Symptoms
• CNS tumors (gliomas)• Eye (retinal plaques)• Heart (benign rhabdomyomas)• Hamartomas of mixed cell type in
kidney, liver, thyroid, testes, or GI
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Tuberous Sclerosis Clinical Diagnostic Criteria2012 Consensus Conference
Major Features Hypomelanotic macules (≥3) (> 5mm diameter) Angiofibromas (≥3) or fibrous cephalic plaque Ungual fibromas (≥2) Shagreen patch Multiple retinal hamartomas Cortical dysplasia Subependymal nodules Subependymal giant cell astrocytoma Cardiac rhabdomyoma Lymphangioleiomyomatosis (LAM)* Angiomyolipomas (≥2)*
Minor Features “Confetti” skin lesions Dental enamel pits (≥3) Intraoral fibromas (≥2) Retinal achromic patch Multiple renal cysts Nonrenal hamartomas
Definitive Diagnosis Two major features OR One major with ≥ 2 minor
Possible Diagnosis One major feature OR ≥ 2 minor
*Combination of major criteria LAM and angiomyoplipoma without other features does not meet criteria for a definitive diagnosis
Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference(Northrup, H., and D. Krueger, 2013, Pediatric Neurology)
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Case 3: History Continued
Maria returns to clinic at age 13 years and is concerned about the angiofibromas on her face
Physical Exam: 0.1-0.5 cm dome shaped, smooth, red, purple or skin colored papules
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Angiofibromas: Management
Observation only
Laser ablation (PDL, CO2 or other)
New off label topical therapy: rapamycin• Rapamycin is an immunosuppressent that blocks the mTOR
pathway. It can be used to successfully prevent and treat angiofibromas of the face in TS
Pre-treatmentPartial improvement after
3 months of topical rapamycin
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TS Surveillance Recommendations
Specialty Recommendation (2012 International Tuberous Sclerosis Consensus Conference)
Genetics Genetic testing and family counseling
Neurology • MRI of brain at diagnosis and every 1-2 years in asymptomatic patients < 25 years (more frequently if subependymal giant cell astrocytoma present)
• Screen for neuropsychiatric disorders annually with formal evaluation in infancy, childhood, adolescence, and early adulthood
• Obtain baseline EEG and repeat in patients with known or suspected seizure activity
Renal • MRI of abdomen at diagnosis every 1-3 years throughout lifetime• GFR and blood pressure annually
Lung • Screen for LAM symptoms annually (exertional dyspnea)• High resolution chest CT and PFTs at diagnosis• High resolution chest CT every 5-10 years in asymptomatic patients at risk of LAM• If lung cysts on baseline CT, PFT yearly and CT every 2-3 years
Skin/Teeth Skin and dental inspection and exam annually
Heart • Echocardiogram every 1-3 years in asymptomatic pediatric patients until regression of cardiac rhabdomyoma is documented
• ECG every 3-5 years in asymptomatic patients of all ages
Eye Annual ophthalmologic evaluation if previous lesions or symptoms at baseline evaluation
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Case Four
Thomas
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Case Four: History
• Thomas is a 3 week old male who was found to have this pink/purple vascular patch on his face since birth. It gets darker when he cries, but has not grown or become raised since birth.
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Case Four: Physical Exam
• Physical Exam: Pink/purple vascular patch in a unilateral V1 distribution involving the eyelids
• Diagnosis: Port Wine Stain/Capillary Malformation
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Case Four, Question 1
Involvement of the eyelid in this case makes referral to ophthalmology important to screen regularly for what condition?
A. Cataracts
B. Conjunctivitis
C. Glaucoma
D. Uveitis
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Case Four, Question 1
Answer C
Involvement of the eyelid makes referral to ophthalmology important to screen regularly for what?
A. Cataract
B. Conjunctivitis
C. Glaucoma – can occur at any age in patients with port wine stains involving the eyelid
D. Uveitis
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Port-wine Stain (PWS)
• Cutaneous capillary malformation (CM)• Do not regress, unlike infantile hemangiomas, which
are vascular tumors that proliferate and then involute
• May become darker in color or thickened over time• Incidence is 3/1000 newborns• May be associated with soft tissue or bony
overgrowth• Sturge Weber syndrome is associated with CM/PWS
in the V1 distribution of the face
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Sturge-Weber Syndrome (SWS)
• Sporadic genetic syndrome• 1/20-50,000 live births, no sex predominance• Caused by a mutation in the GNAQ gene
– also present in non-syndromic port-wine stains– same mutation causes a different effect depending
on the embryonic stage (in SWS mutation is earlier)
• Port-wine stain most often in V1 distribution• Associated with vessel abnormalities of
leptomeninges and the eye clinically presenting as seizures and glaucoma, respectively
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Port-wine Stain Treatment
Port-wine stains may be safely and effectively treated with laser to minimize darkening, thickening and avoid the psychological distress they may cause There is no cure for the neurologic manifestations of
SWS Considerations in pediatric patients include the risk of
general anesthesia or sedation which may be required in young patients
Side effects include pain, bruising, pigmentation changes or blistering (rarely scaring)
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Genodermatoses SummaryFeature NF1 TS SWS
Gene Neurofibromin TSC1 (hamartin) or TSC2 (tuberin)
GNAQ
Skin Findings
CALS, skin fold freckling, plexiform neurofibroma, cutaneous neurofibromas
Hypopigmented spots, angiofibromas, ungual fibromas, fibrous cephalic plaque
Capillary Malformation/Port Wine stain of the face, usually V1 distribution
Tumors Optic glioma, malignant peripheral nerve sheath, rhabdomyosarcoma, glioblastoma, pheochromocytoma
Retinal hamartomas, cortical tubers, subependymal nodules. subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangioleiomyomatosis (LAM), nonrenal hamartomas
Not associated with tumors/malignancies
Other SystemsAffected
Renal artery stenosis, skeletal dysplasias, learning disabilities
Cortical dysplasia in brain Leptomeningeal angiomatosis, seizures, glaucoma, learning disabilities
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Take Home Points: Neurofibromatosis
Café au lait spots are common in healthy individuals, but more than 6 lesions should prompt evaluation for NF1
Frequency of café au lait spots varies with ethnicity and is higher in people with darker skin pigmentation
NF1 is an autosomal dominant disease; however 50% of mutations are de novo with no family history
Other symptoms associated with NF1 are axillary or inguinal freckling, neurofibromas, lisch nodules, optic gliomas, skeletal abnormalities, and various other tumors
Children with NF1 need yearly ophthalmology exams starting at 1 year Legius syndrome is another Ras-opathy with similar dermatologic
findings without the increased risk of neoplasms
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Take Home Points: Tuberous Sclerosis and Sturge-Weber Syndrome
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TS• Hypopigmented macules may be accentuated by examination with a
Wood’s lamp Tuberous sclerosis is a disorder with early manifestations including
hypomelanotic macules, mental retardation, and seizures Facial angiofibromas are pathognomonic for TS Topical rapamycin is an effective treatment for facial angiofibromas SWS Port wine stain in a V1 distribution should prompt evaluation for Sturge
Weber syndrome (SWS) Port wine stains with involvement of the eyelid should prompt
evaluation for glaucoma SWS is associated with capillary abnormalities of leptomeninges and
the eye Port wine stains may be treated with laser
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Acknowledgements
This module was developed by the Society for Pediatric Dermatology Education Committee for the AAD Basic Dermatology Curriculum
Primary author: Kimberly Jablon, MD and Patrick McMahon, MD
Peer reviewers: Erin Mathes, MD and Sheilagh Maguiness, MD
Revisions: Patrick McMahon, MD Last revised: 3/1/15
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