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F001 Oral Signs of Genetic Disease DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY Jennifer L. Hand, MD Jennifer L. Hand MD F001- Oral Signs of Genetic Disease Associate Professor of Dermatology, 10:10 AM – 10:30 AM Clinical Genomics, and Pediatrics DISCLOSURES Mayo Clinic, Rochester, MN I do not have any relevant relationships with industry.

Objectives Syndromes Connective Tissue Dysplasia • Marfan Syndrome • Diagnose oral signs of genetic disease more Neoplastic accurately • Peutz- Jegher • Ehlers-Danlos syndrome • Familial Adenomatous • Osteogenesis Imperfecta • Recognize benign skin findings that indicate Polyposis (FAP) • Dentinogenesis imperfecta an increased risk for systemic disease • MEN2B Ectodermal dysplasia • Obtain a targeted family history for genetic • • Hypohydrotic Ectodermal syndromes with oral features dysplasia • •

Which associated skin change is most likely? A) Striae B) Mucosal neuromas C) Syringomas D) Basal cell nevi E) Mucous cysts

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Which associated skin change is Marfan syndrome most likely? • Autosomal dominant, variable expressivity A) Striae • 1:5,000 persons B) Mucosal neuromas • 25% new (de novo) mutations C) Syringomas • Affects skeletal, ocular and cardiovascular systems D) Basal cell nevi • Potentially fatal; may not be evident until adolescence E) Mucous cysts

Ghent Systemic Score Marfan.org Marfan syndrome Score > or = 7 is significant. Marfan Syndrome • Fibrillin-1 (FBN1) mutation Feature Value Feature Value • Extracellular matrix protein Wrist and thumb sign 3 Protrusio acetabulae 2 • Elastic fibrils of lens, aorta, skin Wrist or thumb sign 1 Reduced elbow extension 1 • regulator of TGF-b (transforming growth factor beta) Pectus carinatum 2 Skin striae 1 signaling Pectus excavatum or chest 1 Reduced upper-to-lower segment 1 asymetry and increased arm span to height ratio • Rarely, mutations in TGFBR1 and TGFBR2 Hindfoot deformity 2 Scoliosis 1 • type called “Loey’s-Dietz” Pes Planus 1 Craniofacial features 1 Pneumothorax 2 Myopia 1 • additional traits: bifid uvula, easy bruising or abnormal Dural ectasia 2 Mitral Valve Prolapse 1 scars

Marfan : Facial Skeletal Features Marfan Syndrome Down-slanting, deep eyes Skeletal abnormalities • Long extremities Malar hypoplasia • Reduced arm-span to height; upper to lower segment ratios Micro-, retrognathia • Pectus High, arched palate • Scoliosis • Pes planus Tooth crowding

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Marfan syndrome Marfan: vascular abnormalities Definitive diagnosis: • Aortic root ≥2 z score and ectopia lentis • Aortic dilatation • Aortic root ≥2 z score and FBN1 mutation • Z-score >= 2.0 • Aortic root ≥2 z score and systemic score ≥7 • Dissection • Ectopia lentis and FBN1 mutation • Mitral valve prolapse • Family history and ectopia lentis • Arrhythmia Normal Aorta Marfan • Family history and systemic score ≥7

Marfan syndrome Hypermobility Syndromes

• Prognosis by cardiovascular defects: common cause of death, aortic abnormalities in adults • Advice: Minimize contact sports, Avoid isometric exercises, Valsalva maneuver. • Long-term propranolol decreases myocardial contractility, risk of aortic dilatation. Losartan (ARBs) superior to beta-blockers • Prosthetic replacement of aneurysmal and valve heart defects, aortic root

Ehlers-DanlosTable syndrome from Jouni Uitto Eur J Dermatol 2005; 15 (5): 311-2

6 Types Old Features Inherita Gene EDS Classical Type Type nce (After 1997) Classical I, II Extensible Skin, AD, Type V Collagen Joints,Scars, Bruising AR Major Diagnostic Criteria Hypermobility III Joint Hypermobility, Pain, AD Unknown dislocations Skin hyperextensibility Vascular IV Thin skin, GI or uterine AD Type III Collagen rupture Kyphoscoliosis VI Hypotonia, lax joints, AR Lysyl eyes, scoliosis hydroxylase Widened, atrophic scars

Arthrochalasia VIIa, Severe joint mobility, AD Type I Collagen b birth dislocation Joint Hypermobility Dermatosparaxis VIIc Severe skin fragility, AR Procollagen N- extensibility peptidase

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Beighton Scale

Frenulum is smaller, atrophic in EDS.

EDS  GeneReviews/ NIH

Normal 

Drawings from Joint Hypermobility Association UK Used with permission. Celletti et al. Am J Med Gene. 2011.

Collagen Type I • Comprise 30% of human body “I have had pain in my mouth” weight “I have had discomfort when eating” • Found in bones, fascia, tendons, sclera, dermis and organ capsules “I have been forced to interrupt meals” • Quantitative defects more severe Berglund, Bjorck. J Orofac Pain 2012 Fall;26(4):307-14 than qualitative defects

Collagen Type I Osteogenesis Imperfecta Type Family FragileB Easy Short Other • Osteogenesis Imperfecta: ones Bruise I Mild to Blue Inherited disorder associated with AD Yes Yes bone fragility Mod Sclera II AD or Infant • Why would a dermatologist be AR Death III White AR Severe consulted? Yes Very Sclera IV Easy bruising AD Mod Mod

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Osteogenesis Imperfecta Osteogenesis Imperfecta • Thin, atrophic, translucent skin • Scars frequently atrophic like EDS • Most patients present with pathologic • Teeth susceptible to caries, break easily, and are amber yellow to bluish-gray fractures and osteoporosis • Width of cortex, amount of cancellous bone decreased • Mild form • Intraoperative brittle bones underdiagnosed • Prognathism

The following fact sheets and articles were written with the help of young people who have OI. College: Career Planning for Students with OI Checklist for College Accommodations College Search Resources College Financial Aid Resources

Guidelines for College Selection Process

Learning How to Drive Transition from Pediatric to Adult Care

Which of following diagnoses should Which of following diagnoses should be considered ? be considered ? A) Multiple mucosal neuromas A) Multiple mucosal neuromas B) Myxoid neurofibromas B) Myxoid neurofibromas C) Syringomas C) Syringomas D) Basal cell nevi D) Basal cell nevi E) Mucous cysts E) Mucous cysts

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Multiple Mucosal Neuromas

Multiple Endocrine Neoplasia MEN 2B Type 2B • Medullary (MTC) in virtually • Also called Mucosal Neuroma Syndrome all (100 %) • Autosomal Dominant Early (< age1) • Pheochromocytoma (50%) •RET is the only gene; testing detects 98% • Gastrointestinal symptoms from • Oral mucosal neuromas may be first to (ganglioneuromas) present • Hyperparathyroidism (30%)

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MEN2B 24-year-old; metastatic Medulllary Thyroid Cancer Oral Mucosal Neuromas

• On tongue, pathognomonic for MTC

• “Blubbery” lips • Oral findings benign PET Scan

MEN2B Characteristic appearance

MEN2B • “blubbery” lips • prominent jaw • Elongated face • “Lanky” build

Cowden syndrome

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Cowden syndrome Cowden syndrome

• •“Overgrowth” syndrome

PTEN PTEN Hamartoma Cowden Syndrome Criteria Cowden syndrome Pathognomonic Major • Cancers of the thyroid (35%), breast (up to 67%),colon (9%), renal (35%), • Adult Lhermitte-Duclos • melanoma (5%) and endometrium (30%) disease • Thyroid cancer • Mucocutaneous • Macrocephaly • Thyroid cancer: follicular or papillary, •Facial not medullary • •Acral keratoses • Numerous benign hamartomas •Papillomas

PTEN Hamartoma: Cowden Syndrome PTEN Hamartoma What is Lhermitte–Duclos Cowden Syndrome Criteria •Diagnostic Criteria updated every year disease? by the National Comprehensive Cancer • Adult onset in Network (NCCN) Cowden •Operational diagnosis if: • Hamartomatous •6 or more facial papules-at least 3 overgrowth of the cerebellum •Cutaneous papules and oral papules From Int J Neuroradiology official blog; •6 or more palmo/plantar keratoses Jan 12, 2013 • Gangliocytoma

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PTEN Hamartoma: PTEN Hamartoma: Cowden syndrome Cowden syndrome

Acral papules Palmar “pits”

PTEN Hamartoma PTEN Hamartoma Facial Tricholemmomas Oral Papillomas

PTEN Hamartoma PTEN Hamartoma Syndrome Banayan-Riley Ruvalcaba Surveillance • Allelic to Cowden (PTEN), autosomal dominant • Age < 18: annual thyroid ultrasound, skin check, physical exam • Adults: annual thyroid ultrasound, dermatology exam, colonoscopy, renal imaging. For family cancer hx, begin screening 5-10 years prior to youngest Penile diagnosis Hyperpigmented • For women: mammogram, breast MRI, Macules transvaginal ultrasound or endometrial biopsy

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With digital pigment and anemia, With digital pigment and anemia, risk of which cancer is increased ? risk of which cancer is increased ?

A) Gastrointestinal A) Gastrointestinal B) Lung B) Lung C) Esophageal C) Esophageal D) Skin D) Skin E) Breast E) Breast (54%)

Peutz-Jeghers Peutz-Jeghers Syndrome Syndrome • STK11 mutation, autosomal dominant • 94% with clinical diagnosis have a mutation • Association of gastrointestinal (P-J) polyps and mucocutaneous pigmentation • Polyps most common in small intestine (jejunum > ileum > duodenum)

Peutz-Jeghers Syndrome Genetics Referral Indications Associated Tumors • Epithelial: colorectal, gastric, pancreatic, • Mucocutaneous Pigmentation and breast, ovarian cancer one or more P-J polyps • Females: Sex cord tumors with annular • Ovarian sex cord/ Sertoli cell tumor tubules (SCTAT), Adenoma malignum of the cervix • Adenoma malignum of the cervix • Males: Sertoli cell tumors that secrete • Pancreatic or breast cancer estrogen, gynecomastia

• Overall cancer relative risk up by 10% Hampel et al. Genetics in Medicine. 17:1 January, 2015

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Risk of which cancer(s) is increased ?

A) Gastrointestinal B) Thyroid C) Testicular D) Pancreatic E) Breast

Risk of which cancer(s) is increased ?

A) Gastrointestinal B) Thyroid C) Testicular D) Pancreatic E) Breast

Carney syndrome: Carney Complex A Multiple Endocrine Neoplasia • Pale at birth • Embolic stroke secondary to cardiac • Brown to black • Endocrine abnormalities: Cushing’s • “ink spot” lentigines syndrome caused by PPNAD (pigmented • Increased at puberty nodular adrenocortical disease); 25% • Face, lips, mucosa • acromegaly due to growth hormone/ pituitary adenomas • Inner or outer canthi, vaginal or penile mucosa • prolactinemia

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Carney Complex Carney Complex • Psammomatous Melanotic Schwannomas (10%) • Also known as • Myxomas: skin, breast, • NAME (nevi, atrial , ephelides) oropharynx, female genital • LAMB (lentigines, atrial myxoma, blue tract nevi) • Large-cell calcifying Sertoli cell tumors (LCCSCT) in , Autosomal Dominant, 71% •PRKAR1A almost all by adult  detection rate • Multiple thyroid nodules • Locus heterogeneity: other unknown genes (75%)

Carney Complex Primary Pigmented Nodular Adrenocortical Disease (PPNAD) • Weight gain •causes Cushing • Growth Cessation syndrome • “moon facies” • Hirsutism •75% of females, • Striae 100% have • Hypertension PPNAD at • Buffalo hump • Weakness autopsy • Easy bruising • Psychological disturbance

Basal Cell syndrome Jaw Keratocysts

Appear age 8 to 30’s; Benign, cause tooth loss, appear clinically after damage

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Autosomal Dominant Inheritance Basal Cell Nevus Syndrome I. • Also Gorlin syndrome or Nevoid Basal Cell Carcinoma syndrome (NBCCS) II. • Autosomal dominant; 1:30,000 • Patched (PTCH1) mutation on 9q22.3; also in sporadic BCC III. • 20-30% de novo mutation • Tumor suppressor

Sonic Hedgehog Nevoid Basal Cell Carcinoma Syndrome (NBCCS) PTCH1 Major Criteria Minor Criteria Acts as Tumor Cell Membrane Suppressor • Falx calcification • Medulloblastoma • Pleural cysts PTCH1 Smoothened • Jaw keratocysts • Macrocephaly • Vertebral or rib abnormalities • Palm/ plantar pits Transcription Cascade • Polydactyly • Ovarian or Cardiac fibromas Patched1, when not bound with Sonic hedgehog, joins • > 5 BCC’s in a lifetime • Eye anomalies Smoothened to suppress transcription.

In Summary….

• Multiple similar benign growths suggest a single gene cancer predisposition might be present • A pedigree is a visual tool to recognize a genetic disorder • Certain benign pathology diagnoses warrant further consideration e.g. Fibrofolliculoma, jaw keratocyst, multiple mucosal neuroma

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Thank You!

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