F001 Oral Signs of Genetic Disease DISCL ISCLOSURE OF RELATIO - PDF document

2/14/2017 F001 Oral Signs of Genetic Disease DISCL ISCLOSURE OF RELATIO IONSHIPS IPS WITH WITH IN INDUSTRY Jennifer L. Hand, MD Jennifer L. Hand MD F001- Oral Signs of Genetic Disease 10:10 AM – 10:30 AM Associate Professor of Dermatology, 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 • Ehlers-Danlos syndrome • Peutz- Jegher accurately • Osteogenesis Imperfecta • Familial Adenomatous • Recognize benign skin findings that indicate • Dentinogenesis imperfecta Polyposis (FAP) an increased risk for systemic disease • MEN2B Ectodermal dysplasia • Obtain a targeted family history for genetic • Cowden syndrome • Hypohydrotic Ectodermal syndromes with oral features dysplasia • Carney Complex • Incontinentia Pigmenti Which associated skin change is most likely? A) Striae B) Mucosal neuromas C) Syringomas D) Basal cell nevi E) Mucous cysts 1

2/14/2017 Which associated skin change is Marfan syndrome most likely? • Autosomal dominant, variable expressivity A) Striae • 1:5,000 persons • 25% new (de novo) mutations B) Mucosal neuromas • Affects skeletal, ocular and cardiovascular C) Syringomas systems D) Basal cell nevi • Potentially fatal; may not be evident until adolescence E) Mucous cysts Ghent Systemic Score Marfan syndrome Marfan.org Score > or = 7 is significant. Marfan Syndrome • Fibrillin-1 ( FBN1 ) mutation Feature Value Feature Value • Extracellular matrix protein • Elastic fibrils of lens, aorta, skin Wrist and thumb sign 3 Protrusio acetabulae 2 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 • Rarely, mutations in TGFBR1 and TGFBR2 ratio • type called “ Loey’s -Dietz ” Hindfoot deformity 2 Scoliosis 1 Pes Planus 1 Craniofacial features 1 • additional traits: bifid uvula, easy bruising or abnormal Pneumothorax 2 Myopia 1 scars Dural ectasia 2 Mitral Valve Prolapse 1 Marfan : Facial Skeletal Features Marfan Syndrome Skeletal abnormalities Down-slanting, deep eyes • Long extremities • Reduced arm-span to Malar hypoplasia height; upper to lower segment ratios Micro-, retrognathia • Pectus • Scoliosis High, arched palate • Pes planus Tooth crowding 2

2/14/2017 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 Table from Jouni Uitto Eur J Dermatol 2005; 15 (5): 311-2 Ehlers-Danlos syndrome EDS Classical Type 6 Types Old Features Inherita Gene Type nce (After 1997) Extensible Skin, AD, Type V Collagen Major Diagnostic Criteria Classical I, II Joints,Scars, Bruising AR III Joint Hypermobility, Pain, AD Unknown Hypermobility  Skin hyperextensibility dislocations Vascular IV Thin skin, GI or uterine AD Type III Collagen rupture  Widened, atrophic scars Kyphoscoliosis VI Hypotonia, lax joints, AR Lysyl eyes, scoliosis hydroxylase Severe joint mobility, Type I Collagen Arthrochalasia VIIa, AD  Joint Hypermobility birth dislocation b Severe skin fragility, Dermatosparaxis VIIc AR Procollagen N- extensibility peptidase 3

2/14/2017 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 • Found in bones, fascia, tendons, eating” sclera, dermis and organ capsules “I have been forced to interrupt meals” • Quantitative defects more severe than qualitative defects Berglund, Bjorck. J Orofac Pain 2012 Fall;26(4):307-14 Collagen Type I Osteogenesis Imperfecta Type Family FragileB Easy Short Other • Osteogenesis Imperfecta: ones Bruise Inherited disorder associated with I Blue Mild to AD Yes Yes Mod Sclera bone fragility II AD or Infant Death • Why would a dermatologist be AR III White AR consulted? Yes Very Severe Sclera IV Easy bruising AD Mod Mod 4

2/14/2017 Osteogenesis Imperfecta Osteogenesis Imperfecta • Thin, atrophic, translucent skin • Most patients present • Scars frequently atrophic like EDS with pathologic • Teeth susceptible to caries, break easily, fractures and and are amber yellow to bluish-gray 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 5

2/14/2017 Multiple Mucosal Neuromas Multiple Endocrine Neoplasia MEN 2B Type 2B • Medullary Thyroid Cancer (MTC) in virtually • Also called Mucosal Neuroma Syndrome all (100 %)  Early thyroidectomy (< age1) • Autosomal Dominant • Pheochromocytoma (50%) • RET is the only gene; testing detects 98% • Gastrointestinal symptoms from • Oral mucosal neuromas may be first to hamartomas (ganglioneuromas) present • Hyperparathyroidism (30%) 6

2/14/2017 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 7

2/14/2017 Cowden syndrome Cowden syndrome • Macrocephaly • “Overgrowth” syndrome PTEN Hamartoma PTEN Hamartoma Cowden Syndrome Criteria Cowden syndrome Major Pathognomo Pat monic • Cancers of the thyroid (35%), breast (up • Breast cancer • Adult Lhermitte-Duclos to 67%),colon (9%), renal (35%), disease • Thyroid cancer melanoma (5%) and endometrium (30%) • Mucocutaneous • Macrocephaly • Thyroid cancer: follicular or papillary, • Facial • Endometrial cancer trichilemmomas not medullary • Acral keratoses • Numerous benign hamartomas • Papillomas PTEN Hamartoma PTEN Hamartoma: Cowden Syndrome Cowden Syndrome Criteria What is Lhermitte – Duclos • 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 trichilemmoma overgrowth of the • Cutaneous papules and oral papules cerebellum • 6 or more palmo/plantar keratoses From Int J Neuroradiology official blog; • Gangliocytoma Jan 12, 2013 8

2/14/2017 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 Surveillance Banayan-Riley Ruvalcaba • Age < 18: annual thyroid ultrasound, skin • Allelic to Cowden (PTEN), autosomal dominant 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 9