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Skin Findings in Genetic Disorders

Recorded on Feb 8th 2021

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Skin Findings in Genetic Disorders

  1. 1. Skin Clues to Genetic Disorders Leah W. Burke, MD February 8, 2021
  2. 2. Goals • Review pigmentary differences in skin that might indicate a genetic disorder • Describe common skin findings that indicate a need for a genetic evaluation • Recognize the differences in age of onset, family history, number of lesions, or other unusual presentations that should alert the primary care provider
  3. 3. Classification of skin findings • Types of abnormalities • Primary finding or secondary to the disease process • Age of onset • Regional involvement
  4. 4. Characteristics of Primary Lesions Spots and Bumps Cysts Patches Macules Plaques Nodules Papules
  5. 5. Spots: Pigmentary macules • White – Ash leaf spots – Punctate loss of pigmentation • Brown – Café au lait spots – Nevi – Brown patches
  6. 6. “Ash Leaf” spots
  7. 7. Question #1
  8. 8. Tuberous Sclerosis COMPLEX
  9. 9. Skin Features • Hypopigmented macules – “Ash leaf spots” • Shagreen patches • Facial angiofibromas • Ungual fibromas
  10. 10. Tuberous Sclerosis Complex • Skin findings – Ash-leaf spots (hypomelanotic macules) – Shagreen patches – Facial angiofibromas – Ungual fibromas • Teeth pits • Cardiac – Rhabdomyomas – Arrhythmias • CNS findings – Cortical tubers – Subependymal nodules – Intellectual disability – Seizures – Autism • Kidney findings – Angiolipomas – Cysts
  11. 11. Presentations in Infancy • Rhabdomyomas – Sometime identified on prenatal ultrasound – Can present as a neonatal arrhythmias although this is rare • Infantile spasm/hypsarrhythmia syndrome – a severe hard to control type of seizures
  12. 12. TSC in childhood • Intellectual disability occurs in around 50% • Autism occurs in around 25% • Around 90% have some neuropsychiatric manifestation over their lifetime
  13. 13. Tuberous Sclerosis Complex Genetics Gene Chromosomal Locus Protein Name % of Patients with TSC TSC1 9q34.13 Hamartin 24% TSC2 16p13.3 Tuberin 66%
  14. 14. Spots • White – Ash leaf spots – Punctate loss of pigmentation • Brown – Café au lait spots – Nevi – Brown patches
  15. 15. Skin Manifestions: Café au Lait Spots 16
  16. 16. Question #2
  17. 17. Neurofibromatosis Type 1
  18. 18. Neurofibromatosis Type 1 Diagnostic Criteria – 2 or more of the following • Six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals • Two or more neurofibromas of any type or one plexiform neurofibroma • Freckling in the axillary or inguinal regions • Optic glioma • Two or more Lisch nodules (iris hamartomas) • A distinctive osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis • A first-degree relative (parent, sib, or offspring) with NF1 as defined by the above criteria
  19. 19. Skin Manifestations • Café au lait spots – Usually present at birth – Increase in number in the first couple of years – Increase in size – More than 6 are needed for diagnostic criteria • Axillary and Inguinal Freckling – Usually present by 10 years of age • Subcutaneous neurofibromas – Often not present in early childhood – Proliferation can occur in puberty of in pregnancy
  20. 20. Skin Manifestations: Axillary Freckling
  21. 21. Skin Manifestations: Subcutaneous Neurofibromas
  22. 22. NF1 Other Findings Neurological • Intellectual disability and/or autism in some • Headaches Ophthalmologic • Optic Gliomas • Lisch nodules Skeletal • Scoliosis • Short stature Other • Plexiform neurofibromas • Macrocephaly • High blood pressure
  23. 23. Neurofibromatosis Type 1 Genetics • The NF1 gene is large (~350 kilobases and 60 exons) • More than 1000 different pathogenic variants in NF1 have been identified – most unique to a particular family • Many different kinds of mutations have been observed, so a multi-step mutation detection protocol is used (>95% detection)
  24. 24. Patches or large spots GeneReviews: https://www.ncbi.nlm.nih.gov/books/NBK274564/
  25. 25. Question #3
  26. 26. McCune-Albright Syndrome • Giant café au lait spots with irregular borders • Follow the lines of Blaschko (developmental lines of embryonic cell migration) • Fibrous dysplasia develops • At risk for a whole host of endocrine abnormalities, including precocious puberty, testicular lesions, thyroid lesions, growth hormone excess, and others
  27. 27. McCune–Albright Syndrome Genetics • Involves an early embryonic postzygotic somatic activating pathogenic variant in GNAS • Genetic testing is done on a biopsy of affected tissue, because the pathogenic variant is found in ~80% in affected tissue, but only ~20%-30% in peripheral blood
  28. 28. Port Wine Stains • Sturge Weber – In the distribution of the first division of the trigeminal nerve – May have a vascular malformation of the ipsilateral meninges, cerebral cortex, and eye – Seizures, mental retardation, hemiplegia, and glaucoma may develop during the first several years of life – SOMATIC - not well characterized From Pediatric Dermatology, Bernard A. Cohen, Ed.
  29. 29. Port Wine Stains • Klippel-Trenauney – Port Wine stain or capillary malformation can involve any part of the body – Often unilateral – Often accompanied by overgrowth of affected side – No genetic cause is known
  30. 30. Patchy Hypopigmentation: Piebaldism • Can occur by itself as an autosomal dominant condition • Can also be the dermatologic sign of Waardenburg
  31. 31. Waardenburg Syndrome • White forelock • Patchy areas of hypopigmentation • Widely spaced eyes • Different colored eyes • Congenital hearing loss From eScholarship Dermatology Online
  32. 32. Skin Findings in Late Childhood/Adolescence
  33. 33. Stretch Marks: When to worry? From Marfan Foundation
  34. 34. Striae Atrophica in Marfan Syndrome From DermNet NZ
  35. 35. Marfan Syndrome Skeletal • Tall stature with long bone overgrowth • Long narrow face • High-arched palate • Arachnodactyly • Pectus deformities • Joint hypermobility • Scoliosis Eye • Subluxation of lenses Cardiac • Aortic root dilation and dissection • Mitral regurgitation Skin • Striae dystrophica • Recurrent hernias Pulmonary • Spontaneous pneumothoraces
  36. 36. Marfan Syndrome • Due to a pathogenic variant in FBN1 (fibrillin 1) • Related conditions due to pathogenic variants in TGFBR1 and TGFBR2
  37. 37. Stretch Marks - Striae Atrophicae • Can also be seen in other connective disorders such as the Ehlers-Danlos syndromes • Classical EDS also has hyperelastic skin and atrophic scarring, which are more diagnostic features • Classical EDS is caused by the collagen genes COL5A1/2 DermNet NZ
  38. 38. Yellow or Brownish Papules on the Neck S Laube, and C Moss Arch Dis Child 2005;90:754-756
  39. 39. Pseudoxanthoma Elasticum (PXE) • Connective tissue disorder that affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems • Skin findings can appear as early as 5 and can mimic other causes • Retinal findings between 10 and 30 • Can have other vascular involvement – Gastrointestinal angina and/or bleeding – Intermittent claudication of arm and leg muscles – Stroke – Renovascular hypertension
  40. 40. Pseudoxanthoma Elasticum (PXE) • Autosomal recessive inheritance ** • Caused by pathogenic variants in the ABCC6 gene • Important to diagnose so that monitoring for the other complications can take place
  41. 41. Telangiectasia
  42. 42. Hereditary Hemorrhagic Telangiectasia (HHT) • Previously known as Osler-Weber-Rendu • Frequent nosebleeds is often the presenting complaint – begin in childhood • Arteriovenous malformations (AVM) can occur throughout, but more commonly occur in the lung, liver and brain • Radiographic surveillance is important
  43. 43. Hereditary Hemorrhagic Telangiectasia (HHT) • Autosomal dominant condition • Caused by pathogenic variants in one of a group of genes
  44. 44. Telangiectasias Differential diagnosis for telangiectasias in childhood in the absence of liver disease include ataxia-telangiectasia • Progressive cerebellar ataxia beginning between age one and four years • Oculomotor apraxia • Frequent infections • Choreoathetosis • Telangiectases of the conjunctivae • Immunodeficiency • Increased risk for malignancy, particularly leukemia and lymphoma • Autosomal recessive inheritance
  45. 45. Mimic: Pigmented macules around lip From MedlinePus.gov
  46. 46. Peutz-Jeghers Syndrome • Characterized by the development of noncancerous growths called hamartomatous polyps in the gastrointestinal tract • Children with P-J develop pigmented macules around lips, inside the mouth, near the eyes and nostrils, around the anus and sometimes on the hands and feet • They appear during childhood and often fade as the person gets older • Highly increased risk of cancers of the gastrointestinal tract, pancreas, cervix, ovary, and breast
  47. 47. Peutz-Jegher Syndrome • Autosomal dominant Inheritance • Associated with a pathogenic variant in the STK11 gene in most cases
  48. 48. More bumps: Papillomatous papules Tricholimmoma GeneReviews: https://www.ncbi.nlm.nih.gov/books/NBK1488/
  49. 49. Pigmented spots on glans penis
  50. 50. Cowden and PTEN-Related Syndromes Skin features • Papillomatous papules around the face elsewhere • Tricholimmomas • Melanocytic macules on the glans penis
  51. 51. Cowden and PTEN-Related Syndromes Other features • Associated with hamartomas as well as various types of cancer – Thyroid – Breast – Endometrial • Macrocephaly • Intellectual disability and autism spectrum
  52. 52. Spots and Bumps: Clues to Underlying Conditions

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