This document discusses various skin findings that can indicate underlying genetic disorders. It describes spots and bumps commonly seen in tuberous sclerosis complex (ash leaf spots), neurofibromatosis type 1 (cafe au lait spots and freckling), and McCune-Albright syndrome (irregular cafe au lait spots). Stretch marks are discussed as a potential sign of Marfan syndrome. Yellow patches on the neck can indicate pseudoxanthoma elasticum, while frequent nosebleeds may point to hereditary hemorrhagic telangiectasia. Pigmented macules around the lips are a hallmark of Peutz-Jeghers syndrome.

1. Skin Clues to Genetic Disorders
Leah W. Burke, MD
February 8, 2021

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. Classification of skin findings
• Types of abnormalities
• Primary finding or secondary to the
disease process
• Age of onset
• Regional involvement

4. Characteristics of Primary Lesions
Spots and Bumps
Cysts
Patches
Macules
Plaques
Nodules
Papules

5. Spots: Pigmentary macules
• White
– Ash leaf spots
– Punctate loss of pigmentation
• Brown
– Café au lait spots
– Nevi
– Brown patches

6. “Ash Leaf” spots

7. Question #1

8. Tuberous Sclerosis COMPLEX

9. Skin Features
• Hypopigmented macules – “Ash leaf spots”
• Shagreen patches
• Facial angiofibromas
• Ungual fibromas

11. 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

12. 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

13. TSC in childhood
• Intellectual disability occurs in around
50%
• Autism occurs in around 25%
• Around 90% have some
neuropsychiatric manifestation over
their lifetime

14. Tuberous Sclerosis Complex Genetics
Gene Chromosomal
Locus
Protein Name % of Patients with
TSC
TSC1 9q34.13 Hamartin 24%
TSC2 16p13.3 Tuberin 66%

15. Spots
• White
– Ash leaf spots
– Punctate loss of pigmentation
• Brown
– Café au lait spots
– Nevi
– Brown patches

16. Skin Manifestions: Café au Lait Spots
16

17. Question #2

18. Neurofibromatosis Type 1

19. 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

20. 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

21. Skin Manifestations: Axillary Freckling

22. Skin Manifestations: Subcutaneous
Neurofibromas

23. 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

24. 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)

25. Patches or large spots
GeneReviews: https://www.ncbi.nlm.nih.gov/books/NBK274564/

26. Question #3

27. 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

28. 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

29. 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.

30. 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

31. Patchy Hypopigmentation: Piebaldism
• Can occur by itself as an
autosomal dominant
condition
• Can also be the
dermatologic sign of
Waardenburg

32. Waardenburg Syndrome
• White forelock
• Patchy areas of
hypopigmentation
• Widely spaced eyes
• Different colored eyes
• Congenital hearing loss
From eScholarship Dermatology Online

33. Skin Findings in Late
Childhood/Adolescence

34. Stretch Marks: When to worry?
From Marfan Foundation

35. Striae Atrophica in Marfan Syndrome
From DermNet NZ

37. 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

38. Marfan Syndrome
• Due to a pathogenic variant in FBN1 (fibrillin
1)
• Related conditions due to pathogenic variants
in TGFBR1 and TGFBR2

39. 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

40. Yellow or Brownish Papules on the Neck
S Laube, and C Moss Arch Dis Child 2005;90:754-756

41. 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

42. 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

43. Telangiectasia

44. 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

45. Hereditary Hemorrhagic Telangiectasia (HHT)
• Autosomal dominant condition
• Caused by pathogenic variants in one of a
group of genes

46. 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

47. Mimic: Pigmented macules around lip
From MedlinePus.gov

48. 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

49. Peutz-Jegher Syndrome
• Autosomal dominant Inheritance
• Associated with a pathogenic variant in
the STK11 gene in most cases

50. More bumps: Papillomatous papules
Tricholimmoma
GeneReviews: https://www.ncbi.nlm.nih.gov/books/NBK1488/

51. Pigmented spots on glans penis

52. Cowden and PTEN-Related Syndromes
Skin features
• Papillomatous papules around the face
elsewhere
• Tricholimmomas
• Melanocytic macules on the glans penis

53. 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

54. Spots and Bumps: Clues to Underlying
Conditions