Cutaneous Mosaicism : a Molecular and Clinical point of view

1. CutaneousMosaicism: a Molecular and Clinical point of view By Lamia Elgarhy Assistant lecturer

2. INTRODUCTION • Since Blaschko first reported the patterns of epidermal nevi in 1901, dermatologists have recognized that many inherited and sporadic skin conditions appear in distinct cutaneouspatterns • The concept of genetic mosaicismhas been used to explain these patterns.

3. Lines of Blaschko

4. INTRODUCTION • Genetic mosaicism defined as two or more cell populations with distinct karyotypes or genotypes in one individual. • At the same time, Montgomery proposed the theory that the patterned lines on the skin represented the dorsoventral outgrowth, as embryonic cells follow a path of migration from the neural crest in the developing embryo.

5. INTRODUCTION • For mutations that occur early in embryologic development, the condition may be apparent over a broader body surface area; • whereas later mutations will be apparent in smaller, more confined anatomic regions.

6. PATTERNS OF CUTANEOUS MOSAICISM

8. Lines of Blaschko

9. Type Ia:Ia:narrow lines of Blaschko Demonstration of the narrow lines of Blaschko on the neck and chest (A) and abdomen (B), showing sharp midline demarcation in a child with porokeratoticeccrineostial and dermal duct nevus.

12. CELL MIGRATION

13. A- Melanocytes • Melanoblasts are neural crest-derived cells that migrate via the mesenchyme as single cells during embryogenesis. • 10-weeks gestation, the melanocytes are located diffusely in the dermis. • Later, some melanocytes undergo a presumed programmed cell death, while others continue the migration to the epidermis and basal layer of the hair matrix in the outer root sheath of the hair follicles.

14. B- keratinocytes • Dorsoventral migration pattern. • Later curving in lines, which likely explains the appearance of the whorls and streaks along the lines of Blaschko (type 1), such as in incontinentiapigmenti. • The lines of Blaschko can also be seen in the oral mucosa, the bone, and the eye.

15. C- Angioblasts • originate in the central body axis with a lateral migration. • Vascular birthmarks commonly present in a segmental or dermatomal pattern, and are therefore possibly caused by a postzygoticmutation, leading to abnormal migration or formation of the vasculature in a localized area. (not yet been proven)

16. Current and future • Historically, conventional cytogenetic analysis has been the most common tool for screening for chromosomal anomalies; however, this technique is time consuming, labor intensive, and requires cell culture. • Array comparative genomic hybridization (CGH) is emerging as a new technique for high-resolution, genome-wide scanning in congenital anomaly syndromes. This technique has also been referred to as chromosomal microarray analysis.

17. mosaicism

18. Gonadalmosaicism • in the germ-line tissues only • autosomal dominant • proven in the sperm of fathers • Examples: • Cornelia de Lange, Pallister-Hall, • Conradi-Hu¨ nermann-Happlesyndrome • hereditary angioedema

19. Gonadalmosaicism Cornelia de Lange syndrome is characterized by: • distinctive facial features, • short stature, • hirsutism and synophrys, • long eyelashes, • and limb reduction defects. • The disorder is caused by mutations in the Nipped-B-like (NIPBL) gene

21. Gonosomalmosaicism • mutations are present in both somatic tissue and in the gonadal tissue. • This has been implicated in cases of segmental presentations in the parent and subsequent full-blown expression in the affected offspring.

22. Gonosomalmosaicism Examples have included: • segmental neurofibromatosis (NF) type 1 in a parent with full expression of NF1 in the offspring.

23. Gonosomalmosaicism The classic example is an individual with epidermal nevi of the epidermolytic hyperkeratosis-type who has an offspring with generalized epidermolytic hyperkeratosis.

25. MOLECULAR MECHANISMS

26. Segmental mosaicism

27. Segmental mosaicism Type 1: • segmental changes occur as a postzygotic mutation. • the cutaneous changes are seen only in a localized segment, while the remaining skin is unaffected.

28. Segmental mosaicism Type 2 loss of heterozygosity(LOH) • a generalized phenotype is apparent with an exaggerated expression localized to one region. • Examples : neurofibromatosis, Hailey-Hailey disease, and Darier’s disease in individuals with typical lesions and a superimposed segmental presentation

30. Functional mosaicism • occurs in females as a result of X-inactivation. • The mechanism for inactivation is via the X-inactivation site, located at Xq13.2 containing the XIST gene.

31. Revertantmosaicism • often demonstrated in autosomal recessive conditions. • Example:non-Herlitzjunctionalepidermolysisbullosa (EB) in which mutations in the type XVII collagen gene, COL17A1. • Mechanism: • it is proposed that one allele converts the mutated sequence of the other allele to the wild-type sequence, possibly by nonreciprocal exchange. • Recently,It is hypothesized that this may have been because of the expansion of clonal epidermal stem cells.

32. Chromosomal numeric or structural abnormalities Examples: • structural abnormalities, such as: • ring chromosomes, • deletions, or • duplications, • numeric abnormalities, such as: • in mosaic trisomy 21. • Chromosomal mosaicismresults from events that take place after fertilization and result in failure of the chromosomes to separate properly during cell division;this is also known as nondisjunction.

33. Chimerism • Blood chimerism can result from twin-twin transfusion in dizygotic twins • Chimerism can occur from a transfusion between a mother and her fetus as well

34. Epigenetic mosaicism • the total number of genes in the human genome was less than expected: approximately 20,000 to 25,000 genes. • Epigenetic regulation refers to a variety of heritable mechanisms for altering gene expression • The epigenetic factors that control changes in gene expression can be heritable and in some cases are transmitted to the next generation. In other cases, the epigenetic controls may only be effective during embryogenesis.

35. Imprinting’’ is the term used to describe the situation in which gene expression is dependent on the sex of the transmitting parent. • Examples of diseases that are influenced by imprinting include Albright syndrome, Beckwith-Wiedemann syndrome,Prader-Willi syndrome, and Angelman syndrome

36. Twin-spotting • It is proposed as a potential mechanism for the development of coexisting birthmarks, such as nevus simplex with adjacent Mongolian spots or pigmentary nevi.

37. Autosomal dominant conditions CLINICAL EXAMPLES

39. Segmental neurofibromatosis Type I:The proposed mechanism for development of segmental NF1 is a postzygotic somatic mutation in the NF1 gene. Type II: typical generalized skin lesions with a superimposed segmental manifestation Axillary freckling and cafe´-au-laitmacules in the segmental pattern on the axilla and chest of a toddler with segmental neurofibromatosis

40. Segmental Darier’s disease • The molecular basis of Darier’s disease is a causative mutation in the ATPase, calcium dependent gene (ATP2A2) • In segmental Darier’s disease, the warty papules are localized in a Blaschko-linear pattern in one region of the body. • ATP2A2 mutations were identified in the lesionalskin, but not in the blood or unaffected skin, confirming a mosaic mutation

41. Autosomal lethal mutations surviving by mosaicism CLINICAL EXAMPLES

42. McCune-Albright syndrome • caused by sporadic postzygotic-activating mutations in guanine nucleotide-binding protein, alpha-stimulating activity polypeptide 1, (GNAS1 gene)

43. McCune-Albright syndrome • The clinical features: • large, segmental, unilateral cafe´-au-lait patches, which in some cases have been described as following the broad lines of Blaschko and in other cases have been described as having a ‘‘coast of Maine’’ appearance • polyostotic fibrous dysplasia • and endocrine abnormalities, including precocious puberty.

44. X-linked conditions • X-linked dominant conditions occur predominantly in females who are presumed to survive because of the functional mosaicism created by X-inactivation. • X-linked dominant conditions are generally lethal in hemizygous males. • Affected males have been reported for each of these conditions; some were shown to have Kleinfelter syndrome (XXY), while others were presumed to survive because of postzygotic mutations leading to somatic mosaicism

45. Focal dermal hypoplasia (Goltz syndrome • X-linked dominant disorder affecting both mesodermal and ectodermal structures, including the skin, eyes, teeth, and digits • atrophic, hypopigmented, linear streaks with telangiectasia and punctuate cribiform scarring, as well as subcutaneous fat herniations into the dermis along the lines of Blaschko.

46. Focal dermal hypoplasia (Goltz syndrome) Raspberry-like papillomas frequently appear in the perioral and anogenital regions.

47. Focal dermal hypoplasia (Goltz syndrome) • The classic radiologic features are osteopathiastriata (noted in the mid-portion of the lower extremities), • limb reduction abnormalities, and syndactyly.

48. Conradi-Hunermann-Happle syndrome (X-linked chondrodysplasiapunctata) in the neonate presented after birth byerythroderma and linear hyperkeratosis and psoriasiform scale. later in childhood As the erythroderma resolves, linear streaks with fine scale and ichthyosis along Blaschko’s lines become apparent

49. Conradi-Hunermann-Happle syndrome (X-linked chondrodysplasiapunctata) • Scarring alopecia on the scalp along Blaschko’s lines is also common. • Cataracts may develop

50. Conradi-Hunermann-Happle syndrome (X-linked chondrodysplasiapunctata) • The extracutaneous features include limb reduction, distinctive facial features with asymmetry, frontal bossing, and saddle nose.