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Cutaneous Mosaicism: a Molecular and Clinical point of view

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Presentation on theme: "Cutaneous Mosaicism: a Molecular and Clinical point of view"— Presentation transcript:

1 Cutaneous Mosaicism: 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 cutaneous patterns The concept of genetic mosaicism has 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.

Type I Ia:narrow lines of Blaschko. Ib:broad lines of Blaschko Type II checkerboard Type III phylloid

7 Type IV large patches without midline separation Type V lateralization

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 porokeratotic eccrine ostial and dermal duct nevus.

10 Type Ib segmental pigmentation disorder McCune-Albright syndrome Type II Becker’s nevus congenital melanocytic nevi segmental neurofibromatosis Type III leaf-like or oblong patterns hypopigmented patches in trisomy

11 Type IV bathing-trunk distribution of giant congenital melanocytic nevi Type V the type of nevus seen in CHILD syndrome

12 CELL MIGRATION Keratinocytes Melanocytes Angioblasts

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 incontinentia pigmenti. 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 postzygotic mutation, 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 Gonadal Gonosomal

18 Gonadal mosaicism in the germ-line tissues only autosomal dominant
proven in the sperm of fathers Examples: Cornelia de Lange, Pallister-Hall, Conradi-Hu¨ nermann-Happle syndrome hereditary angioedema

19 Gonadal mosaicism 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 Gonosomal mosaicism 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 Gonosomal mosaicism Examples have included:
segmental neurofibromatosis (NF) type 1 in a parent with full expression of NF1 in the offspring.

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

24 Mechanism Definition Postzygotic (somatic) mutation A mutation or chromosomal replication error that occurs after fertilization. Lyonization In females, one X-chromosome (either the maternal or the paternal X chromosome), is randomly inactivated in early embryologic development; that change is carried on in all future cell divisions Chimerism When an organism is composed of two or more genetically distinct cell lines with completely different genetic makeup. This may occur after bone marrow or organ transplant or maternal-fetal transfusion. Revertant mosaicism Spontaneous correction of an inherited mutation.

25 Chromosomal structural abnormalities
MOLECULAR MECHANISMS Epigenetic mosaicism Chimerism Segmental Twin-spotting Chromosomal structural abnormalities Revertant Functional

26 Loss of heterozygosity
Segmental mosaicism Segmental Postzygotic Loss of heterozygosity

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

29 Mechanism Definition Mitotic recombination The formation of new combinations of alleles because of the exchange of a segment of DNA by crossing over between homologous chromosomes. Gene conversion One allele converts the mutated sequence of the other allele to the wild-type sequence, possibly by nonreciprocal exchange Point mutation A change in a single base pair Deletion Loss of a portion of sequence of DNA; may range from one base pair to a large portion of the chromosome. Mitotic nondisjunction Failure of the chromosomes to separate properly during meiosis or mitosis; the result is that one daughter cell receives both chromatids and the other receives neither chromatid

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 Revertant mosaicism often demonstrated in autosomal recessive conditions. Example:non-Herlitz junctional epidermolysis bullosa (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 mosaicism results 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 Autosomal dominant conditions

38 X-linked-dominant mutations: lethal in the hemizygous male Autosomal lethal mutations surviving by mosaicism (gene known) Sporadic conditions: presumed autosomal lethal, but genetic basis not yet determined Revertant mosaicism Polygenic with superimposed segmental presentation Incontinentia pigmenti (NEMO gene) Conradi-Hunermann- Happle syndrome (EBP gene) Goltz syndrome (PORCN gene) CHILD syndrome (NSDHL gene) McCune-Albright (GNAS gene) Encephalo-cerebrocutaneous lipomatosis Proteus syndrome Epidermolysis bullosa (LAMB3, KRT14, and COL17A1 genes) Linear psoriasis Linear lichen planus Linear systemic lupus Erythematosus Linear pemphigus vulgaris

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 lesional skin, but not in the blood or unaffected skin, confirming a mosaic mutation

41 Autosomal lethal mutations surviving by mosaicism
CLINICAL EXAMPLES Autosomal lethal mutations surviving by mosaicism

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 osteopathia striata (noted in the mid- portion of the lower extremities), limb reduction abnormalities, and syndactyly.

48 Conradi-Hunermann-Happle syndrome (X-linked chondrodysplasia punctata)
in the neonate presented after birth by erythroderma 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 chondrodysplasia punctata)
Scarring alopecia on the scalp along Blaschko’s lines is also common. Cataracts may develop

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

51 Incontinentia pigmenti
Incontinentia pigmenti (IP) is an X-linked dominant disorder affecting the skin, teeth, hair, nails, and eyes caused by amorphic mutations in the NEMO (necrosis factor kappaB or NFkB essential modulator) gene in which the altered gene product lacks the molecular function of the wild-type gene. The Blaschko-linear pattern of the cutaneous lesions reflects functional mosaicism because of Lyonization.

52 Incontinentia pigmenti
Females are able to survive because of Lyonization. In boys the mutation is presumed to be lethal because of expression of the mutant allele in all cells. Males who survive are presumed to have had postzygotic mutations or have Kleinfelter syndrome (XXY)

53 Incontinentia pigmenti

54 Incontinentia pigmenti
The cutaneous lesions of IP evolve through four distinct phases: First: vesiculobullous phase Second : verrucous lesions Third: hyperpigmented streaks and whorls along the lines of Blaschko Fourth: subtle hypopigmented atrophic streaks with absent eccrine glands and hair follicles

55 Incontinentia pigmenti
The teeth: conical and peg-shaped nail dystrophy. The characteristic eye findings :retinal vascular anomalies and optic atrophy. neurologic : developmental delay and seizures.

56 Ectodermal dysplasia with immunodeficiency
It is due to hypomorphic mutations in the NEMO gene which result in an altered gene product that possesses a reduced level of activity, or in which the wild-type gene product is expressed at a reduced level. (ED-ID) is an X-linked recessive disorder; the phenotype occurs in hemizygous males. Females are spared because they have one X-chromosome with the wild-type gene.

57 Ectodermal dysplasia with immunodeficiency
The features of ED-ID are combined humoral and cell-mediated immunodeficiency and variable features of ectodermal dysplasia, including reduced sweating and dental anomalies.

58 X-linked recessive hypohidrotic ectodermal dysplasia
Occurs in hemizygous males by mutations in the ectodysplasin A gene Features: a characteristic facial phenotype with full lips and periorbital ridging, thin, sparse, blond hair, lack of sweating, and abnormal teeth. The clinical features in carrier females may include patchy absence of vellus hair and stripes of hypotrichosis on the limbs and back, and mild to moderate hypotrichosis of the scalp hair.

59 X-linked recessive hypohidrotic ectodermal dysplasia

60 X-linked recessive hypohidrotic ectodermal dysplasia
The carrier status in females may be difficult to diagnose clinically. Interestingly, the functional mosaicism in these female carriers can be demonstrated using a starch iodine test, which reveals a lack of sweating along the lines of Blaschko

61 Chromosomal mosaicism
It is based on pigmentary alteration along the lines of Blaschko in children with developmental delay and additional congenital anomalies. chromosomal abnormalities reported, include structural abnormalities, balanced translocations, and polyploidy.

62 Chromosomal mosaicism
In some cases, the chromosomal abnormalities were reported in all cells and in other cases the changes were reported as mosaic (affecting only a subset of cells).

63 Other sporadic conditions

64 Proteus syndrome is named after the Greek sea-god, known for the ability to assume many different shapes. The general criteria for the diagnosis of Proteus syndrome include: mosaic distribution of the lesions, sporadic occurrence, and progressive course. a cerebriform connective tissue nevus on the soles of the feet is present, the diagnosis of Proteus syndrome can be made


66 Proteus syndrome If not, then additional diagnostic criteria include :
asymmetric, disproportionate overgrowth of the limbs or viscera, and hyperostosis. Specific tumors can also be seen, including bilateral ovarian cystadenoma or parotid monomorphic adenoma. Finally, dysregulation of adipose tissue, vascular malformations, and lung cysts may be additional features.

67 Proteus syndrome Surgical intervention is not recommended unless ‘‘absolutely necessary,’’ because the complication rate is high [62]. Deep vein thrombosis is one of the most common causes of death. it is theorized that it is caused by mutations that would be lethal in a nonmosaic state; in other words, the embryo would not survive if the mutation was present in all cells

68 Segmental pigmentation disorder (patterned dyspigmentation)
It is pigmentary changes along the lines of Blaschko or large segmental cafe´-au-lait patches do not have associated congenital anomalies or other systemic associations.

69 Segmental manifestations of polygenic and inflammatory skin disorders
Several inflammatory and polygenic conditions have been reported with linear or segmental presentations. Generally, these conditions present with a more severe segment overlying a milder background of generalized involvement.

70 Segmental manifestations of polygenic and inflammatory skin disorders
examples in the literature include linear psoriasis, linear lichen planus, linear systemic lupus erythematosus, linear pemphigus vulgaris, linear atopic dermatitis, linear graft-versus-host disease, segmental granuloma annulare, and linear fixed-drug eruptions

71 Thank you Thank you

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