Presentation on theme: "Cutaneous Mosaicism: a Molecular and Clinical point of view"— Presentation transcript:
1Cutaneous Mosaicism: a Molecular and Clinical point of view ByLamia ElgarhyAssistant lecturer
2INTRODUCTIONSince Blaschko first reported the patterns of epidermal nevi in 1901, dermatologists have recognized that many inherited and sporadic skin conditions appear in distinct cutaneous patternsThe concept of genetic mosaicism has been used to explain these patterns.
4INTRODUCTIONGenetic 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.
5INTRODUCTIONFor 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.
6PATTERNS OF CUTANEOUS MOSAICISM Type IIa:narrow lines of Blaschko.Ib:broad lines of BlaschkoType IIcheckerboardType IIIphylloid
7Type IVlarge patches without midline separationType Vlateralization
9Type 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.
10Type Ibsegmental pigmentation disorderMcCune-Albright syndromeType IIBecker’s nevuscongenital melanocytic nevisegmental neurofibromatosisType IIIleaf-like or oblong patternshypopigmented patches in trisomy
11Type IVbathing-trunk distribution of giant congenital melanocytic neviType Vthe type of nevus seen in CHILD syndrome
13A- MelanocytesMelanoblasts 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.
14B- 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.
15C- Angioblastsoriginate 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)
16Current and futureHistorically, 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.
18Gonadal mosaicism in the germ-line tissues only autosomal dominant proven in the sperm of fathersExamples:Cornelia de Lange, Pallister-Hall,Conradi-Hu¨ nermann-Happle syndromehereditary angioedema
19Gonadal 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
21Gonosomal mosaicismmutations 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.
22Gonosomal mosaicism Examples have included: segmental neurofibromatosis (NF) type 1 in a parent with full expression of NF1 in the offspring.
23Gonosomal mosaicismThe classic example is an individual with epidermal nevi of the epidermolytic hyperkeratosis-type who has an offspring with generalized epidermolytic hyperkeratosis.
24MechanismDefinitionPostzygotic (somatic) mutationA mutation or chromosomal replication error that occursafter fertilization.LyonizationIn females, one X-chromosome (either the maternal or thepaternal X chromosome), is randomly inactivated in earlyembryologic development; that change is carried on in allfuture cell divisionsChimerismWhen an organism is composed of two or more geneticallydistinct cell lines with completely different genetic makeup. This may occur after bone marrow or organ transplantor maternal-fetal transfusion.Revertant mosaicismSpontaneous correction of an inherited mutation.
26Loss of heterozygosity Segmental mosaicismSegmentalPostzygoticLoss of heterozygosity
27Segmental 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.
28Segmental 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
29MechanismDefinitionMitotic recombinationThe formation of new combinations of alleles because of the exchange of a segment of DNA by crossing over betweenhomologous chromosomes.Gene conversionOne allele converts the mutated sequence of the other allele tothe wild-type sequence, possibly by nonreciprocal exchangePoint mutationA change in a single base pairDeletionLoss of a portion of sequence of DNA; may range from onebase pair to a large portion of the chromosome.Mitotic nondisjunctionFailure of the chromosomes to separate properly during meiosisor mitosis; the result is that one daughter cell receives bothchromatids and the other receives neither chromatid
30Functional 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.
31Revertant mosaicismoften 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.
32Chromosomal numeric or structural abnormalities Examples:structural abnormalities, such as:ring chromosomes,deletions, orduplications,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.
33ChimerismBlood chimerism can result from twin-twin transfusion in dizygotic twinsChimerism can occur from a transfusion between a mother and her fetus as well
34Epigenetic mosaicismthe 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 expressionThe 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.
35Imprinting’’ 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
36Twin-spottingIt is proposed as a potential mechanism for the development of coexisting birthmarks, such as nevus simplex with adjacent Mongolian spots or pigmentary nevi.
39Segmental neurofibromatosis Type I:The proposed mechanism fordevelopment of segmental NF1 is a postzygotic somatic mutation in the NF1gene.Type II: typical generalized skin lesionswith a superimposed segmentalmanifestationAxillary freckling and cafe´-au-laitmacules in the segmental pattern on the axilla and chestof a toddler with segmental neurofibromatosis
40Segmental 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
41Autosomal lethal mutations surviving by mosaicism CLINICAL EXAMPLESAutosomal lethal mutations surviving by mosaicism
42McCune-Albright syndrome caused by sporadic postzygotic-activating mutations in guanine nucleotide-binding protein, alpha- stimulating activity polypeptide 1, (GNAS1 gene)
43McCune-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’’ appearancepolyostotic fibrous dysplasiaand endocrine abnormalities, including precocious puberty.
44X-linked conditionsX-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
45Focal dermal hypoplasia (Goltz syndrome X-linked dominant disorder affecting both mesodermal and ectodermal structures, including the skin, eyes, teeth, and digitsatrophic, hypopigmented, linear streaks with telangiectasia and punctuate cribiform scarring, as well as subcutaneous fat herniations into the dermis along the lines of Blaschko.
46Focal dermal hypoplasia (Goltz syndrome) Raspberry-like papillomas frequently appear in the perioral and anogenital regions.
47Focal 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.
48Conradi-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
49Conradi-Hunermann-Happle syndrome (X-linked chondrodysplasia punctata) Scarring alopecia on the scalp along Blaschko’s lines is also common.Cataracts may develop
50Conradi-Hunermann-Happle syndrome (X-linked chondrodysplasia punctata) The extracutaneous features include limb reduction, distinctive facial features with asymmetry, frontal bossing, and saddle nose.
51Incontinentia 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.
52Incontinentia 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)
54Incontinentia pigmenti The cutaneous lesions of IP evolve through four distinct phases:First: vesiculobullous phaseSecond : verrucous lesionsThird: hyperpigmented streaks and whorls along the lines of BlaschkoFourth: subtle hypopigmented atrophic streaks with absent eccrine glands and hair follicles
55Incontinentia pigmenti The teeth: conical and peg-shapednail dystrophy.The characteristic eye findings :retinal vascular anomalies and optic atrophy.neurologic : developmental delay and seizures.
56Ectodermal 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.
57Ectodermal 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.
58X-linked recessive hypohidrotic ectodermal dysplasia Occurs in hemizygous males by mutations in the ectodysplasin A geneFeatures: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.
60X-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
61Chromosomal 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.
62Chromosomal 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).
64Proteus syndromeis 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
66Proteus 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.
67Proteus syndromeSurgical intervention is not recommended unless ‘‘absolutely necessary,’’ because the complication rate is high . 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
68Segmental 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.
69Segmental 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.
70Segmental 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