Postzygotic Mutation Research Articles

Subcortical heterotopic gray matter brain malformations: Classification study of 107 individuals.

ObjectiveTo better evaluate the imaging spectrum of subcortical heterotopic gray matter brain malformations (subcortical heterotopia [SUBH]), we systematically reviewed neuroimaging and clinical data of 107 affected individuals.MethodsSUBH is defined as heterotopic gray matter, located within the white matter between the cortex and lateral ventricles. Four large brain malformation databases were searched for individuals with these malformations; data on imaging, clinical outcomes, and results of molecular testing were systematically reviewed and integrated with all previously published subtypes to create a single classification system.ResultsReview of the databases revealed 107 patients with SUBH, the large majority scanned during childhood (84%), including more than half before 4 years (59%). Although most individuals had cognitive or motor disability, 19% had normal development. Epilepsy was documented in 69%. Additional brain malformations were common and included abnormalities of the corpus callosum (65/102 [64%]), and, often, brainstem or cerebellum (47/106 [44%]). Extent of the heterotopic gray matter brain malformations (unilateral or bilateral) did not influence the presence or age at onset of seizures. Although genetic testing was not systematically performed in this group, the sporadic occurrence and frequent asymmetry suggests either postzygotic mutations or prenatal disruptive events. Several rare, bilateral forms are caused by mutations in genes associated with cell proliferation and polarity (EML1, TUBB, KATNB1, CENPJ, GPSM2).ConclusionThis study reveals a broad clinical and imaging spectrum of heterotopic malformations and provides a framework for their classification.

Gene Mosaicism Screening Using Single-Molecule Molecular Inversion Probes in Routine Diagnostics for Systemic Autoinflammatory Diseases

Diagnosis of systemic autoinflammatory diseases (SAIDs) is often difficult to achieve and can delay the start of proper treatments and result in irreversible organ damage. In several patients with dominantly inherited SAID, postzygotic mutations have been detected as the disease-causing gene defects. Mutations with allele frequencies <5% have been detected, even in patients with severe phenotypes. Next-generation sequencing techniques are currently used to detect mutations in SAID-associated genes. However, even if the genomic region is highly covered, this approach is usually not able to distinguish low-grade postzygotic variants from background noise. We, therefore, developed a sensitive deep sequencing assay for mosaicism detection in SAID-associated genes using single-molecule molecular inversion probes. Our results show the accurate detection of postzygotic variants with allele frequencies as low as 1%. The probability of calling mutations with allele frequencies ≥3% exceeds 99.9%. To date, we have detected three patients with mosaicism, two carrying likely pathogenic NLRP3 variants and one carrying a likely pathogenic TNFRSF1A variant with an allele frequency of 1.3%, confirming the relevance of the technology. The assay shown herein is a flexible, robust, fast, cost-effective, and highly reliable method for mosaicism detection; therefore, it is well suited for routine diagnostics.

Genetic Causes of Rare Pediatric Ovarian Tumors.

Ovarian tumors in childhood and adolescence are distinguished from those that arise in adulthood by their histological subtype. These tumors may arise as the first manifestation of a cancer predisposition syndrome. Correct diagnosis of the syndrome may offer the possibility of surveillance for other members of the patients family. To summarize current knowledge about paediatric ovarian tumors that may be associated with genetically defined cancer syndromes. Juvenile granulosa cell tumors occur in those with Ollier disease and Maffucci syndrome; they are caused by postzygotic IDH1 and IDH2 gene mutations. Sertoli-Leydig cell tumors usually arise in association with DICER1 syndrome, which is caused by germline DICER1 gene mutations. Sex cord tumors with annular tubules and Sertoli cell tumors may arise in patients with Peutz-Jeghers syndrome; this syndrome is caused by germline STK11 gene mutations. The majority of germ cell tumors develop in the context of gonadal dysgenesis. In XY gonadal dysgenesis, the presence of a Y chromosome material renders the patient at increased risk for developing gonadal malignancy. Characteristically, these patients develop gonadoblastoma, which has the potential to evolve into dysgerminoma and exhibit malignant behavior. Sex-chromosome aneuploidy syndromes or mutations in genes involved in gonadal development and differentiation may cause gonadal dysgenesis. Small cell carcinoma of the ovary of a hypercalcaemic type is usually caused by loss-of-function mutations in the SMARCA4 gene. Ovarian tumors are uncommon during childhood and adolescence. It is always necessary to consider gonadal dysgenesis or any of the inherited cancer syndromes. These patients require interdisciplinary care, careful noting of personal and family history, precise clinical examination, laboratory testing, and differential diagnosis by a clinician with a good knowledge of genetic syndromes. Expert pathological review may be required for correct diagnoses. This is necessary for appropriate management and to establish an association with hereditary cancer syndromes. The work was supported by the Ministry of Health of the Czech Republic - Conceptual Development of Research Organization, Faculty Hospital of Ostrava /2015. We thank to Lenka Foretová, M.D., Ph.D., (MMCI, Brno) and Radoslava Tomanová, M.D., (Institute of Pathology, University Hospital Ostrava) for rewarding advice, Mrs. Jana N&#283;mcová (Department of Medical Genetics, University Hospital Ostrava), Bc. Ludmila Stuchlá and Mrs. Lenka Ziv&#269;áková (Medical Library, University Hospital Ostrava) for help during manuscript preparation. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 10. 3. 2019 Accepted: 16. 4. 2019.

Verrucous Epidermal Nevus: Dermoscopy, Reflectance Confocal Microscopy, and Histopathological Correlation.

Citation: VerzAE, Lacarrubba F, Quattrocchi E, Micali G. Verrucous epidermal nevus: dermoscopy, reflectance confocal microscopy, and histopathological correlation. Dermatol Pract Concept.2019;9(3):230-231. DOI: https://doi.org/10.5826/dpc.0903a16

A comparison of neuropsychological function between monozygotic twins with neurofibromatosis, type 1: A case report

Objective: Neurofibromatosis type 1 (NF-1) is an autosomal dominant genetic disorder that commonly presents with cognitive impairment and greater rates of learning disorders and academic difficulty compared to the general population. Investigations of neurological and physiological expression of NF-1 in monozygotic twins identified intrapair similarities and differences. Monozygotic twins with NF-1 have been found to have similar IQ scores as well as concordant diagnoses of attention-deficit/hyperactivity disorder and learning disabilities. There have been no previous reports on similarities and differences in neuropsychological profiles between monozygotic twins with NF-1. The purpose of this article is to examine the results of comprehensive neuropsychological evaluations for a pair of monozygotic twins with NF-1.Method: A pair of 19-year-old female, African-American monozygotic twins with NF-1 underwent neuropsychological evaluations in an outpatient clinic. Findings are reported following the CAse REport (CARE) guidelines.Results: The twins demonstrated similar impairment in processing speed, working memory, and attention span; however, differences also were found.Conclusions: Intrapair similarities and differences on neuropsychological assessment were found between monozygotic twins with NF-1. Primary deficits were suggestive of a frontal-subcortical pattern and could be consistent with remote neuroimaging. When differences did occur, performance was typically better for Twin A, who had also showed greater improvement on neuroimaging. Implications and directions for future research are discussed. Specifically, this case demonstrates the need for inclusion of neuropsychological assessment in studies of larger cohorts of monozygotic twins with NF-1 and correlation of neuropsychological findings with neuroimaging and postzygotic mutations.

Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review.

Fibrous dysplasia is an uncommon mosaic disorder in which bone is replaced by structurally unsound fibro-osseous tissue. It is caused by the sporadic post-zygotic activating mutations in GNAS, resulting in dysregulated GαS-protein signaling in affected tissues. This manifests on a broad clinical spectrum ranging from insignificant solitary lesions to severe disease with deformities, fractures, functional impairment, and pain. Fibrous dysplasia may present in isolation or in association with hyperfunctioning endocrinopathies and café-au-lait macules, known as McCune-Albright Syndrome. This review summarizes thecurrent understanding of pathophysiology in fibrous dysplasia, describes key pre-clinical and clinical investigations, and details the current approach to diagnosis and management.

Overlooked roles of DNA damage and maternal age in generating human germline mutations

The textbook view that most germline mutations in mammals arise from replication errors is indirectly supported by the fact that there are both more mutations and more cell divisions in the male than in the female germline. When analyzing large de novo mutation datasets in humans, we find multiple lines of evidence that call that view into question. Notably, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, even young fathers contribute three times more mutations than young mothers, and this ratio barely increases with parental age. This surprising finding points to a substantial contribution of damage-induced mutations. Indeed, C-to-G transversions and CpG transitions, which together constitute over one-fourth of all base substitution mutations, show genomic distributions and sex-specific age dependencies indicative of double-strand break repair and methylation-associated damage, respectively. Moreover, we find evidence that maternal age at conception influences the mutation rate both because of the accumulation of damage in oocytes and potentially through an influence on the number of postzygotic mutations in the embryo. These findings reveal underappreciated roles of DNA damage and maternal age in the genesis of human germline mutations.

390 Second-hit, post-zygotic PMVKand MVD mutations cause linear porokeratosis

390 Second-hit, post-zygotic PMVKand MVD mutations cause linear porokeratosis

MON-247 Clinical Characterization of Female Peripheral Precocious Puberty Due to McCune-Albright Syndrome

Background: McCune-Albright syndrome (MAS) is a rare and sporadic disease caused by a post-zygotic mutation in GNAS1 gene. It is characterized by the classical triad of polyostotic fibrous dysplasia, café-au-lait skin spots and peripheral precocious puberty (PPP). However, clinical presentation of MAS is highly variable depending on mosaic tissue distribution of mutant-bearing cells. Due to the low prevalence of MAS, detailed data of clinical and laboratory presentation are scarce. Aim: To describe the clinical and hormonal features of PPP due to MAS from a single tertiary center. Patients and Methods: The medical records of girls with PPP due to MAS diagnosed and treated from 1990 and 2018 were systematically revised. We analyzed initial clinical presentation, Tanner stage, gonadotropins and estradiol levels, and pelvic ultrasound findings of a MAS cohort. Results: From a total of 37 patients (35 girls and 2 boys) with clinical diagnosis of MAS, 14 (37.8%) female patients presented PPP. The first clinical manifestation was thelarche in 12/14 (85.7%), followed by vaginal bleeding in 7/14 (50%), and pubarche in 5/14 (35.7%). The mean height (SDS) was 109 ± 35 cm (SDS: 1.3 ± 1.6). All girls had Tanner-staging ≥ B2 (ranging from B2-B4) and 8/14 (57.1%) had pubarche. Fibrous bone dysplasia was detected in 9/14 (64.2%) by bone scintigraphy and café-au-lait skin spots were found in 10/14 (71.4%) of these girls. Menarche occurred at mean age of 3.75 ± 2 yr (2 - 7.2 yr). Mean basal LH and FSH were 0.36 ± 0.24 IU/L and 1.27± 1.0 IU/L, respectively. Estradiol levels ranged from < 13 to 783 pg/mL (mean 96.8 pg/mL). Basal estradiol levels were at prepubertal range in 8/14 (57%) on several occasions. All girls underwent a GnRH-analogue stimulated test showing a prepubertal LH response (2.9 ± 2.1 IU/L); 2 patients showed completely suppressed basal and stimulated gonadotropin levels. Uni- or bilateral ovarian cysts were identified in 9/14 patients (64.2%) being bilateral in 50% of them. Mean ovarian volumes were 2.63 ± 1.4 cm³ for right and 2.05 ± 1.9 cm³ for left ovarian, with mean cyst volumes ranging from 2.7 to 45 cm3. Other endocrine hyperfunctions were not identified in this MAS cohort. Conclusion: PPP in girls with MAS has a heterogeneous clinical presentation. It was characterized by menarche at very early age as a first sign associated with variable values of estradiol levels (pre- and pubertal) and ovarian sizes. Pediatric endocrinologists must be aware of atypical clinical and laboratory presentation of PPP due to MAS.

Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis

Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date. To identify genetic mutations associated with linear porokeratosis. Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis. Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions. Germline and somatic genomic characteristics of participants with linear porokeratosis. Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift). Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.

Neonatal McCune-Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome.

ABSTRACTSomatic gain‐of‐function mutations of GNAS cause a spectrum of clinical phenotypes, ranging from McCune‐Albright syndrome (MAS) to isolated disease of bone, endocrine glands, and more rarely, other organs. In MAS, a syndrome classically characterized by polyostotic fibrous dysplasia (FD), café‐au‐lait (CAL) skin spots, and precocious puberty, the heterogenity of organ involvement, age of onset, and clinical severity of the disease are thought to reflect the variable size and the random distribution of the mutated cell clone arising from the postzygotic mutation. We report a case of neonatal MAS with hypercortisolism and cholestatic hepatobiliary dysfunction in which bone changes indirectly emanating from the disease genotype, and distinct from FD, led to a fatal outcome. Pulmonary embolism of marrow and bone fragments secondary to rib fractures was the immediate cause of death. Ribs, and all other skeletal segments, were free of changes of typical FD and fractures appeared to be the result of a mild‐to‐moderate degree of osteopenia. The mutated allele was abundant in the adrenal glands and liver, but not in skin, muscle, and fractured ribs, where it could only be demonstrated using a much more sensitive PNA hybridization probe‐based FRET (Förster resonance energy transfer) technique. Histologically, bilateral adrenal hyperplasia and cholestatic disease matched the abundant disease genotype in the adrenals and liver. Based on this case and other sporadic reports, it appears that gain‐of‐function mutations of GNAS underlie a unique syndromic profile in neonates characterized by CAL skin spots, hypercortisolism, hyperthyroidism, hepatic and cardiac dysfunction, and an absence (or latency) of FD, often with a lethal outcome. Taken together, our and previous cases highlight the phenotypic severity and the diagnostic and therapeutic challenges of MAS in neonates. Furthermore, our case specifically points out how secondary bone changes, unrelated to the direct impact of the mutation, may contribute to the unfavorable outcome of very early‐onset MAS. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Cloves syndrome: A rare disorder of overgrowth with unusual features – An uncommon phenotype?

CLOVES syndrome characterized by Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Skeletal anomalies is a recently described sporadic syndrome from postzygotic activating mutations in PIK3CA. This 3-year-old boy, born to nonconsanguineous and healthy parents, had epidermal verrucous nevus, lower limb length discrepancy and bilateral genuvalgum, anterior abdominal wall lipomatous mass, central beaking of L2 and L3, and fibrous dysplasia of the left frontal bone. Ocular and dental abnormalities (ptosis, esotropia, delayed canine eruption, dental hypoplasia), ipsilateral asymmetrical deformity of skull, and large left cerebral hemisphere with mild ipsilateral ventriculomegaly were peculiar to him denoting an uncommon phenotype. The parents did not consent for magnetic resonance imaging and genetic studies because of financial constraints. The CLOVES syndrome has emerged as an uncommon yet distinct clinical entity with some phenotypic variations. Its diagnosis is usually from cutaneous, truncal, spinal, and foot anomalies in clinical and radioimaging studies. Proteus syndrome remains the major differential.

Fibrous dysplasia of the jaws: Integrating molecular pathogenesis with clinical, radiological, and histopathological features.

Fibrous dysplasia is a non-neoplastic developmental process that affects the craniofacial bones, characterized by painless enlargement as a result of bone substitution by abnormal fibrous tissue. Postzygotic somatic activating mutations in the GNAS1 gene cause fibrous dysplasia and have been extensively investigated, as well as being helpful in the differential diagnosis of the disease. Fibrous dysplasia may involve one (monostotic) or multiple bones (polyostotic), sporadically or in association with McCune-Albright syndrome, Jeffe-Lichenstein syndrome, or Mazabreud syndrome. This review summarizes the current knowledge on fibrous dysplasia, emphasizing the value of integrating the understanding of its molecular pathogenesis with the clinical, radiological, and histopathological features. In addition, we address important aspects related to the differential diagnosis and patient management.

Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases

Postzygotic de novo mutations lead to the phenomenon of gene mosaicism. The 3 main types are called somatic, gonadal, and gonosomal mosaicism, which differ in terms of the body distribution of postzygotic mutations. Mosaicism has been reported occasionally in patients with primary immunodeficiency diseases (PIDs) since the early 1990s, but its real involvement has not been systematically addressed. We sought to investigate the incidence of gene mosaicism in patients with PIDs. The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n=100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n=92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n=36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics. The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time. This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs.

Successful Use of Denosumab to Manage Pain and Prevent Postoperative Regrowth of Craniofacial Fibrous Dysplasia

Fibrous Dysplasia (FD) is a rare fibro-osseous disease with a predilection for the craniofacial skeleton, caused by post-zygotic activating mutations in the GNAS gene and presenting with a variable phenotype: single bone (monostotic), multiple (polyostotic), or with extraskeletal manifestations (McCune Albright Syndrome). Clinical behavior and progression of disease are difficult to predict. Typical treatment includes surgical contouring/resection; post-operative recurrence and regrowth are common and difficult to manage. The effects of bisphosphonates and other anti-resorptive medications, such as the RANK-L inhibitor denosumab, have been well-documented in diseases such as osteoporosis, skeletal-related events from bone metastases, and giant cell tumors. Bisphosphonates have been used to treat FD-associated bone pain but have not been shown to have an effect on growth of FD lesions. Currently, there are no reliable pharmacologic therapies to treat fibrous dysplasia of bone. Denosumab has been shown to have an effect on FD-related bone pain and tumor growth in the extremities.

De novo Mutations (DNMs) in Autism Spectrum Disorder (ASD): Pathway and Network Analysis

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder (NDD) defined by impairments in social communication and social interactions, accompanied by repetitive behavior and restricted interests. ASD is characterized by its clinical and etiological heterogeneity, which makes it difficult to elucidate the neurobiological mechanisms underlying its pathogenesis. Recently, de novo mutations (DNMs) have been recognized as strong source of genetic causality. Here, we review different aspects of the DNMs associated with ASD, including their functional annotation and classification. In addition, we also focus on the most recent advances in this area, such as the detection of PZMs (post-zygotic mutations), and we outline the main bioinformatics tools commonly employed to study these. Some of these approaches available allow DNMs to be analyzed in the context of gene networks and pathways, helping to shed light on the biological processes underlying ASD. To end this review, a brief insight into the future perspectives for genetic studies into ASD will be provided.

LB1539 Genotype-first phenotyping of 32 patients with post-zygotic GNAQ or GNA11 mutations

LB1539 Genotype-first phenotyping of 32 patients with post-zygotic GNAQ or GNA11 mutations

Minimal mosaicism, maximal phenotype: Discordance between clinical and molecular findings in two patients with tuberous sclerosis

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by hamartomatous growths in the brain, kidneys, lungs, skin, heart, and retina. TSC is caused by loss of function mutations in one of two tumor suppressor genes, TSC1 or TSC2. Two-thirds of individuals with TSC have de novo mutations, and individuals with postzygotic pathogenic variants in both TSC1 and TSC2 have been reported. The development of sensitive molecular methods, such as next generation sequencing, has led to an increased ability to detect low-level mosaic variants, which are typically thought to have milder phenotypes because a smaller fraction of cells in the body harbor the mutation. Here, we describe two patients with TSC who had severe phenotypic involvement, but only low-level mosaicism in TSC2. Given this apparent discrepancy and concern about a missed constitutional variant, we sampled multiple tissues in both cases to confirm these mosaic mutations. Sampling of multiple tissues can be crucial in molecular diagnosis of mosaic TSC. These cases highlight, in general, challenges in molecular diagnosis of genetic conditions due to postzygotic mutations.

Cutis Tricolor

AbstractCutis tricolor is a skin abnormality consisting in a combination of congenital hyper- and hypopigmented skin lesions (in the form of paired macules, patches, or streaks) in close proximity to each other in a background of normal skin. It is currently regarded as a twin-spotting (mosaic) phenomenon. This phenomenon has been reported so far as a purely cutaneous trait, as a part of a complex malformation phenotype (Ruggieri–Happle syndrome), which includes distinct facial features, cataract, skull and vertebral defects, long bones dysplasia, corpus callosum, cerebellar and white matter anomalies, cavum vergae and holoprosencephaly, and other systemic abnormalities. Cutis tricolor has been also reported as a distinct type with multiple, disseminated smaller skin macules (cutis tricolor parvimaculata) or in association with other skin disturbances (e.g., phacomatosis achromico-melano-marmorata) or in the context of other neurocutaneous phenotypes (e.g., ataxia-telangiectasia and phacomatosis pigmentovascularis) or as a sign of complex malformation phenotypes (e.g., microcephaly and dwarfism). More than 20 studies reporting 40 cases are present in the literature with pure cutaneous or syndromic cutis tricolor phenomena and are analyzed in the present study, confirming and expanding the overall phenotype of cutis tricolor. In particular, (1) the skin abnormalities of the cutis tricolor do not evolve over time; (2) there is a typical facial phenotype with long, elongated face, thick and brushy eyebrows, hypertelorism, deep nasal bridge with large bulbous nose, and anteverted nostrils; (3) the skeletal defects are mild-to-moderate and do not progress or cause relevant orthopedic complications; (4) the neurological/behavioral phenotype does not progress and the paroxysmal events (if present) tend to decrease over time; (5) only three patients developed early onset (treatable) cataracts. Different pathologic hypotheses have been postulated, including, early or late postzygotic mutations involving the same gene loci (in the context of the so-called dydymotic theory): such mechanisms can explain the overall skin, bone, lens, and nervous system phenomena of migration of different streaks of clones in the different tissues.

Becker's Nevus Syndrome

The simultaneous occurrence of a patch of light or dark brown hyperpigmentation with hypertrichosis (Becker's nevus) together with (usually ipsilateral) soft tissues hypoplasia (especially breast, in women) and underlying skeletal anomalies (i.e., vertebral hypoplasia, scoliosis, pectus carinatum or excavatum) represents the Becker's nevus syndrome (BNS) phenotype. It was first described (as a single cutaneous lesion) by Becker in 1949 and then associated with the surrounding musculoskeletal disorders. The syndrome has also been reported as pigmentary hairy epidermal nevus syndrome. Less than 100 cases have been reported in the literature, with a slightly higher incidence in females and only few familiar cases: paradominant postzygotic mutations and/or an androgen-dependent hyperactivation have been reported as the causes of the diseases.The extracutaneous lesions are congenital and nonprogressive, and the natural history of the Becker's nevus is the same as that of isolated nevi: in prepubertal boys, the pigmentation may be less intense and the hairiness may be absent or mild, as occurs in women, whereas in men, there is an increase of hairiness after puberty. The treatment is essentially cosmetic, and potential therapeutic options include electrolysis, waxing, makeup, or laser.