Linear cutaneous lupus erythematosus in children-report of two cases and review of the literature: A case report.

Linear cutaneous lupus erythematosus is an unusual presentation of cutaneous lupus following Blaschko's lines. It is described mostly in children and young adults and is usually not associated with systemic involvement. We report two cases of linear cutaneous lupus erythematosus in children who significantly improved after treatment with hydroxychloroquine in combination with topical corticosteroids and tacrolimus. These rare cases underline the importance of including linear cutaneous lupus erythematosus in the differential diagnosis of blaschkoid inflammatory lesions.

An Early Description of a "Human Mosaic" Involving the Skin: A Story from 1945.

In 1945, the Journal of Heredity published an impressive article entitled "A human mosaic: bilaterally asymmetrical noevus pigmentosus pilosus et mollusciformis unilateralis." The author was M. Zlotnikoff, a Russian physician working in Ivanovo, a city located approximately 250 km northeast of Moscow. Zlotnikoff described a 24-year-old woman with a congenital linear epidermal naevus in a systematized and strictly unilateral arrangement. For the first time, the author explained this disorder as a mosaic resulting from a somatic mutation that occurred at an early stage of embryonic development. However, because this article was published immediately after the war, it fell into oblivion, despite the fact that it was of utmost importance in clinical dermatology. Zlotnikoff's work is all the more remarkable as the author had never heard of the lines of Blaschko.

Progressive Cribriform and Zosteriform Hyperpigmentation: A Case Series and Review of the Literature / 대한피부과학회지

Progressive cribriform and zosteriform hyperpigmentation (PCZH) is a distinctive pigmentary disorder observed along the lines of Blaschko. Clinically, the lesions appear as uniformly tan, cribriform macular hyperpigmentation with a zosteriform distribution, without a history of rash, injury, inflammation, or other associated cutaneous or internal abnormalities. Histopathological specimens show increased melanin pigmentation in the basal cell layer with a complete absence of nevus cells. We report 8 cases of PCZH and review the literature on this peculiar disorder.

Mosaicism in Cutaneous Disorders.

Genetic mosaicism arises when a zygote harbors two or more distinct genotypes, typically due to de novo, somatic mutation during embryogenesis. The clinical manifestations largely depend on the differentiation status of the mutated cell; earlier mutations target pluripotent cells and generate more widespread disease affecting multiple organ systems. If gonadal tissue is spared-as in somatic genomic mosaicism-the mutation and its effects are limited to the proband, whereas mosaicism also affecting the gametes, such as germline or gonosomal mosaicism, is transmissible. Mosaicism is easily appreciated in cutaneous disorders, as phenotypically distinct mutant cells often give rise to lesions in patterns determined by the affected cell type. Genetic investigation of cutaneous mosaic disorders has identified pathways central to disease pathogenesis, revealing novel therapeutic targets. In this review, we discuss examples of cutaneous mosaicism, approaches to gene discovery in these disorders, and insights into molecular pathobiology that have potential for clinical translation.

A Large Deletion in the NSDHL Gene in Labrador Retrievers with a Congenital Cornification Disorder.

In heterozygous females affected by an X-linked skin disorder, lesions often appear in a characteristic pattern, the so-called Blaschko's lines. We investigated a female Labrador Retriever and her crossbred daughter, which both showed similar clinical lesions that followed Blaschko's lines. The two male littermates of the affected daughter had died at birth, suggesting a monogenic X-chromosomal semidominant mode of inheritance. Whole genome sequencing of the affected daughter, and subsequent automated variant filtering with respect to 188 nonaffected control dogs of different breeds, revealed 332 hetero-zygous variants on the X-chromosome private to the affected dog. None of these variants was protein-changing. By visual inspection of candidate genes located on the X-chromosome, we identified a large deletion in the NSDHL gene, encoding NAD(P) dependent steroid dehydrogenase-like, a 3ß-hydroxysteroid dehydrogenase involved in cholesterol biosynthesis. The deletion spanned >14 kb, and included the last three exons of the NSDHL gene. By PCR and fragment length analysis, we confirmed the presence of the variant in both affected dogs, and its absence in 50 control Labrador Retrievers. Variants in the NSDHL gene cause CHILD syndrome in humans, and the bare patches (Bpa) and striated (Str) phenotypes in mice. Taken together, our genetic data and the known role of NSDHL in X-linked skin disorders strongly suggest that the identified structural variant in the NSDHL gene is causative for the phenotype in the two affected dogs.

Unilateral Blaschkoian Lichen Planus: A Series of Cases with Review of literature.

A number of congenital and acquired dermatological diseases are known to follow lines of Blaschko. Lichen Planus (LP), commonly acquired inflammatory dermatosis, presents with various morphological forms but Blaschkoian variant is very less published in literature. We herein report a case series of six patients of various age groups with Blaschkoian LP, without any underlying predisposing factors. All these cases presented with asymptomatic to mildly pruritic, violaceous to hyperpigmented papules and plaques following the Blaschko lines. In all the patients, lesions responded well to topical steroids and oral antihistamines, leading to gradual resolution of lesions with post-inflammatory hyperpigmentation. Blaschkoian LP is not a rare condition and may remain under reported because of its insignificant clinical features especially the absence of pruritus. Thus, the physician should always keep this entity in mind while considering the lesions following lines of blaschko.

Pulmonary hypertension and vasculopathy in incontinentia pigmenti: a case report.

Incontinentia pigmenti (IP; Bloch-Sulzberger syndrome) is a rare, genetic syndrome inherited as an X-linked dominant trait. It primarily affects female infants and is lethal in the majority of males during fetal life. The clinical findings include skin lesions, developmental defects, and defects of the eyes, teeth, skeletal system, and central nervous system. Cardiovascular complications of this disease in general, and pulmonary hypertension in particular, are extremely rare. This report describes the case of a 3-year-old girl with IP complicated by pulmonary arterial hypertension. Extensive cardiology workup done to the patient indicates underlying vasculopathy. This report sheds light on the relationship between IP and pulmonary hypertension, reviews the previously reported cases, and compares them with the reported case.

Two females with mutations in USP9X highlight the variable expressivity of the intellectual disability syndrome.

The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5'UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated.

Segmental Vitiligo.

Segmental vitiligo is characterized by its early onset, rapid stabilization, and unilateral distribution. Recent evidence suggests that segmental and nonsegmental vitiligo could represent variants of the same disease spectrum. Observational studies with respect to its distribution pattern point to a possible role of cutaneous mosaicism, whereas the original stated dermatomal distribution seems to be a misnomer. Although the exact pathogenic mechanism behind the melanocyte destruction is still unknown, increasing evidence has been published on the autoimmune/inflammatory theory of segmental vitiligo.

An Intronic MBTPS2 Variant Results in a Splicing Defect in Horses with Brindle Coat Texture.

We investigated a family of horses exhibiting irregular vertical stripes in their hair coat texture along the neck, back, hindquarters, and upper legs. This phenotype is termed "brindle" by horse breeders. We propose the term "brindle 1 (BR1)" for this specific form of brindle. In some BR1 horses, the stripes were also differentially pigmented. Pedigree analyses were suggestive of a monogenic X-chromosomal semidominant mode of inheritance. Haplotype analyses identified a 5 Mb candidate region on chromosome X. Whole genome sequencing of four BR1 and 60 nonbrindle horses identified 61 private variants in the critical interval, none of them located in an exon of an annotated gene. However, one of the private variants was close to an exon/intron boundary in intron 10 of the MBTPS2 gene encoding the membrane bound transcription factor peptidase, site 2 (c.1437+4T>C). Different coding variants in this gene lead to three related genodermatoses in human patients. We therefore analyzed MBTPS2 transcripts in skin, and identified an aberrant transcript in a BR1 horse, which lacked the entire exon 10 and parts of exon 11. The MBTPS2:c1437+4T>C variant showed perfect cosegregation with the brindle phenotype in the investigated family, and was absent from 457 control horses of diverse breeds. Altogether, our genetic data, and previous knowledge on MBTPS2 function in the skin, suggest that the identified MBTPS2 intronic variant leads to partial exon skipping, and causes the BR1 phenotype in horses.

Hypomelanosis of Ito.

Hypomelanosis of Ito, initially referred to as incontinentia pigmenti achromians, is a rare neurocutaneous disorder. Hypopigmented lesions following the lines of Blaschko are usually the presenting feature. Multiple organ systems can be involved including brain, musculoskeletal, cardiovascular, eyes, kidneys, and teeth. The neurologic complications can include seizures, hemimegalencephaly, developmental delay and abnormalities in tone. Genetic mosaicism is the most likely explanation for its inheritance. It must be distinguished from incontinentia pigmenti because at early stages, skin lesions can appear similar between the two conditions. Consensus recommendations for screening of associated extracutaneous conditions do not exist and management is symptomatic, but regular evaluation of somatic growth, neurodevelopment, endocrine status, eyes, and teeth should occur. Initial screening of renal function has also been recommended. Awareness of this disorder will allow for diagnosis, genetic counseling and appropriate screening.

Extragenital lichen sclerosus et atrophicus along the lines of Blaschko.

Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory dermatosis of unknown etiology. Extragenital involvement is uncommon and commonly affects the neck, shoulders, and upper portion of the trunk. It is predominant in women with a male-to-female ratio of 1:6 and occurs at any age. Linear pattern along the lines of Blaschko are seen. There is no cure for LSA. Topical corticosteroids and calcineurin inhibitors, such as tacrolimus, pimecrolimus, PUVA antimalarial agents, and topical retinoids have been tried with varying results. A case of a 33-year-old man with LSA over right lower limb along the lines of Blasckho is reported here.

Acquired, Idiopathic, Patterned Facial Pigmentation (AIPFP) Including Periorbital Pigmentation and Pigmentary Demarcation Lines on Face Follows the Lines of Blaschko on Face.

BACKGROUND: Acquired, non-nevoid, apparently idiopathic facial pigmentation are distributed over some specific locations like periorbital area, zygomatic area, malar area, root of nose, perioral and mandibular area. Periorbital pigmentation is the most well known entity in this group. These are bilaterally distributed homogenously diffuse gray to dark gray or slate-gray colored patches showing progressive intensification of pigmentation. These are often considered as physiologic or constitutional pigmentation. Some portions of the margins of these patches were described previously as pigmentary demarcation line (PDL- F, G, H). AIM: To analyze the distributional patterns of acquired, apparently idiopathic facial pigmentations and to evaluate the etiologic aspects of these conditions. MATERIALS AND METHODS: Spatial patterns, distribution, and orientation were analyzed among 187 individuals with idiopathic non-nevoid, facial pigmentation. Observed patterns were compared with various pigmentary nevi and Blaschko's lines on face. RESULTS: It was found that most of the idiopathic facial pigmentary alterations including periorbital pigmentation and PDL on face had specific patterned distribution that had high similarity to that of the pigmentary nevi and Blaschko's lines on face. CONCLUSION: It is hypothesized here that phenotypic expression of acquired patterned pigmentation (AIFPFP) is due to genetically determined increased pigmentary functional activity to various known and unknown yet natural factors like UV rays and aging. Mosaicism was a definite possibility. We also consider that the patterns actually reflected the normal patterns of embryological human pigmentation on face.

Co-existence of Lichen Sclerosus et Atrophicus and Morphoea Along Lines of Blaschko.

Lichen sclerosus (LS) is an inflammatory dermatitis of unknown etiology that mostly affects the genital region in both the sexes. In active cases the histopathologic changes differentiate between LS and morphoea though in chronic cases it is very difficult to diagnose with certainty. Coexistence of both the conditions in a single patient indicates that these lesions represent a spectrum of similar pathologic process. Coexistence of both the conditions along Blaschko's lines is so far not described in literature. We report an Indian patient with both LS and morphoea occurring along Blaschko's lines.