Transmission electron microscopy of pili annulati.

BACKGROUND: Little is known about the ultrastructure of pili annulati. OBJECTIVES: To examine with transmission electron microscopy affected hairs of a family, whose diagnosis had been confirmed in five individuals with scanning electron microscopy, which showed surface undulations with "curtain-like" folding of the hair cuticula and to compare the findings with normal control. METHODS: Hairs of two affected patients and one control were embedded in resin and cut lengthwise to produce ultra-thin sections. RESULTS: The normal hair showed a parallel arrangement of dark lines associated with less electron-dense wide bands. Small cavities could be observed, mostly in the dark lines, affected hairs had a large number of cavities, associated or not with the insertion of melanosomes and loss of parallelism of the dark lines. Higher magnification showed a significant loss of this parallelism, resembling "wood grooves". Widened dark lines were observed in some areas. STUDY LIMITATIONS: Only a few hairs were examined. CONCLUSIONS: The present results suggest that the microcanaliculi of the hair surface, easily found with scanning electron microscopy, may be secondary not only to the cavities seen in the sections but also to the disorder of proteins that form this region, demonstrated by the changes of the cortex dark lines.

Segmental basaloid follicular hamartomas derive from a post-zygotic SMO p.L412F pathogenic variant and express hair follicle development-related proteins in a pattern that distinguish them from basal cell carcinomas.

Basaloid follicular hamartomas (BFH) are benign small basaloid skin tumors that can present as solitary or multiple lesions. Congenital BFH lesions arranged in a segmental distribution have been described, suggesting they derive from a somatic post-zygotic mutational event. Previously, BFH were described in Happle-Tinschert syndrome, which results from a post-zygotic SMO variant and is characterized by segmental BFH with variable involvement of the teeth, skeleton, and central nervous system. Here, we describe two patients with isolated segmental BFH and no systemic involvement. Paired whole exome sequencing of BFH and normal tissue revealed a pathogenic SMO c.1234 C>T, p.L412F variant restricted to BFH tissue. We characterized the proliferation index and expression of Hedgehog and Wnt/beta-catenin pathway related proteins in segmental BFH compared to sporadic basal cell carcinomas (BCCs) and found that segmental BFH had a lower proliferation index. Although segmental BFH expressed a similar level of Gli-1 compared to BCCs, levels of LEF-1 and SOX-9 expression in BFH were weaker for both and patchier for LEF-1. Our results show that a somatic SMO activating variant causes segmental BFH. Since these patients are prone to developing BCCs, differences in SOX9, LEF1, and Ki-67 expression can help distinguish between these two basaloid lesions.

Congenital atrichia with papular lesions.

Congenital atrichia with papular lesions is a rare, autosomal recessive and irreversible form of total alopecia of the body hair characterized by hair loss soon after birth and the development of keratinfilled cysts or horny papules over extensive areas of the body. The condition is associated with a mutation of the human hairless gene on chromosome region 8p12. We report a 1-year-old boy presenting with the absence of scalp and body hair since birth. On examination, he had complete absence of hair on the scalp, eyebrows, and eyelashes. Multiple, discrete, pearly-to-skin-colored papules of 1-3mm in size were present over the scalp. The skin biopsy from a scalp papule revealed normal overlying epidermis with multiple keratin cysts and hypoplastic hair follicles in the upper dermis.

Apparent darkening of scalp hair related to pili multigemini Following dabrafenib and trametinib.

The combination of dabrafenib and trametinib is an important immunotherapy option for patients with BRAF V600 mutation-positive melanoma. This regimen has been reported to cause cutaneous eruptions. However, hair dysmorphology is not a reported side effect to these or any other medications to date. Herein, we highlight a case of pili multigemini formation in a patient with stage IV melanoma receiving treatment with dabrafenib and trametinib and the corresponding clinical findings.

Identification of a recurrent nonsense mutation in HR gene responsible for atrichia with papular lesions in two Kashmiri families.

BACKGROUND: Congenital atrichia (CA) is a rare form of irreversible alopecia with an autosomal recessive mode of inheritance. This form of hair loss is mainly associated with mutations in the human hairless (HR) gene located at chromosome 8p21.3. An additional unique feature atrichia with papular lesions (APL) comprises keratin-filled cysts known as papules. The present study aimed to uncover the underlying genetic causes of APL in two consanguineous Kashmiri families. METHODS: In the present study, two consanguineous families of Kashmiri origin with APL displaying an autosomal recessive mode of inheritance were investigated. Whole exome and Sanger sequencing followed by bioinformatic studies, variant prioritization, Sanger validation and segregation analysis was performed to find the mutation. RESULTS: A recurrent nonsense (NM_005144: c.2818C > T:p.Arg940*) mutation was detected in exon 13 of the human HR gene. CONCLUSIONS: Whole exome sequencing analysis has widely been used in the screening of single gene disorders mutations, both in research and diagnostic laboratories. Sanger sequencing alone for genes such as HR becomes expensive and time consuming. Instead, it is recommended that a patient is to screen by whole exome sequencing and then special attention first focuses on known genes of the APL phenotype. This is helpful for intime diagnosis, being more efficient and economic. The results obtained in the present study may contribute to prenatal diagnosis, carrier secreening and the genetic counseling of families with the APL phenotype in Kashmiri poplution.

The Wave complex controls epidermal morphogenesis and proliferation by suppressing Wnt-Sox9 signaling.

Development of the skin epidermis requires tight spatiotemporal control over the activity of several signaling pathways; however, the mechanisms that orchestrate these events remain poorly understood. Here, we identify a key role for the Wave complex proteins ABI1 and Wave2 in regulating signals that control epidermal shape and growth. In utero RNAi-mediated silencing of Abi1 or Wasf2 induced cellular hyperproliferation and defects in architecture of the interfollicular epidermis (IFE) and delayed hair follicle growth. Unexpectedly, SOX9, a hair follicle growth regulator, was aberrantly expressed throughout the IFE of the mutant embryos, and its forced overexpression mimicked the Wave complex loss-of-function phenotype. Moreover, Wnt signaling, which regulates SOX9+ cell specification, was up-regulated in Wave complex loss-of-function IFE. Importantly, we show that the Wave complex regulates filamentous actin content and that a decrease in actin levels is sufficient to elevate Wnt/ß-catenin signaling. Our results identify a novel role for Wave complex- and actin-regulated signaling via Wnt and SOX9 in skin development.

Cutaneous inflammation as a marker of malignant transformation in a patient with linear unilateral basaloid follicular hamartoma.

Basaloid follicular hamartoma is a rare, benign and superficial malformation of hair follicles, characterized histologically by epithelial proliferation of basaloid cells with radial disposition. It can be mistaken for basal cell carcinoma. Even though these hamartomas are considered benign lesions, malignant transformation has rarely been reported. We report the case of a 45-year-old healthy woman, with linear, unilateral basaloid follicular hamartoma which developed inflamed papules histologically suggestive of basal cell carcinoma. We believe that identification of local inflammation could be a clinical clue to guide us towards a malignant transformation of basaloid follicular hamartoma.

Localized unilateral basaloid follicular hamartoma along Blaschko's lines on face.

Basaloid follicular hamartoma (BFH) is a rare hamartoma of hair follicle. Clinical presentations may vary but are united by the same histopathological features in the form of folliculocentric basaloid or squamoid cell proliferation in the superficial dermis, which represents malformed and distorted hair follicles. It is important to recognize this entity as its simulant is basal cell carcinoma, a low-grade malignancy. Here, we report a case of localized unilateral BFH in a Blaschkoid distribution on the face of a 14-year-old female.

Trichoscopy in Hair Shaft Disorders.

Trichoscopy allows analyzing the structure and size of growing hair shafts in their natural environment in children and adults. The method replaces light microscopy, which requires pulling of multiple hairs for investigation. In monilethrix, trichoscopy shows uniform elliptical nodosities with intermittent constrictions. In trichorrhexis nodosa nodular thickenings along hairs shafts are visible (low magnification) or splitting into numerous small fibers along the hair shaft may be observed (high magnification). In trichorrhexis invaginata (bamboo hair) the hair shaft telescopes into itself at several points along the shaft. Trichoscopy shows small nodules along the shaft. Hairs bend and break in these diseases. Trichoscopy of pili torti shows twists of hair shafts along their long axis. In pili annulati hair shafts with alternating white and dark bands are visible. In woolly hair the examination demonstrates hair shafts with waves at very short intervals. For trichothiodystrophy polarized trichoscopy should be used. In ectodermal dysplasias, trichoscopy shows a variety of hair abnormalities, but the most characteristic finding is hair shaft pigmentation heterogeneity.

Generalized basaloid follicular hamartoma syndrome versus Gorlin syndrome: A diagnostic challenge.

Basaloid follicular hamartoma is a relatively rare benign neoplasm of follicular origin that can be mistaken histologically for basal cell carcinoma, but hereditary forms of basaloid follicular hamartoma are associated with nevoid basal cell carcinoma syndrome, or Gorlin syndrome. The pathophysiology of basaloid follicular hamartoma development involves mutations in the patched gene, which is also causative in nevoid basal cell carcinoma syndrome. We present a mother and daughter with basaloid follicular hamartomas, with genetic testing confirming patched gene mutation in the daughter.

Congenital atrichia with papular lesions: a rare cause of irreversible childhood alopecia.

Congenital atrichia with papular lesions (APL) is a disease characterized by the complete absence of hair from the whole body occurring within a few months of birth and the presence of papules distributed over the body. A 9-year-old boy presented with sparse hair over his body and with a history of losing his hair soon after birth. Multiple skin-colored papules were observed over the scalp. A biopsy from a papule showed keratinous cysts in the dermis and the absence of hair follicles. A diagnosis of congenital APL was made after vitamin D-dependent rickets was excluded. This case highlights congenital APL as a cause of total alopecia.

PTCH1 Germline Mutations and the Basaloid Follicular Hamartoma Values in the Tumor Spectrum of Basal Cell Carcinoma Syndrome (NBCCS).

BACKGROUND/AIM: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominantly inherited disorder characterized by multiple basal cell carcinomas (BCC), odontogenic tumors and various skeletal anomalies. Basaloid follicular hamartomas (BFHs) constitute rare neoplasms that can be detected in sporadic and familial settings as in the Basaloid Follicular Hamartoma Syndrome (BFHS). Although BFHS shares clinical, histopathological and genetic overlapping with the NBCCS, they are still considered two distinctive entities. The aim of our single-institution study was the analysis of a cohort of PTCH1-mutated patients in order to define clinical and biomolecular relationship between NBCCS and BFHs. MATERIALS AND METHODS: In our study we evaluated PTCH1 gene-carrier probands affected by NBCCS to detect the incidence of BFHs and their correlation with this rare syndrome. RESULTS: Among probands we recognized 4 patients with BFHs. We found 15 germline PTCH1 mutations, uniformly distributed across the PTCH1 gene. Six of them had familial history of NBCCS, two of them were novel and have not been described previously. CONCLUSION: NBCCS and BFHS may be the same genetic entity and not two distinctive syndromes. The inclusion of BFH in the NBCCS cutaneous tumor spectrum might be useful for the recognition of misdiagnosed NBCCS cases that could benefit from tailored surveillance strategies.

Human Hairless Protein Roles in Skin/Hair and Emerging Connections to Brain and Other Cancers.

The mammalian hairless protein (HR) is a 130 kDa nuclear transcription factor that is essential for proper skin and hair follicle function. Previous studies have focused on the role of HR in skin maintenance and hair cycling. However, the hairless gene (HR) is also expressed in brain and other tissues, where its role remains poorly understood. HR has been reported to contain functional domains that potentially serve in DNA binding, histone demethylation, nuclear translocation and protein-protein interactions. Indeed, HR has been shown to interact with and repress the action of the nuclear receptors for vitamin D and thyroid hormone as well as RAR-related orphan receptor alpha, possibly via recruitment of histone deacetylases. HR may also have important functions in non-skin tissues given that nearly 200 HR mutations have been identified in patients with various cancers, including prostate, breast, lung, melanoma, uterine, and glioma. This suggests that HR and/or mutants thereof have relevance to the growth and survival of cancer cells. For example, the reported intrinsic histone H3K9 demethylase activity of HR may activate dormant genes to contribute to carcinogenesis. Alternatively, the demonstrated ability of HR to interact with p53 and/or the p53 DNA response element to influence p53-regulated pathways may explain, at least in part, why many cancers express mutated HR proteins. In this review, we summarize the current knowledge of HR bioactions, how HR mutations may be contributing to alopecia as well as to cancer, and, finally, outline future directions in the study of this largely enigmatic nuclear protein. J. Cell. Biochem. 119: 69-80, 2018. © 2017 Wiley Periodicals, Inc.