A novel TRAF3IP2 variant causing familial scarring alopecia with mixed features of discoid lupus erythematosus and folliculitis decalvans.

Discoid lupus erythematosus (DLE) is an autoimmune disorder with a poorly defined etiology. Despite epidemiologic gender and ethnic biases, a clear genetic basis for DLE remains elusive. In this study, we used exome and RNA sequencing technologies to characterize a consanguineous Lebanese family with four affected individuals who presented with classical scalp DLE and generalized folliculitis. Our results unraveled a novel biallelic variant c.1313C > A leading to a missense substitution p.(Thr438Asn) in TRAF3IP2(NM_147200.3). Expression studies in cultured cells revealed mis-localization of the mutated protein. Functional characterization of the mutated protein showed significant reduction in the physical interaction with the interleukin 17-A receptor (IL17RA), while interaction with TRAF6 was unaffected. By conducting a differential genome-wide transcriptomics analysis between affected and non-affected individuals, we showed that the hair follicle differentiation pathway is drastically suppressed, whereas cytokine and inflammation responses are significantly upregulated. Furthermore, our results were highly concordant with molecular signatures in patients with DLE from a public dataset. In conclusion, this is the first report on a new putative role for TRAF3IP2 in the etiology of DLE. The identified molecular features associated with this gene could pave the way for better DLE-targeted treatment.

Sustained obesity reduces litter size by decreasing proteins regulating folliculogenesis and ovulation in rats - A cafeteria diet model.

Global rise in obesity at early age due to overconsumption of energy-dense food is the major health problem which increases the exposure to obesity over longer duration. Recently we reported that the severity of ovarian dysfunction depends on the duration of obesity. In the present study, we examined the consequences of sustained obesity on reproductive outcome and the underlying mechanism. Sprague Dawley female rats (21 days old) were fed ad libitum with a standard diet (control group) and a cafeteria diet (Obese group) for 32 weeks. We observed hypoprolactinemia, sub-fecundity, sub-fertility, delayed conception and macrosomic pups of reduced litter size in sustained obese rats. The observed decrease in the number of ovarian follicles (primordial, primary, secondary and antral follicles) and corpus luteum indicates impairment in folliculogenesis and ovulation. This impairment might be due to decreased level of ovarian proteins (PRLR, AR, GDF-9, OCT-4, COX-2, PPARγ, ER and PR subtypes) in obese rats. We conclude that sustained obesity impaired folliculogenesis and ovulation thereby increased the severity of reproductive deficits.

Influence of allelic Variations of hypoxia-related and DNA repair genes on patient outcome and toxicity in head and neck cancer treated with radiotherapy plus cetuximab.

Although cetuximab plus radiotherapy is a standard treatment for patients with inoperable head and neck squamous cell carcinoma (HNSCC), its efficacy varies greatly among individuals. To identify predictive markers of efficacy, we examined the effects of single nucleotide polymorphisms (SNPs) in hypoxia-related and DNA repair genes on the clinical outcome and occurrence of skin toxicity. We analyzed 61 consecutive patients with HNSCC for the presence of specific SNPs (HIF-1α, HIF-2α, HIF-1ß, VHL, FIH-1, XRCC1, and XRCC5). The results were then correlated with time to progression (TTP), overall survival (OS), and toxicity (epithelitis, mucositis, and folliculitis). The median TTP and OS were better in patients with severe vs mild mucositis (17 vs 7 months, p = 0.03; and 26 vs 12 months, p = 0.016, respectively) and folliculitis (10 vs 7 months, p = 0.01, and 26 vs 10 months, p < 0.001, respectively). Patients with the HIF-1α CT/TT genotype had better OS than those with the wild-type HIF-1α CC genotype (28 vs 13 months, p = 0.035). Patients with the XRCC5 GG/AA genotype had longer TTP than patients with the XRCC5 AG genotype (11 vs 7 months, p = 0.035). Severe skin toxicity and SNPs of HIF-1α and XRCC5 were associated with different outcomes among patients treated with radiotherapy plus cetuximab.

Screening of differentially expressed genes in pathological scar tissues using expression microarray.

Pathological scar tissues and normal skin tissues were differentiated by screening for differentially expressed genes in pathologic scar tissues via gene expression microarray. The differentially expressed gene data was analyzed by gene ontology and pathway analyses. There were 5001 up- or down-regulated genes in 2-fold differentially expressed genes, 956 up- or down-regulated genes in 5-fold differentially expressed genes, and 114 up- or down-regulated genes in 20-fold differentially expressed genes. Therefore, significant differences were observed in the gene expression in pathological scar tissues and normal foreskin tissues. The development of pathological scar tissues has been correlated to changes in multiple genes and pathways, which are believed to form a dynamic network connection.

Medical genetics: Sporadic dystrophic epidermolysis bullosa with albopapuloid and prurigo- and folliculitis-like lesions.

A case of sporadic dystrophic epidermolysis bullosa (DEB) with albopapuloid and prurigo- and folliculitis-like lesions is reported. Histopathology of the scalp biopsy showed hyperkeratosis, a subepidermal cleft near the orifice of a hair follicle, dermal fibrosis, and a moderate perivascular and perifollicular lymphohistiocytic inflammatory cell infiltrate in the papillary dermis, without neutrophilic infiltrate in the orifice of the hair follicle. It is uncertain whether the present case should be classified as DEB pruriginosa or represents a new subtype of DEB.

Hyperplasia of hair follicles and other adnexal structures in cutaneous lymphoproliferative disorders: a study of 53 cases, including so-called pseudolymphomatous folliculitis and overt lymphomas.

We studied 53 cutaneous lymphoproliferative disorders, all of which manifested hair follicle hyperplasia. There were 42 cases conforming to the description of pseudolymphomatous folliculitis (PLF) and 11 cases of authentic lymphomas including mycosis fungoides, CD30+ anaplastic large cell lymphoma, diffuse large B-cell lymphoma, B-cell small cell lymphoma/leukemia, and peripheral T-cell lymphoma, not otherwise specified. All patients with PLF clinically presented with a solitary nodule preferentially involving the face. Beside hair follicle hyperplasia, the typical features were a dense infiltrate of small well-differentiated lymphocytes, lymphoplasmacytoid cells, plasma cells, and epithelioid histiocytes forming tiny granulomas. Some unusual or worrisome features recognized included eccrine/apocrine duct hyperplasia, subcutis/muscle infiltration, lymphocyte "smudging," single file infiltration, and large atypical cells. Immunohistochemically, T-cell predominant cases dominated in the series. All 34 tested cases revealed a polyclonal pattern of kappa and lambda immunoglobulin (Ig) light chain expression. In 4 cases, scattered CD30+ cells were identified. Monoclonal rearrangements of T-cell receptor (TCR) and IgH genes were detected in 19 and 3 cases respectively, including 1 case with dual T-cell receptor/IgH rearrangement. Three of 30 tested cases proved positive for herpes simplex virus-1, whereas herpes simplex virus-2 always tested negative. Of 31 cases tested for Borrelia burgdorferi, 30 specimens were negative. In 9 cases, fluorescent in situ hybridization for t(11;18) and t(14;18) revealed none of the above translocations. The most common treatment modality was surgical removal. Forty patients with a mean follow-up of 3.7 years included 39 patients with no evidence of disease and 1 individual with local recurrence. The comparison of "clonal cases of PLF" and those with polyclonal population or in which clonality remained undetermined revealed no differences between the 2 groups in the clinical presentation, pathologic, and immunohistochemical features. We conclude that hyperplasia of hair follicles and other adnexa can be seen not only in the condition currently known as PLF, but also in genuine cutaneous lymphomas and may be just a happenstance secondary to a basic pathologic process.

Failure to detect clonality in eosinophilic pustular folliculitis with follicular mucinosis.

Eosinophilic pustular folliculitis is characterized by an eosinophil-rich inflammatory follicular and perifollicular infiltrate primarily centred at the level of the follicular isthmus and sebaceous duct. Follicular mucinosis has been observed in lesions of eosinophilic pustular folliculitis. Clinical and histological features of eosinophilic pustular folliculitis with follicular mucinosis and alopecia mucinosa are very similar. Alopecia mucinosa may be a clonal T-cell dermatosis. A monoclonal re-arrangement of the T-cell receptor gene was detected in about half of the cases in alopecia mucinosa. To investigate T-cell clonality in a series of eosinophilic pustular folliculitis with follicular mucinosis, we performed heteroduplex analysis of re-arranged T-cell receptor gamma gene in seven cases of eosinophilic pustular folliculitis with follicular mucinosis. All cases were negative for heteroduplex-PCR analysis. The failure to demonstrate clonality may be consistent with a reactive nature of eosinophilic pustular folliculitis with follicular mucinosis.

A novel connexin 26 gene mutation associated with features of the keratitis-ichthyosis-deafness syndrome and the follicular occlusion triad.

We report the case of a congenitally deaf white male with mild palmoplantar keratoderma, ichthyosiform scaling, follicular hyperkeratosis, and mild keratitis, features consistent with keratitis-ichthyosis-deafness syndrome. His major problem was severe, disfiguring, inflammatory dissecting folliculitis of the scalp, hidradenitis suppurativa, and cystic acne, features comprising the follicular occlusion triad. This unusual phenotype is associated with a novel heterozygous point mutation (C119T) in the gap junction beta2 gene that substitutes a valine for alanine at codon 40 (A40V) in the connexin 26 protein. Through Xenopus oocyte expression studies, this mutant protein was shown to significantly disrupt the function of the specialized gap junctions connecting the cytoplasm of adjacent cells critical for tissue homeostasis. Mutations within the connexin 26 protein are associated with syndromes involving both sensorineural deafness and hyperkeratotic skin disorders. This is the first report of an association between a connexin 26 protein mutation, follicular hyperkeratosis of keratitis-ichthyosis-deafness syndrome, and severe follicular occlusion triad.

The medical and surgical therapy of pseudofolliculitis barbae.

Pseudofolliculitis barbae (PFB) is a common, chronic, inflammatory skin disorder seen mainly in individuals with curly hair. This condition is seen most frequently in black men who shave their beards but may also be seen in women of all races who wax or shave the axillary and pubic skin. The etiology of PFB is multifactorial, and heretofore a cure has been considered impossible for those desiring a clean-shaven face. The following article serves to discuss the current medical and surgical therapies available for this condition. Medical treatments for this condition include various combinations of topical antibiotics, corticosteroids, and retinoids. In the surgical arena, laser therapy has revolutionized the treatment of PFB and has enabled cure for the first time for those plagued by this disorder and for whom a beardless face is acceptable.

Chemical peeling in ethnic/dark skin.

Chemical peeling for skin of color arose in ancient Egypt, Mesopotamia, and other ancient cultures in and around Africa. Our current fund of medical knowledge regarding chemical peeling is a result of centuries of experience and research. The list of agents for chemical peeling is extensive. In ethnic skin, our efforts are focused on superficial and medium-depth peeling agents and techniques. Indications for chemical peeling in darker skin include acne vulgaris, postinflammatory hyperpigmentation, melasma, scarring, photodamage, and pseudofolliculitis barbae. Careful selection of patients for chemical peeling should involve not only identification of Fitzpatrick skin type, but also determining ethnicity. Different ethnicities may respond unpredictably to chemical peeling regardless of skin phenotype. Familiarity with the properties each peeling agent used is critical. New techniques discussed for chemical peeling include spot peeling for postinflammatory hyperpigmentation and combination peels for acne and photodamage. Single- or combination-agent chemical peels are shown to be efficacious and safe. In conclusion, chemical peeling is a treatment of choice for numerous pigmentary and scarring disorders arising in dark skin tones. Familiarity with new peeling agents and techniques will lead to successful outcomes.

An unusual Ala12Thr polymorphism in the 1A alpha-helical segment of the companion layer-specific keratin K6hf: evidence for a risk factor in the etiology of the common hair disorder pseudofolliculitis barbae.

Pseudofolliculitis barbae (PFB) is a common hair disorder characterized by a pustular foreign body inflammatory reaction that is induced by ingrown hairs of the facial and submental (barbea) regions after regular shaving. It occurs predominantly in black males, while it is rather rare and usually far less severe in Caucasian males. Black individuals have a higher propensity of developing PFB due to their genetic predisposition for curly hair which inherently possesses a much higher risk of growing back into the skin than straight or wavy hair. The PFB process is, however, not gender dependent nor restricted to the face, but can occur in any skin region once regular shaving, plucking, or other traumatic means of hair removal are instituted. Through a family study and a large-scale investigation of randomly sampled PFB-affected and -unaffected individuals, this study demonstrates that an unusual single-nucleotide polymorphism, which gives rise to a disruptive Ala12Thr substitution in the 1A alpha-helical segment of the companion layer-specific keratin K6hf of the hair follicle, is partially responsible for the phenotypic expression and represents an additional genetic risk factor for PFB.

Foliculitis por traccion asociada a queratosis pilar / Folliculitis with traction associated with keratosis pilaris

La queratosis pilar es una dermatosis frecuente, relacionada, en ocasiones a otras enfermedades. Nosotros presentamos un estudio en 50 pacientes con foliculitis por tracción, quines en un 56 por ciento de los casos presentaron una queratosis pilar asociada. Este hallazgo es probable debido al hecho de que ambas patologías tienen etiopatogenia similares. (AU)

Hereditary perioral pigmented follicular atrophoderma associated with milia and epidermoid cysts.

Eight members of a single family all presented the characteristic changes of facial, especially perioral, pigmented follicular atrophoderma, with numerous milia and epidermoid cysts. For this condition. diagnosis at a glance may be possible because of the perioral cutaneous manifestations. Histopathological examination of follicular atrophoderma revealed proliferation of basaloid cells continuous with the epidermis and coarse collagen fibres, with a decreased density of elastic fibres around the basaloid cells. Two of the eight individuals also showed generalized hypohidrosis. The eight affected persons were the proband, her son, mother, uncle, two younger sisters, cousin and nephew: an autosomal dominant mode of transmission was suggested from this family tree. The patients' symptoms resembled those of Bazex-Dupré-Christol syndrome, except for the different distribution of the follicular atrophoderma and the absence of basal cell carcinoma and hypotrichosis. This disease may be an entirely new syndrome characterized by perioral pigmented follicular atrophoderma associated with milia and epidermoid cysts.

[Sterile eosinophilic pustulosis (Ofuji). A rare entity in Europe]. / Sterile eosinophile Pustulose (Ofuji). Eine in Europa seltene Entität.

This case report refers to a German patient with sterile eosinophilic pustulosis of the Ofuji type (SEP), which is rarely described in non-Japanese humans. The distinctive histomorphology, with intraepidermal eosinophilic abscesses and eosinophilic folliculitis, is complemented in this patient by marked eosinophilia, evident eosinophilic bone marrow reaction and involvement of the oral mucosa with eosinophilic spongiosis, which is a feature that had not previously been reported. Possible transitions between cutaneous and internal hypereosinophilic syndromes are discussed. Despite the initial good effect of topical corticosteroids on the cutaneous changes, long-term follow-up to check for internal involvement is necessary.

Atrophoderma vermiculatum. Case reports and review.

Two patients, a father and a daughter, with atrophoderma vermiculatum are presented. The chief characteristics of this rare, benign condition that usually begins in childhood are a symmetric worm-eaten or reticular atrophy of the cheeks that may extend to the ears or forehead. An autosomal dominant mode of inheritance is present in this family. The prominent characteristics, cause, histologic findings, and rare associated medical conditions are reviewed. The prognosis is good, with many instances of spontaneous regression. Primarily a cosmetic problem, therapy for this condition is aimed at reassurance, genetic counseling, and dermabrasion where appropriate.

[Cutaneous signs of Noonan's syndrome. Apropos of a case with ulerythema ophyogenes, disseminated pilar and sudoral keratosis and progressive alopecia]. / Les signes cutanés du syndrome de Noonan. A propos d'une observation avec ulérythème ophryogène, kératose pilaire et sudorale disséminée et alopécie progressive.

A case of typical Noonan syndrome (NS) with eye abnormalities, pterygium colli, cryptorchid testes, lymphoedema and asymmetrical cardiac septal hypertrophy is reported in a 8-month old infant. This case was particularly interesting since it included skin manifestations which enabled an early diagnosis to be made. Ulerythema ophryogenes has already been proposed as a cutaneous marker of NS, but the keratinization disorders in our patient also included disseminated keratosis of both hair follicles and sweat glands orifices. Abnormally brittle short curly hair has already been reported, but our patient exhibited progressive alopecia which is very rare in NS. Biochemical hair analysis did not show any abnormalities of aminoacids. All these features were suggestive of keratosis follicularis spinulosa decalvans. It therefore seems very likely that NS is associated with keratinization disorders but ulerythema ophryogenes might only be the limited form of these disorders. The other skin manifestations of NS are reviewed. Since the patient had 4 "café au lait" spots, the relation of NS with Von Recklinghausen syndrome, and neurofibromatosis-Noonan syndrome is discussed. Watson's Leopard and cardio-facial syndromes overlap with, and may represent subsets of NS.

Pyoderma eczema and folliculitis with defective leucocyte and lymphocyte function: a new familial immunodeficiency disease responsive to a histamine-1 antagonist.

A new familial immunodeficiency disease characterised by recurrent and persistent pyoderma, folliculitis, and atopic dermatitis is described in a father and son. It is accompanied by abnormalities of lymphocyte function (including defective proliferative responses to phytomitogens, and subnormal response in immunoglobulin production after stimulation of the lymphocytes by pokeweed mitogen) and defective leucocyte chemiluminescence responses, which were associated with defective ability for intracellular killing of microbial organisms. The abnormalities of lymphocyte and leucocyte function, as well as the clinical manifestations, responded dramatically to treatment with the histamine-1 antagonist, chlorpheniramine, suggesting that the underlying defect in this disease may relate to defective histamine metabolism or abnormal expression of histamine receptors on lymphocytes and leucocytes.