Adnexotropic Variants of the Interface Dermatitides: A Review

The interface dermatitides encompass a vast array of cutaneous entities which, at times, may present with particular clinical variants with adnexal predilection. Similarly, hair follicle and eccrine gland involvement of some of these entities has been observed on histopathology. This review aims to describe the various adnexotropic presentations of the interface dermatitides. Recognizing that the adnexa can be a frequent site of involvement of these conditions may aid dermatopathologists in making the correct diagnosis and avoid misinterpreting adnexotropism for other conditions such as the great imitator, mycosis fungoides.

Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution

Humans sweat to cool their bodies and have by far the highest eccrine sweat gland density among primates. Humans’ high eccrine gland density has long been recognized as a hallmark human evolutionary adaptation, but its genetic basis has been unknown. In humans, expression of the Engrailed 1 (EN1) transcription factor correlates with the onset of eccrine gland formation. In mice, regulation of ectodermal En1 expression is a major determinant of natural variation in eccrine gland density between strains, and increased En1 expression promotes the specification of more eccrine glands. Here, we show that regulation of EN1 has evolved specifically on the human lineage to promote eccrine gland formation. Using comparative genomics and validation of ectodermal enhancer activity in mice, we identified a human EN1 skin enhancer, hECE18. We showed that multiple epistatically interacting derived substitutions in the human ECE18 enhancer increased its activity compared with nonhuman ape orthologs in cultured keratinocytes. Repression of hECE18 in human cultured keratinocytes specifically attenuated EN1 expression, indicating this element positively regulates EN1 in this context. In a humanized enhancer knock-in mouse, hECE18 increased developmental En1 expression in the skin to induce the formation of more eccrine glands. Our study uncovers a genetic basis contributing to the evolution of one of the most singular human adaptations and implicates multiple interacting mutations in a single enhancer as a mechanism for human evolutionary change.

A Rare Case of Porocarcinoma and Trichoblastoma Arising in a Nevus Sebaceus of Jadassohn

Nevus sebaceus of Jadassohn, or “organoid nevus,” is a common, benign hamartoma of the skin consisting of epithelial and adnexal components. Its natural history and association with neoplastic growths is well documented. The majority of concomitant neoplasms are benign—trichoblastoma and syringocystadenoma papilliferum are most frequently discovered—but malignant tumors have been described. We present the case of a 58-year-old male with a congenital nevus sebaceus of Jadassohn on his left parietal scalp that had been enlarging, changing color, and bleeding over the prior year. Clinical exam and histology disclosed the presence of a trichoblastoma and porocarcinoma arising within the nevus sebaceus. Porocarcinoma is a rare, intermediately aggressive, malignant eccrine gland tumor that is frequently metastasized at presentation. Otolaryngology performed wide local resection with sentinel lymph node biopsy. This case highlights the diversity of tumors associated with nevus sebaceus of Jadassohn, potential for malignant expansion, and necessity for close monitoring and maintaining a low threshold for biopsy in evolving lesions.

Cetuximab Induced Hidrocystomas: A Case Report

Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor that commonly results in follicular-based acneiform eruptions. EGFR is expressed in the epidermis, hair follicle epithelium, sweat gland apparatus, and plays an important role in the differentiation and development of the hair follicle. In this report we describe a 70-year-old man who developed an acneiform eruption on his nose, cheeks, neck, and back when cetuximab was started for metastatic colorectal carcinoma. This initial eruption improved with cessation of cetuximab but left residual cystic papules on his nose and multiple superficial white cysts on his bilateral cheeks, neck and back. Skin biopsy of a representative lesion on the nose revealed a cyst-like cavity lined with epithelium similar to sweat glands within the dermis consistent with a hidrocystoma. In this case, it is plausible that the use of an EGFR inhibitor resulted in a cutaneous inflammatory reaction, that subsequently healed with blockage of the sweat duct apparatus causing the formation of cutaneous cysts, including both hidrocystomas and milia. Alternatively, the blockage of the duct may have resulted from inhibition of basal cell migration and increased cell adhesion within the eccrine gland causing accumulation of eccrine gland secretion, and eventually hidrocystomas. To our knowledge, this is the first case describing the resolution of a typical cetuximab-induced acneiform eruption with residual hidrocystomas and milia.

An Engrailed1 enhancer underlies human thermoregulatory evolution

SummaryHumans rely on sweating to cool off and have the highest eccrine sweat gland density among mammals. We investigated whether altered regulation of the Engrailed 1 (EN1) gene, the levels of which are critical for patterning eccrine glands during development, could underlie the evolution of this defining human trait. First, we identify five EN1 candidate enhancers (ECEs) using comparative genomics and validation of enhancer activity in mouse skin. The human ortholog of one ECE, hECE18, contains multiple derived substitutions that together dramatically increase the activity of this enhancer in keratinocytes. Targeted repression of hECE18 reduces EN1 expression in human keratinocytes, indicating hECE18 upregulates EN1 in this context. Finally, we find that hECE18 increases ectodermal En1 in a humanized knock-in mouse to increase eccrine gland number. Our study uncovers a genetic basis for the evolution of one of the most singular human adaptations and implicates the recurrent mutation of a single enhancer as a novel mechanism for evolutionary change.

Chilblains

Summary: Idiopathic chilblain is a relatively common yet poorly recognized acrosyndrome. This literature review aims to better understand and draw attention to this disorder. Chilblain is a localized inflammation of the skin that occurs on exposure to cold but non-freezing wet weather. It usually resolves spontaneously. The etiology is uncertain, but vasospasm seems to play a role in this abnormal reaction to cold. Diagnosis is most often based on clinical presentation, but a skin biopsy can be useful in dubious cases. In histology, dermal edema and an inflammatory infiltrate are usually present. A distribution of the infiltrate particularly around the eccrine gland is typical. Systemic symptoms and underlying autoimmune disease should be screened. Avoiding cold and keeping extremities warm is the first recommendation for management, as well as smoking cessation. Calcium channel blockers (in particular nifedipine) seems to be the treatment that has been most evaluated in chilblains. However, their effectiveness is not confirmed by all studies. Topical betamethasone is often used but its effect has not been confirmed by randomized clinical trials. Other treatments, such as pentoxifylline, hydrochloroquine and topical nitroglycerin have shown positive effects only in a reduced number of patients. Acupuncture seems to bring a benefit.

Clinical and histopathological profile of benign appendageal tumours of skin: a descriptive study from Andhra Pradesh

<p class="abstract"><strong>Background:</strong> Skin adnexal tumors are those neoplasms that arise from pilosebaceous units, eccrine sweat glands or apocrine sweat glands. Vast majority of appendageal tumors are benign and most of the benign skin adnexal tumors are asymptomatic papules or nodules and often difficult to diagnose clinically. The objective of the study was to study the clinical and histological features suggestive of benign skin appendageal tumors.</p><p class="abstract"><strong>Methods:</strong> This is a descriptive observational study conducted among 50 patients presenting with clinical features suggestive of benign skin appendageal tumors attending at outpatient department of DVL, Kurnool medical college/ GGH, Kurnool between January 2016 to June 2017.<strong></strong></p><p class="abstract"><strong>Results:</strong> The highest age incidence was in the age group of 21-30 years- 24 cases (48%). The commonest tumors in this study were eccrine gland tumors i.e 43 cases (86%). Syringomas were the commonest tumors (38 cases, 76%). Commonest presenting lesion was papule (82%). Commonest site is face (94%).</p><p class="abstract"><strong>Conclusions:</strong> The commonest tumors recorded were eccrine gland tumors (86%). Syringomas constitute the largest group (76%) followed by trichoepitheliomas (6%). The highest age incidences was in 3^rd decade (48%), followed by 4^th decade (42%).</p>

Comparative evidence for the independent evolution of hair and sweat gland traits in primates

Humans differ in many respects from other primates, but perhaps no derived human feature is more striking than our naked skin. Long purported to be adaptive, humans’ unique external appearance is characterized by changes in both the patterning of hair follicles and eccrine sweat glands, producing decreased hair cover and increased sweat gland density. Despite the conspicuousness of these features and their potential evolutionary importance, there is a lack of clarity regarding how they evolved within the primate lineage. We thus collected and quantified the density of hair follicles and eccrine sweat glands from five regions of the skin in three species of primates: macaque, chimpanzee and human. Although human hair cover is greatly attenuated relative to that of our close relatives, we find that humans have a chimpanzee-like hair density that is significantly lower than that of macaques. In contrast, eccrine gland density is on average 10-fold higher in humans compared to chimpanzees and macaques, whose density is strikingly similar. Our findings suggest that a decrease in hair density in the ancestors of humans and apes was followed by an increase in eccrine gland density and a reduction in fur cover in humans. This work answers longstanding questions about the traits that make human skin unique and substantiates a model in which the evolution of expanded eccrine gland density was exclusive to the human lineage.