Kelly B. Cha

WNT signaling affects gene expression in the ventral diencephalon and pituitary gland growth

We examined the role of WNT signaling in pituitary development by characterizing the pituitary phenotype of three WNT knockout mice and assessing the expression of WNT pathway components. Wnt5a mutants have expanded domains of Fgf10 and bone morphogenetic protein expression in the ventral diencephalon and a reduced domain of LHX3 expression in Rathkes pouch. Wnt4 mutants have mildly reduced cell differentiation, reduced POU1F1 expression, and mild anterior lobe hypoplasia. Wnt4, Wnt5a double mutants exhibit an additive pituitary phenotype of dysmorphology and mild hypoplasia. Wnt6 mutants have no obvious pituitary phenotype. We surveyed WNT expression and identified transcripts for numerous Wnts, Frizzleds, and downstream pathway members in the pituitary and ventral diencephalon. These findings support the emerging model that WNT signaling affects the pituitary gland via effects on ventral diencephalon signaling, and suggest additional Wnt genes that are worthy of functional studies. Developmental Dynamics 237:1006–1020, 2008.

WNT5A signaling affects pituitary gland shape

Wnt signaling is important in organogenesis, and aberrant signaling in mature cells is associated with tumorigenesis. Several members of the Wnt family of signaling molecules are expressed in the developing pituitary gland. Wnt5a is expressed in the neuroectoderm that induces pituitary gland development and has been proposed to influence pituitary cell specification. We discovered that mice deficient in Wnt5a display abnormal morphology in the dorsal part of the developing pituitary. The expression of downstream effectors of the canonical Wnt pathway is not altered, and expression of genes in other signaling pathways such as Shh, Fgf8, Fgf10 and Fgfr2b is intact. Prop1 and Hesx1 are also important for normal shape of the pituitary primordium, but their expression is unaltered in the Wnt5a mutants. Specification of the hormone-producing cell types of the mature anterior pituitary gland occurs appropriately. This study suggests that the primary role of Wnt5a in the developing pituitary gland is in establishment of the shape of the gland.

Transcriptome profiling identifies HMGA2 as a biomarker of melanoma progression and prognosis.

The genetic alterations contributing to melanoma pathogenesis are incompletely defined, and few independent prognostic features have been identified beyond the clinicopathological characteristics of the primary tumor. We used transcriptome profiling of 46 primary melanomas, 12 melanoma metastases, and 16 normal skin (N) samples to find genes associated with melanoma development and progression. Results were confirmed using immunohistochemistry and real-time PCR and replicated in an independent set of 330 melanomas using AQUA analysis of tissue microarray (TMA). Transcriptome profiling revealed that transcription factor HMGA2, previously unrecognized in melanoma pathogenesis, is significantly upregulated in primary melanoma and metastases (P-values=1.2 × 10(-7) and 9 × 10(-5)) compared with N. HMGA2 overexpression is associated with BRAF/NRAS mutations (P=0.0002). Cox proportional hazard regression model and log-rank test showed that HMGA2 is independently associated with disease-free survival (hazard ratio (HR)=6.3, 95% confidence interval (CI)=1.8-22.3, P=0.004), overall survival (OS) (stratified log-rank P=0.008), and distant metastases-free survival (HR=6.4, 95% CI=1.4-29.7, P=0.018) after adjusting for American Joint Committee on Cancer (AJCC) stage and age at diagnosis. Survival analysis in an independent replication TMA of 330 melanomas confirmed the association of HMGA2 expression with OS (P=0.0211). Our study implicates HMGA2 in melanoma progression and demonstrates that HMGA2 overexpression can serve as an independent predictor of survival in melanoma.

Comprehensive histopathological comparison of epidermotropic/dermal metastatic melanoma and primary nodular melanoma

Metastatic melanoma involving the epidermis and/or upper dermis may show significant histological overlap with primary cutaneous melanoma, especially the nodular subtype. Proper histopathological classification is crucial to appropriate staging and management, but is often challenging. The aim of this study was to identify helpful histopathological features for differentiating epidermotropic/dermal metastatic melanoma (EDMM) and primary nodular melanoma (PNM).

Blaschkolinear acquired inflammatory skin eruption, or blaschkitis, with features of lichen nitidus

Blaschkolinear acquired inflammatory skin eruption (BLAISE) encompasses a variety of skin conditions in children and adults that show striking distribution along the lines of Blaschko and are characterized histopathologically by an inflammatory infiltrate. The most common presentations of BLAISE are blaschkitis, which affects adults, typically along multiple lines of Blaschko on the trunk, and lichen striatus, which is more commonly seen as a linear dermatosis on the extremities of children. More rarely, dermatoses such as lichen nitidus, illustrated by our patient, can also fit within this spectrum.

Chronic Translucent Papules of the Palms and Soles

Awoman inher50swithamedical historyof asthmaandseasonal allergiespresentedwith numerousasymptomatic flesh-colored to translucentpapulesonherpalmsandpalmar and lateral aspects of her fingers (Figure, A and B). Many of the papules were depressed centrally. Therewasnoextensiononto thedorsal aspectof thehands. Therewere similar translucent papules over themargins of her feet, particularly her great toes, and hyperkeratotic yellow plaques with scattered pits over her bilateral soles, concentrated in areas of pressure. The lesions onher hands first developed inher40s andwere exacerbatedby alcoholbased hand sanitizer at work. They became more prominent with exposure to water but remained asymptomatic. Occasional application of urea cream to her feet did not lead to significant improvement. Shealsohad fine-texturedhair, present sincechildhoodwith thinning noted in thepast 7 years. She hadnohistory of eczema. At the time, shedenied a family historyof similar skin findingsbut recently reported similar handand foot findings inher mother. Two punch biopsies were performed from the left thenar eminence (Figure, C). A

Painful linear ulcers: A case of cutaneous sporotrichosis mimicking pyoderma gangrenosum

INTRODUCTION The differential diagnosis of cutaneous ulcers is broad, including infection, neoplasm, vascular disease, trauma, and inflammatory processes such as pyoderma gangrenosum. Nodulo-ulcerative lesions on an extremity are a common presentation of sporotrichosis, an infection with a saprophytic dimorphic fungus. A high index of suspicion for infection is required when chronic ulcers do not respond to treatment.

A new POT1 germline mutation—expanding the spectrum of POT1-associated cancers

Melanomas are associated with several hereditary conditions. We present a large family with several family members affected with primary melanomas and dysplastic nevi as well as thyroid cancer and other malignant tumors. Clinical work-up did not reveal a mutation in any of the genes usually considered with evaluation for predisposition to melanoma (BRCA1/2, CDKN2A, CDK4, PTEN, TP53). Whole exome sequencing of five affected family members showed a new variant in POT1. POT1 is associated with the telomere shelterin complex that regulates telomere protection and telomerase access. Germline mutations in POT1 were recently shown to be associated with hereditary predisposition to melanoma. Our findings support a role of POT1 germline mutations in cancer predisposition beyond melanoma development, suggesting a broader phenotype of the POT1-associated tumor predisposition syndrome that might also include thyroid cancer as well as possibly other malignant tumors.

Treatment of Imipramine-Induced Dyspigmentation with Q-Switched Alexandrite Laser Therapy

The development of blue or gray cutaneous hyperpigmentation is a rare complication of chronic imipramine therapy. Treatment options for imipramine-induced hyperpigmentation are limited but include topical retinoids, bleaching agents, and laser therapy, with varying degrees of success. We report a case in which Q-switched alexandrite laser therapy alone led to nearly complete resolution of imipramine-induced dyspigmentation in a patient who had been taking this medication for 4 decades. Paradoxical darkening of imipramine-induced hyperpigmentation after combined Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) and Q-switched ruby laser therapy has recently been demonstrated. Here, we further report a similar pattern of focal paradoxical hyperpigmentation after treatment of imipramine-induced hyperpigmentation with Q-switched alexandrite laser therapy that resolved with additional treatment sessions.