B lymphocytes spread and extend membrane processes when searching for antigens and form immune synapses upon contacting cells that display antigens on their surface. Although these dynamic morphological changes facilitate B cell activation, the signaling pathways underlying these processes are not fully understood. We found that activation of the Rap GTPases was essential for these changes in B cell morphology. Rap activation was important for B cell receptor (BCR)- and lymphocyte-function-associated antigen-1 (LFA-1)-induced spreading, for BCR-induced immune-synapse formation, and for particulate BCR ligands to induce localized F-actin assembly and membrane-process extension. Rap activation and F-actin assembly were also required for optimal BCR signaling in response to particulate antigens but not soluble antigens. Thus by controlling B cell morphology and cytoskeletal organization, Rap might play a key role in the activation of B cells by particulate and cell-associated antigens.

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Cowden syndrome (CS) is a rare autosomal dominant disorder characterized by multisystem hamartomatous growths and carcinomas. CS is linked to germ line mutations in PTEN (phosphatase and tensin homolog) located on chromosome 10q23.3. PTEN acts as a tumor suppressor to negatively control cellular growth and survival via the PI3K/AKT signaling pathway. Presented here are 2 patients with multiple, persistent, and asymptomatic papules on the face and the upper body, histologically consistent with trichilemmomas. Diagnosis of CS was made in each case based on the established diagnostic criteria and confirmed using immunohistochemistry directed against PTEN. We propose that the assessment of PTEN expression levels can aid in the identification of patients with CS.

We present a case of a 26-year-old lady who developed tender multiple skin colored to erythematous papules over her upper trunk over the course of seven years. This gradually started spreading to her upper arm and thighs. Interestingly these lesions were treated as acne for several years with antitopical therapy in Poland. Prior to seeking dermatologist advice in the UK, she had been under the care the gynecologist for menorrhagia secondary to uterine fibroids. Concurrently she was under the care of the renal team as magnetic resonance imaging (MRI) revealed findings of kidney cysts. In view of family history her mother and grandmother are known to have uterine fibroids, though of unknown severity. Her father and brother are asymptomatic. A diagnostic skin biopsy revealed poorly circumscribed smooth muscle bundles in the dermis in keeping with a leiomyoma. Her genetic testing revealed a mutation in the fumarate hydratase (FH) gene. A diagnosis of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) was made on the basis of the clinical manifestation of multiple cutaneous leiomyomas, symptomatic uterine fibroids and a possible positive family history. HLRCC is an autosomal dominant tumor. Germline mutations in FH, plus somatic mutations and loss of heterozygosity in tumor tissue, suggest that loss of function of the fumarate hydratase protein is the basis of tumor formation in HLRCC. In cutaneous lesions surgical treatment such as cryoablation, and ablative lasers are employed in limited distribution. Medical therapy such as calcium channel blockers, anti-depressant and anti-epileptic can be used to control pain. Our patient responded well to systemic Azathioprine (3 mg/kg) under close observation. As for the future, target therapies for HLRCCassociated tumors may include antiehypoxia-inducible factor, this of which are responsible in HLRCC tumorigenesis. All patients with HLRCC are warranted to have bi-annual cutaneous examination, annual gynecology review and annual renal imaging. Preimplantation genetic diagnosis is made available to families with disease-causing mutations. Our case highlights the importance of a multidisciplinary approach and close surveillance of HLRCC patients. The main focus of management in HLRCC is prevention of disease and death due to renal cancer.Commercial support: None identified.