Introduction

ADVANCES IN DERMATOLOGY AND INTERNAL MEDICINE

Introduction

Dec
2006
Vol. 25. No. 4
Lindy P. Fox, MD

INTRODUCTION

Systemic syndromes with cutaneous manifestations represent a continually evolving entity. New syndromes are described, while improved understanding of others, with new features of disease or enhanced genetic understanding of the disease are discovered. This review highlights the latest information on syndromes with cutaneous manifestations and presents several newly described dermatologic diagnoses.

Birt-Hogg-Dubé Syndrome Birt-Hogg-Dubé syndrome (BHD, OMIM 135150) is a rare, autosomal-dominant genodermatosis characterized by benign skin lesions, renal tumors, and pulmonary abnormalities. The classic cutaneous triad includes fibrofolliculomas, trichodiscomas, and acrochordons. Internal manifestations include renal tumors (both benign and malignant), as well as lung cysts that may lead to spontaneous pneumothorax. The cutaneous manifestations develop in early adulthood as 1- to 4-mm flesh-colored, round, flat-topped papules, numbering in the teens to hundreds, and are clinically indistinguishable from one another (Fig. 1). Aside from the renal and pulmonary issues, multiple other less commonly reported associations have been made, including colon polyps and carcinoma.
This topic will be specifically referenced, because no consensus exists regarding the understanding of the data. Other cutaneous and systemic features anecdotally linked to BHD are more equivocally associated and have been reviewed recently.1 Initially, recombination mapping in BHD families isolated a susceptibility locus on chromosome 17p11.2. Subsequent investigations identified the BHD gene, and its gene product, a novel protein, folliculin.2 Folliculin is a highly conserved protein across species, although its functional role in cell biology is not known. Presumably, BHD and its protein serve as tumor suppressors, as all mutations reported to date are predicted to cause loss of function.3 Thus far, diverse genetic mutations have been reported, including insertions/deletions leading to frameshifts, nonsense mutations, and splice-site mutations, most of which have been predicted to truncate folliculin.4 Specific genotype–phenotype correlation, however, has yielded mixed results. Phenotypic variations occur within families with the same germline mutation, and even within individual patients, without clear predictors.5 Other data have shown that specific defects may confer a lower risk of renal tumors and that inherited mutations in the 3= half of the BHD gene account for 96% of all patients with spontaneous pneumothorax.4 Still, no clear correlation between mutation location on the BHD gene and phenotype has emerged. The precise incidence of renal tumors that arise in conjunction with BHD is unknown. Current information suggests that at least 20% of patients with BHD develop renal tumors.4 The average age at presentation is between 48 and 50 years old, with men predominating over women (2.5-5:1). An average of 5 tumors per patient has been reported, with a mean size of 5.7 cm. A total of 60% of patients have bilateral tumors at the time of presentation.6 The most common tumor is a hybrid of chromophore renal cell carcinoma (RCC) and oncocytoma, which is reported in 50% of cases, whereas less commonly, a heterogeneous group of tumors may present, including renal oncocytoma, clear cell RCC, chro-

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Figure 4 Acquired brachial cutaneous dyschromatosis: irregular,
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