Amy Theos

Neurofibromatosis type 1

UNLABELLED Neurofibromatosis type 1 (NF1) is an autosomal dominant, multisystem disorder affecting approximately 1 in 3500 people. Significant advances in the understanding of the pathophysiology of NF1 have been made in the last decade. While no medical therapies for NF1 are currently available, trials are ongoing to discover and test medical treatments for the various manifestations of NF1, primarily plexiform neurofibromas, learning disabilities, and optic pathway gliomas. In addition, mutational analysis has become available on a clinical basis and is useful for diagnostic confirmation in individuals who do not fulfill diagnostic criteria or when a prenatal diagnosis is desired. There are several disorders that may share overlapping features with NF1; in 2007, a disorder with cutaneous findings similar to NF1 was described. This paper addresses the dermatologists role in diagnosis and management of NF1 and describes the variety of cutaneous and extracutaneous findings in NF1 to which the dermatologist may be exposed. LEARNING OBJECTIVES After completing this learning activity, participants should be able to discuss the indications and limitations of genetic testing in neurofibromatosis type 1, distinguish common and uncommon cutaneous findings, and recognize the dermatologists role in diagnosis and management.

Pathophysiology of Neurofibromatosis Type 1

Clinical Principles Neurofibromatosis type 1 (NF1) was formerly known as von Recklinghausen disease. It has autosomal dominant inheritance with complete penetrance, variable expression, and a high rate of new mutation. It affects approximately 1 in 3500 individuals worldwide. Diagnostic clinical signs include neurofibromas, caf-au-lait macules, skinfold freckling, skeletal dysplasia, Lisch nodules, and optic gliomas. Persons with NF1 are at increased risk for malignant conditions, especially malignant peripheral nerve sheath tumor (MPNST), leukemia, and rhabdomyosarcoma. Other complications include cognitive problems and vascular dysplasias. Molecular genetic testing is available. Clinical trials of potential therapies for plexiform neurofibromas are under way. Pathophysiologic Principles Neurofibromatosis type 1 is a classic single-gene disorder with a high rate of new mutations. The NF1 gene is located on chromosome 17. The protein product, neurofibromin, consists of 2818 amino acids. Protein includes a domain with guanosine triphosphatase (GTPase)activating protein (GAP) function. Neurofibromin GAP regulates conversion of Rasguanosine triphosphate (GTP) to Rasguanosine diphosphate (GDP). NF1 gene mutations are highly diverse and are found throughout the gene. Most mutations lead to lack of expression of the gene product. Few genotypephenotype correlations are known, although complete gene deletions lead to severe disease. Loss of function of both NF1 alleles in Schwann cells of neurofibromas indicates that NF1 functions as a tumor suppressor gene. Neurofibromas consist of Schwann cells with both NF1 alleles mutated, along with heterozygous fibroblasts, perineurial cells, and mast cells. Malignant tumors require loss of NF1 function, as well as additional genetic changes. Pathophysiology of nontumor manifestations is unknown; NF1 haploinsufficiency may play a role. Modifying genes probably contribute to variable expression. For definition of terms used, see Glossary. Neurofibromatoses are a set of inherited disorders, designated as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis, that tend to result in the development of benign tumors of the nerve sheath. The 3 entities are distinguished by specific clinical features and are due to mutations in distinct genes (Table 1). Neurofibromatosis type 1 is the most common of the disorders, affecting approximately 1 in 3500 individuals worldwide. The hallmark lesion in NF1 is the neurofibroma, whereas schwannomas (see Glossary) are characteristic of NF2 and schwannomatosis. These tumors may be difficult to distinguish clinically, but they can be differentiated histologically. Unlike the other 2 disorders, NF1 also includes nontumor manifestations, which makes it a true multisystem disorder. The NF1 gene, which produces the NF1 phenotype, was identified in 1990, and much has been learned about the pathophysiology of the disorder since. This has resulted in the availability of molecular diagnostic testing, and clinical trials for drugs to treat neurofibromas are beginning. Our review will briefly consider the NF1 phenotype, the current understanding of basic mechanisms, and the status of translation of this knowledge into clinical application. Table 1. National Institutes of Health Criteria for Neurofibromatosis Type 1 The NF1 Phenotype Neurofibromatosis type 1 is a highly variable disorder with signs and symptoms that may begin at birth and evolve over a lifetime. Phenotypic features can be broadly divided into tumors and nontumor manifestations. Tumors The most characteristic tumor in NF1 is the neurofibroma. Neurofibromas arise from cells of the nerve sheath and consist of a mixture of Schwann cells, fibroblasts, perineurial cells, and mast cells (1). They arise along peripheral nerves, including the nerve root; on sites along the course of nerves; or at nerve endings. Neurofibromas may be focal growths or can extend along the length of a nerve, involving several fascicles and including nerve branches. The latter are called plexiform neurofibromas (2). Dermal neurofibromas may project above the surface of the skin or may reside within the skin (Figure 1). Dermal neurofibromas usually first appear in the preadolescent years and continue to occur throughout life. Aside from puberty, pregnancy seems to be a time of growth or appearance of dermal neurofibromas. The number of dermal tumors that an individual will develop is unpredictable. Some people are covered with thousands of tumors, leading to major cosmetic burden and a reclusive life. Spinal neurofibromas can cause nerve root compression and may invade the spinal canal and compress the spinal cord. Plexiform neurofibromas can grow very large, leading to deformity, and can lead to compression of nerves and other structures and erosion of bones. Plexiform neurofibromas can occur congenitally, although deeper tumors may not be recognized until later in life. Figure 1. Several dermal neurofibromas that are visible as raised lesions but are sometimes first detected by palpation. Neurofibromas are histologically benign, but transformation to malignant peripheral nerve sheath tumors (MPNSTs) is a risk. These tumors arise predominantly from preexisting plexiform neurofibromas. Signs of malignant tumors are pain or sudden growth, although benign tumors can be associated with these signs as well. The lifetime risk for MPNST in patients with NF1 is about 10%, and prognosis is poor (3). The poor outcome may be partly due to delayed diagnosis and poor therapeutic success with sarcomas in general. The tumors tend to be treated with surgery. Whether radiation or chemotherapy markedly improves outcome is not clear. In addition to peripheral nerve sheath tumors, tumors of the central nervous system may occur in affected individuals. Optic gliomas are low-grade pilocytic astrocytomas that occur in 15% of children with NF1 (4). Although at least 50% are asymptomatic, progressive tumors can cause loss of vision, constriction of visual fields, or neuroendocrine disturbances, such as precocious puberty. Optic gliomas progressing after 7 to 8 years of age are rare, and therefore, annual screening in adults is not usually performed. Gliomas can occur elsewhere in the central nervous system, especially in the brainstem. These can also be indolent or may progress (5). Malignant tumors seen in patients with NF1, predominantly children, include leukemia, especially juvenile myelomonocytic leukemia, and rhabdomyosarcoma (6). Individuals with NF1 are also at increased risk for pheochromocytoma. Nontumor Manifestations Major nontumor manifestations of NF1 include pigmentary features, skeletal dysplasias, learning disabilities, and vascular dysplasias. These manifestations have characteristic times of appearance. We will further discuss only the features that are salient to adults. Learning disabilities are among the most common complications of NF1 (7). While most research has focused on children, NF1 results in global cognitive impairment among adults as well. Adults with NF1 may have deficits in inductive reasoning, visuoconstructive skill, memory, logical abstraction, coordination, and mental flexibility (8). In addition to cognitive problems, affective disorders, most commonly dysthymia, occur with increased frequency (9). The vascular complications of NF1, vasculopathy and hypertension, are a major cause of premature death. Vasculopathy consists of arterial stenoses due to proliferation of cells in the intima. Involvement of the renal arteries can lead to hypertension, which most often presents in childhood or in pregnancy (Figure 2). Cerebral artery stenosis can lead to strokes or to the moyamoya syndrome, where collateral vessels develop around the stenotic areas and appear as a puff of smoke on cerebral angiography. Arterial dissection and hemorrhage can be other complications of the vascular involvement of NF1. Pheochromocytoma should be considered in adult patients with NF1 who have refractory hypertension and symptoms of catecholamine excess, such as headache, palpitations, and diaphoresis (10). Figure 2. Angiogram showing renal artery stenosis in a patient with neurofibromatosis type 1. Neurofibromatosis type 1 has many additional clinical features (Table 2) (11). Individually, the features are relatively uncommon, but they must be considered in the management of affected individuals. Two of three individuals with NF1 are estimated to experience relatively minor problems (12). Also, many of the more severe problems, such as tibial or vertebral dysplasia or deformity due to plexiform neurofibroma, tend to occur early in life (Figure 3). Nevertheless, severity is highly variable and unpredictable. Average life expectancy is reduced, mostly due to malignant tumors and vascular complications (13). Table 2. Summary of Neurofibromatoses Figure 3. Skeletal dysplasias in neurofibromatosis type 1. Top. Bottom. Genetics of NF1 Germline and Somatic Mosaicism Neurofibromatosis type 1 is a classic autosomal dominant, single-gene disorder. Approximately half of affected individuals have no affected parent, which is indicative of new mutation. It has the highest rate of new mutation of any known single-gene disorder. An affected individual has a 50% chance of passing NF1 to any offspring. Severity can vary from generation to generation or between affected siblings. The parents of a sporadically affected child are at low risk for having another affected child if both parents are without signs, barring the rare possibility of germline mosaicism (see Glossary) in 1 parent (14). Some affected individuals have manifestations that are confined to a restricted region of the body (15), called segmental neurofibromatosis. At least some cases are due to somatic mosaicism (see Glossary) for an NF1 gene mutation (16), but only a few have been analyzed at the molecular level. Moreover, some instances of somatic mosaicism hav

Mitotically active proliferative nodule arising in a giant congenital melanocytic nevus: A diagnostic pitfall

Proliferative (cellular) nodules (PN) which mimic malignant melanoma clinically and histologically are described in congenital melanocytic nevi (CMN) and may pose significant diagnostic challenges. We report the case of a 10-day-old male with a giant congenital nevus involving the neck, upper chest, back, and left shoulder containing several nodular lesions, some crusted. Biopsy of a nodule revealed densely packed nevus cells with hyperchromatic round to oval and occasionally irregularly shaped nuclei. There was no necrosis or pushing border, and the nodule blended with the adjacent nevus; however, the lesion demonstrated a significant number of mitoses (27 per mm2) and a 60% labeling index with Ki-67. Further analysis by fluorescence in situ hybridization (FISH) with a 4-color probe set targeting 6p25, 6q23, 11q13, and centromere 6 revealed increased chromosomal copy numbers of all 4 probes, which was interpreted as evidence of polyploidy. In addition, analysis of DNA copy number changes using a single nucleotide polymorphism microarray (Affymetrix, Santa Clara, CA) showed no chromosomal aberrations. The diagnosis of PN in a giant congenital nevus was eventually rendered. At 13-month follow-up, the nodules showed no evidence of growth. Our case illustrates that PNs in the neonatal period might demonstrate extreme mitotic activity. This feature is worrisome when encountered in melanocytic lesions; however, it should not trigger by itself a diagnosis of melanoma in the absence of other histologic criteria of malignancy. In addition, we document polyploidy by FISH in PN, which can potentially be misinterpreted as a FISH-positive result.

Atrichia with papular lesions resulting from novel compound heterozygous mutations in the human hairless gene.

Abstract:  Atrichia with papular lesions is a rare form of complete, irreversible alopecia that is inherited in an autosomal recessive manner. Several studies have implicated mutations in the human hairless gene as the underlying cause of this disorder. We describe two novel heterozygous mutations in exons 3 and 8 of the hairless gene in a 2‐year‐old Caucasian boy with complete alopecia of his scalp. These novel mutations add to the growing literature of mutations in the hairless gene found in nonconsanguineous families and expands the allelic series of mutations in this gene.

Inpatient management of atopic dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that is generally managed on an outpatient basis. However, a significant percentage of patients may develop complications severe enough to require inpatient treatment. The most common complications of AD that may require hospital admission include erythroderma, eczema herpeticum, and systemic bacterial infection. Hospital admission can also be useful for chronic and severe disease that has not responded to standard therapy or in situations where nonadherence is suspected as the cause of treatment failure. In these cases, inpatient treatment can offer an opportunity for caretaker education and allow for an objective evaluation of a patients response to a structured treatment plan. This article will review the indications for inpatient management of AD and the therapies that can be used to acutely manage severe disease and associated complications.

Multiple Congenital Red-Brown Macules, Thrombocytopenia, and Gastrointestinal Bleeding

Case Presentation A 13-year-old Caucasian boy presented with a history of periorificial and acral skin lesions, present since 3 months of age. Family history was unremarkable. Past medical history revealed irritability, growth retardation and hypogonadism. The patient complained of considerable discomfort that hampered walking and routine daily activities. Repeated treatments for atopic dermatitis, widespread candidiasis and psoriasis had been undertaken without clinical improvement. On physical examination, erythematous-desquamative lesions with seborrheic-like features were evident on the face (Fig. 1). Sharply demarcated and mildly infiltrated erythematous and scaling psoriasiform plaques were evident on the wrists and knees (Fig. 2). The palmoplantar areas and the skin folds in the axillary, popliteal, inguinal, and intergluteal regions were also involved, with psoriasiform plaques sometimes showing maceration, erosions and painful fissures. Routine laboratory investigations showed a low alkaline phosphatase level at 90 IU ⁄L (normal range in children: 130–700 IU ⁄L). Multiple microbiologic swabs were negative. Histologic examination of a biopsy from the knee is shown in (Fig. 3).

Successful treatment of refractory Hailey-Hailey disease with a 595-nm pulsed dye laser: A series of 7 cases

REFERENCES 1. Gawkrodger DJ, Ormerod AD, Shaw L, et al. Guideline for the diagnosis and management of vitiligo. Br J Dermatol. 2008; 159:1051-1076. 2. Anbar TS, Westerhof W, Abdel-Rahman AT, El-Khavvat MA. Evaluation of the effects of NB-UVB in both segmental and non-segmental vitiligo affecting different body sites. Photodermatol Photoimmunol Photomed. 2006;22:157-163. 3. Nov ak Z, B onis B, Balt as E, et al. Xenon chloride ultraviolet B laser is more effective in treating psoriasis and in inducing T cell apoptosis than narrow band ultraviolet B. J Photochem Photobiol B. 2002;67:32-38. 4. Bianchi B, Campolmi P, Mavilia L, Danesi A, Rossi R, Cappugi P. Monochromatic excimer light (308 nm): an immunohistochemical study of cutaneous T cells and apoptosis-related molecules in psoriasis. J Eur Acad Dermatol Venereol. 2003;17: 408-413. 5. Morelli JG, Kincannon J, Yohn JJ, Zekman T, Weston WL, Norris DA. Leukotriene C4 and TGF-alpha are stimulator of human melanocyte migration in vitro. J Invest Dermatol. 1992; 98:290-295.

Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease

Background Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor &kgr;B, c‐Jun N‐terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B‐cell expansion with nuclear factor &kgr;B and T‐cell anergy (heterozygous, gain‐of‐function mutations), and severe atopic disease (loss‐of‐function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole‐exome sequencing. Objectives We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss‐of‐function alleles. Methods Cell transfections and primary T‐cell assays were used to evaluate signaling and function of CARD11 variants. Results Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X‐linked–like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled‐coil domains of the CARD11 protein. Conclusion These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

Utility of Wood's light in margin determination of melanoma in situ after excisional biopsy

BACKGROUND Margin evaluation of melanoma in situ (MIS) is difficult because of its ill-defined clinical borders. Woods light examination is commonly used to help delineate MIS margin before excision. OBJECTIVE To prospectively study the accuracy of preoperative Woods light examination for margin assessment of MIS. MATERIALS AND METHODS The authors evaluated 60 patients before excision of MIS under white light and Woods light. Staged excision was performed using the square procedure technique. After achieving clear margins, they compared final wound size with expected wound size if surgical margins had been based on Woods light examination. RESULTS Seven patients (11.7%) had Woods light enhancement beyond the visible margin of the biopsy site. In all 7, increased wounding would have occurred if the surgical margins had been based on Woods light examination. In 1 of the 7, use of the Woods light examination would have reduced the surgical stages needed by 1 stage but would have increased the wound size by 83.3%. CONCLUSION Woods light examination has limited utility if complete excisional biopsy of MIS is performed before treatment. In this study, surgical margin based on the Woods light examination would have resulted in an increased average wound size and would not have reduced the number of stages needed when performing the square procedure.

Red-brown macules in a linear distribution on the arm

A 5-year-old African-American girl presented with a 2-month history of an expanding, mildly itchy rash on her left arm. It had begun on her volar arm and spread to the dorsum of her hand, upper arm, and upper back. Her mother denied involvement of the mouth, palms, and soles. Her symptoms and progression had not responded to hydrocortisone 2.5% cream. The patient’s mother also denied recent illness, trauma to the area, and history of a tick bite, and the patient had not traveled outside of the southeastern United States. She had no functional impairment of the left arm or hand. A recent complete blood count and complete metabolic panel were within normal limits. Her medical history was insignificant, and she had no family history of skin or autoimmune diseases. Physical examination revealed numerous 0.5to 2-cm grouped red-brown macules and patches extending in a linear distribution from the left medial upper back to the left arm, volar forearm, and dorsal hand (Figure 1). There was no induration, atrophy, or scale, and the Darier sign was negative. A punch biopsy was obtained (Figures 2, 3).