Subcutaneous Neurofibromas Research Articles

Patterns of associations of clinical features in neurofibromatosis 1 (NF1).

Neurofibromatosis 1 (NF1) is a common, fully penetrant autosomal dominant disease. The clinical course is generally progressive but highly variable, and the pathogenesis is poorly understood. We studied statistical associations among 13 of the most common or important clinical features in data from four separate sets of NF1 patients: a "developmental sample" of 1,413 probands from the NNFF International Database, an independent "validation sample" of 1,384 probands from the same database, 511 affected relatives of these probands, and 441 patients from a population-based registry in northwest England. We developed logistic regressive models for each of the 13 features using the developmental sample and attempted to validate these models in the other three samples. Age and gender were included as covariates in all models. Models were successfully developed and validated for ten of the 13 features analysed. The results are consistent with grouping nine of the clinical features into three sets: (1) café-au-lait spots, intertriginous freckling and Lisch nodules; (2) cutaneous, subcutaneous and plexiform neurofibromas; (3) macrocephaly, optic glioma and other neoplasms. In addition, three-way interactions among café-au-lait spots, intertriginous freckling and subcutaneous neurofibromas indicate that the first two groups are not independent. Our studies show that some individuals with NF1 are more likely than others to develop certain clinical features of the disease. Some NF1 features appear to share pathogenic mechanisms that are not common to all features.

Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1).

The relationship of genetic factors to variable expressivity in neurofibromatosis 1 (NF1) is poorly understood. We examined familial aggregation of NF1 features among different classes of affected relatives. Clinical information was obtained from the National NF Foundation International Database on 904 affected individuals in 373 families with 2 or more members with NF1. We used multivariate probit regression to measure the associations between various classes of relatives for each of 10 clinical features of NF1, while simultaneously adjusting for covariates including related features, age, and gender. Two distinct patterns were observed when we compared associations between first- and second-degree relatives, sibs, and parent-child pairs: Lisch nodules and café-au-lait spots had greater associations between first-degree relatives than between second-degree relatives, while subcutaneous neurofibromas, plexiform neurofibromas, café-au-lait spots, and intertriginous freckling had greater associations between sibs than between parents and children. In addition, Lisch nodules, subcutaneous neurofibromas, and cutaneous neurofibromas had greater associations between affected fathers and children than between affected mothers and children. These familial patterns suggest that unlinked modifying genes and the normal NF1 allele may both be involved in the development of particular clinical features of NF1, but that the relative contributions vary for different features.

Unidentified bright objects associated with features of neurofibromatosis 1

Unidentified bright objects are commonly observed on magnetic resonance imaging in young neurofibromatosis 1 patients, but their clinical and pathologic significance is largely unknown. Diagnostic features of neurofibromatosis 1 include café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, bony lesions, and optic glioma. We investigated the relationship between unidentified bright objects and other features of neurofibromatosis 1. Data from the National Neurofibromatosis Foundation International Database included 523 neurofibromatosis 1 patients between 2 and 20 years of age who had cranial magnetic resonance imaging examinations. The presence or absence of unidentified bright objects, diagnostic features of neurofibromatosis 1, and central nervous system neoplasms was known in these patients. Logistic regressive models were used to measure associations between unidentified bright objects and the other features while controlling for age. The occurrence of unidentified bright objects was associated with the number of diagnostic features, but most significantly with central nervous system neoplasms other than optic gliomas [odds ratio (OR) = 9.0, 95% confidence interval (CI) = 1.2-70], optic gliomas (OR = 2.1, 95% CI = 1.2-3.6), subcutaneous neurofibromas (OR = 2.0, 95% CI = 1.3-3.1), and Lisch nodules (OR = 1.6, 95% CI = 1.1-2.3). These findings suggest a common causal mechanism between unidentified bright objects and these cardinal clinical features in children with neurofibromatosis 1.

Neurofibromatosis Type 1: A Diagnostic Mimicker at CT

Neurofibromatosis type 1 (NF1) is the most common of the phakomatoses and has a variety of localized or, more frequently, systemic manifestations throughout the thorax, abdomen, pelvis, and extremities. Classic computed tomographic (CT) findings in NF1 with thoracic involvement include small, well-defined subcutaneous neurofibromas, focal thoracic scoliosis, posterior vertebral scalloping, enlarged neural foramina, and characteristic rib abnormalities due to bone dysplasia or erosion from adjacent neurofibromas. However, more atypical manifestations are occasionally seen, and magnetic resonance (MR) imaging can be useful in equivocal cases. NF1 with abdominopelvic involvement tends to arise in the retroperitoneal, mesenteric, and paraspinal regions; it may be quite extensive and therefore difficult to distinguish from adenopathy at CT. The multiplanar capabilities of MR imaging, particularly with T2 weighting, make this modality helpful in evaluating affected patients and making the diagnosis. The classic peripheral manifestations of NF1 include limb hemihypertrophy, pseudarthrosis, peripheral nerve neurofibromas, and subcutaneous common and plexiform neurofibromas. In some cases of NF1, imaging findings are inconclusive, and biopsy and subsequent pathologic analysis are required. Familiarity with the various manifestations of NF1 in different anatomic locations is important in making the diagnosis and optimizing postdiagnostic treatment.

Café au lait spots: the pediatrician's perspective.

1. Mustafa Tekin, MD* 2. Joann N. Bodurtha, MD, MPH† 3. Vincent M. Riccardi, MD‡ 1. 2. *Clinical Genetics Fellow. 3. 4. †Associate Professor of Human Genetics, Pediatrics, Obstetrics and Gynecology, Virginia Commonwealth University/Medical College of Virginia Hospitals, Richmond, VA. 5. ‡President, The Neurofibromatosis Institute, La Crescenta, CA. Objectives After completing this article, readers should be able to: 1. Define cafe au lait spots typical of neurofibromatosis type 1 (NF1) and describe their frequency and variability in the normal population. 2. List three or more genetic disorders other than NF1 that are associated with cafe au lait spots. 3. Summarize three or more clinical manifestations and molecular bases of NF1 and NF2. 4. List the diagnostic criteria for NF1. 5. Summarize clinical findings of genetic disorders other than NF1 associated with cafe au lait spots. Every pediatrician faces the challenge of deciding if a patient who has cafe au lait (CAL) spots has an underlying genetic condition. CAL spots typical of neurofibromatosis type 1 (NF1) are discrete, round or oval, uniformly hyperpigmented skin patches. Their color varies from light to dark brown, and the border may be smooth or irregular. They usually are smaller in newborns, enlarge as children get older, and are less prominent in adults. The histologic basis of CAL spots is increased melanin content, with the presence of giant melanosomes in both melanocytes and basal keratinocytes and no melanocytic proliferation. The giant melanosomes in CAL spots are not unique to NF1; they can be seen in unaffected skin of adults who have NF1 and occasionally in normal skin of healthy individuals. Therefore, the presence of giant melanosomes is not helpful for diagnosing NF1. The frequency and number of CAL spots vary in the general population according to ethnic background and age. Sometimes otherwise healthy children who have red hair and often are of Irish or Welsh background have multiple areas of patchy hyperpigmentation. Similarly, multiple patchy areas of hyperpigmentation can occur in healthy children who have mixed ethnic backgrounds in which two parents have very different skin colors. CAL spots were noted in 0.3% of Caucasians and 18% of African-Americans …

A Case of Lung Cancer associated with von Recklinghausens Disease

Von Recklinghausen's disease is an autosomal dominant hereditary disease associated with characteristic cafe-au-lait spots of skin and multiple neurofibromatosis. It is complicated by malignancies, which in most cases is neurofibrosarcoma. The development of lung cancer in von Recklinghausen's disease is rare. A 61-year-old male was admitted for cough and sputum for 20 days. He had multiple cafe-au-lait spots and subcutaneous neurofibromas in whole body area and Lisch nodules in both iris and he had been diagnosed von Recklinghausen's disease 35 years ago. Chest radiography showed emphysematous bullae in both upper lung field and mass in right upper lung field. Chest CT scan revealed subcarinal lymph node enlargement. Bronchoscopic biopsy was done in mass in superior segment of right lower lobe and the results showed squamous cell carcinoma. The presence of von Recklinghausen's disease and lung cancer are noteworthy.

Malignant peripheral nerve sheath tumor(malignant schwannoma) of urinary bladder in Von Recklinghausen neurofibromatosis

Von Recklinghausen neurofibromatosis occurs in 1 in 3,000 live births; however, urologic manifestations are rare. There have been over 40 reported cases of neurofibroma of the bladder. Malignant degeneration of subcutaneous neurofibroma occurs in about 5 to 10 percent of patients. We believe we present the second reported case of a malignant peripheral nerve sheath tumor involving the bladder in a patient with this disorder.

Axons induce differentiation of neurofibroma Schwann-like cells

Neurofibromatosis type 1 (NF-1, von Recklinghausen's disease) is characterized by the focal accumulation of Schwann-like cells (SLC) to form subcutaneous and plexiform neurofibromas and schwannomas. The aim of the present study was to determine whether NF-SLC are competent to differentiate in the presence of axons. Five dermal neurofibromas from five patients with NF-type 1 were enzymatically dissociated and the resultant cells were co-cultured with fetal rat dorsal root ganglion neurons. The cultures were studied by indirect immunofluorescence microscopy using antibodies against galactocerebroside (galC), P0 glycoprotein, human nerve growth factor receptor (NGFR) and human myelin-associated glycoprotein (MAG). SLC were strongly NGFR+ but galC- and MAG-SLC for the 2 weeks of coculture. After 3 weeks in vitro, SLC-NGFR was down-regulated but some of the spindle shaped cells had become galC+. MAG-SLC first appeared after 5 weeks in vitro but P0 glycoprotein was never detected when studied up to 6 weeks. Our data demonstrate that axons induce SLC to down-regulate surface NGFR and to express some myelin components in a qualitatively normal fashion.

Neurofibromas: location by scanning with Tc-99m DTPA. Work in progress.

The accumulation of technetium-99m diethylenetriamine pentaacetic acid (Tc-99m DTPA) in benign soft-tissue neurofibromatosis tumors is reported. In a series of 16 patients with clinical stigmata of neurofibromatosis, 28 sites of abnormal soft-tissue localization of the isotope observed scintigraphically were documented to be sites of soft-tissue tumor by clinical and/or radiographic (predominantly computed tomographic) correlations. The smallest lesion detected was a 1.5-cm subcutaneous neurofibroma. Normal physiologic nonrenal distribution of the Tc-99m DTPA was established by scintigraphic imaging of a control population.

Neurofibromatous scoliosis. Natural history and results of treatment in thirty-seven cases

Of 400 patients with the diagnosis of neurofibromatosis on their hospital records, 141 actually had the disease. The presence of at least two of the following features was considered diagnostic: positive family history; positive biopsy; a minimum of six cafe-au-lait spots, each with a diameter of at least 1.5 centimeters; and multiple subcutaneous neurofibromas. Scoliosis was present in thirty-seven patients (26 per cent), most commonly associated with cafe-au-lait spots (thirty-five patients). In many of the patients with scoliosis there were associated medical and surgical problems. Although no standard pattern of spinal deformity could be identified, a sharp single right thoracic curve involving more than five vertebrae was the most common. For the whole group the initial measurement of the scoliosis averaged 42 degrees. Double curves were more sever, buth kyphosis was uncommon and no cases of paraplegia were recorded. In patients with progressive scoliosis, the best results were obtained with early Harrington instrumentation and posterior spine fusion. Progression of the scoliosis was observed both before treatment and postoperatively. The amount of progression was not necessarily related to the severity of other manifestations of neurofibromatosis, and was not significantly dependent on the length of the curve.

Late Effects of 32 MeV Proton Irradiation in Primates

Studies on the long-term cutaneous effects of 32 MeV protons were conducted on rhesus monkeys after single entire body-surface exposures of 280-1880 rad. Radiation doses of 990-1880 rad produced incapacitating subcutaneous fibrosis and skin ulcers of such severity that the monkeys were killed 10-30 months postirradiation. The lesions in monkeys that received 990 rad were late developing as the monkeys did not experience significant acute radiation skin reactions. One 990-rad animal also developed a subcutaneous neurofibroma. Other than a mammary carcinoma in a 560-rad animal all monkeys that received 560 or 280 rad have not exhibited significant lesions up to 4 years postirradiation.

ELEPHANTIASIS NEUROMATOSA

VON RECKLINGHAUSEN'S disease, or multiple neurofibromatosis, is a form of congenital dysplasia manifested by developmental changes in the nervous system, the skin, the bones, and the muscle. The disease is frequently familial and may be associated with endocrine imbalance, muscle weakness, or paralysis due to involvement of the cerebrospinal system. Cutaneous lesions may be divided into three general types: (1) café-au-lait spots associated with freckles or hyperpigmentation; (2) molluscum fibrosum—superficial dermal tumors caused by proliferation of the connective tissue of peripheral nerve sheaths, and (3) subcutaneous neurofibroma, distorting the skin contour. Nervous involvement is due largely to the dominant tissue of the nerve sheath—neurectodermal Schwannian syncytium.¹Although there is a controversy as to the origin of the connective tissue, the majority opinion indicates that the Schwann sheath cells are the source of the connective tissue, causing neurofibrotic growths which may involve one nerve, a sheath or a plexus of