Genodermatoses

Genodermatoses

Usefulness of Screening Investigations in Neurofibromatosis Type 1: A Study of 152 Patients

Background.—Neurofibromatosis type 1 (NF1), one of the most com-mon autosomal dominant disorders, is characterized by multiple brown skin macules, intertriginous freckling, iris hamartomas, and multiple skin neurofibromas. The morbidity and mortality associated with NF1 occur after complications that can involve any body system. The efficacy of screening and the best follow-up for patients with NF1 are described.

Methods and Findings.—One hundred fifty-two patients with NF1 were included in the retrospective analysis. Systemic chest radiographs were obtained in 134. Two patients had intrathoracic nodules thought to be neurofibromas. Cerebral imaging was performed in 93 asymptomatic patients, showing optic pathway glioma in 12. Sixty-two asymptomatic patients underwent abdominal ultrasound, which showed internal neurofibromas in 4, 2 of whom had abdominal surgery. In 83 patients without hypertension, 24-hour urinary specific catecholamine labels were assessed, all proving to be normal. Almost 400 systemic investigations were done with no clinical orientation, yielding 21 abnormal findings. These discoveries led to “therapeutic action in only 2 patients. However, 22 complications needing treatment were detected on clinical assessment.

GenodermatosesConclusions.—Patients with NF1 need regular follow-up assessment, as the nature of the disease is unpredictable. Clinical follow-up appears to be more beneficial than systematic studies.

This well-done study compared the benefits of 5 systemic screening investigations with clinical examination alone in the follow-up and management of patients with neurofibromatosis type 1 (NF1). Of 400 systemic investigations (chest x-ray, cerebral imaging, abdominal ultrasonography, ophthalmologic consultation, or urinary catecholamine analysis), 21 abnormalities were detected. In only 2 of these were therapeutic interventions undertaken. Interestingly, these two interventions involved surgical removal of asymptomatic abdominal neurofibromas. In contrast, a thorough history and physical examination revealed 22 complications requiring treatment.
Other than a screening MRI of optic pathways and brain in children less than 6 years of age, screening tests should probably not be performed routinely in the follow-up of NF1 patients. A thorough history and physical examination (including blood pressure measurements) should be done on a yearly basis and when symptomatology warrants.

Inhibitory Effects of Various Vitamin 03 Analogues on the Growth of Cells Isolated From Neurofibromas in Patients With von Recklinghausen’s Neurofibromatosis-1

Introduction.—Cutaneous neurofibromas (NFs) are comprised of nerve and connective tissue-derived cell types, including Schwann cells, perineural cells, and fibroblasts. When NFs are dissociated and subcultured in vitro, the morphology of the cultured cells gradually becomes fibroblastic. The effects of various vitamin D3 analogues on the growth of NF cells isolated from explant cultures of NFs removed from patients with neurofibromatosis type-1 (NF1) were evaluated. The mechanisms of eliciting NFs and the agents that suppress the growth of NF cells were determined.

Methods.—Three patients with NF1 underwent surgical removal of cutaneous NFs. Primary explant cultures were created to isolate NF cells in each patient. Two normal fibroblast cell lines were also studied. Three vitamin D3 analogues were used: calcitriol, 22-oxacalcitriol, and tacalci- tol. Inhibition of cell growth and DNA synthesis were analyzed.

Results.—Each NF cell line demonstrated a different pattern of response to the 3 vitamin D analogues. Vitamin D3 analogues ranged from 40% to 70% in their ability to inhibit NF fibroblast growth. The suppression rate varied in each cell line according to the vitamin D3 analogue used. Time course experiments showed it took 7 days of incubation for agents to employ clear antiproliferative effects on NF cells. Inhibition of DNA synthesis of NF cells by vitamin D3 analogues was detected as early as 2 days after addition of agents to the culture medium. Normal fibroblast growth was inhibited by 10% to 35%.

Conclusions.—Findings indicate that vitamin D3 analogues can cause suppression of the growth of NF cells and normal fibroblasts. Growth inhibition rates in NF cells, but not normal fibroblasts, varied depending on which vitamin D3 analogue was used. Vitamin D3 analogues may be effective in the suppression of growth of NF in patients with NF1.

These in vitro results are clearly preliminary and require in vivo confirmation. Nevertheless, vitamin D3 analogues may hold some potential for sup-pressing growth of neurofibromas.

Skin Abnormalities in Neurofibromatosis 2

Introduction.—Skin tumors in patients with neurofibromatosis 2 (NF2) have received relatively little attention, perhaps because these tumors are small and inconspicuous. A consecutive sample of patients with NF2 was examined for the prevalence, distribution, and type of skin abnormalities.

Methods.—Eighty-one of 88 patients first examined between 1988 and 1995 met the National Institutes of Health criteria for NF2; diagnosis was established in the remaining 7 patients by mutation or segregation analysis. Twenty-five patients had milder disease and 62 had more severe disease. Because penetrance is dependent on age, 1 patient, an asymptomatic child without skin tumors, was excluded from analysis of disease severity. Twenty-nine skin tumors were examined for histopathologic features.

Results.—Fifty-two patients (59.1%) had a total of 458 skin tumors, and these tumors were the initial sign of disease in 24 patients (27.3%). In most cases, the lesions appeared as flat dysplastic tumors or as subcutaneous spherical nodular tumors of the peripheral nerves. Cafe au lait spots were present in one third of patients, but only 2 patients had as many as 6 spots. The prevalence of skin tumors was significantly greater in patients with more severe disease (71%) than in those with milder disease (24%). Compared with patients with milder disease, those with severe disease had a greater prevalence of both flat dysplastic and subcutaneous spherical nodular tumors (54.8% vs. 8.0% and 58.1% vs. 24.0%, respectively). Only patients with severe disease had more than 10 skin tumors. Twenty- three of the 27 patients whose tumors’were examined histologically had more severe disease. Most tumors (75.9%) were schwannomas; 17.2% were neurofibromas and 6.9% were mixed tumors.

Conclusion.—More than half of these patients with NF2 had skin tumors. In many patients with severe disease, skin tumors were the initial sign of NF2. The lesions usually appeared as flat dermal tumors and spherical subcutaneous nodular tumors of the peripheral nerves on the limbs and trunk. Most of the histologically analyzed tumors were schwannomas.

Neurofibromatosis 2 (NF2) is classically associated with bilateral vestibular schwannomas and not with cutaneous neurofibromas. In this report, 29 skin tumors from 22 patients with NF2 were examined histopathologically. Most were, in fact, skin schwannomas. However, neurofibromas—the classic skin tumor associated with NF1—may be the initial presenting sign of NF2, especially in children. Therefore, the presence of cutaneous neurofibromas does not exclude the possibility of NF2.

Fine Mapping of the Locus for Nevoid Basal Cell Carcinoma Syndrome on Chromosome 9q

Purpose.—Nevoid basal cell carcinoma syndrome (NBCCS) is a well- recognized autosomal dominant disorder. Affected patients have multiple basal cell carcinomas (BCCs), palmar and plantar pitting, odontogenic keratocysts, and calcification of the falx cerebri. The incidence of NBCCS is at least 1 in 55,000, and as high as 1 in 5 among patients in whom BCCs develop before age 19 years. The development of BCCs may be precipitated by ionizing radiation, and they most often occur on sun-exposed sites. Previous studies have mapped the gene for NBCCS, which is believed to act as a tumor suppressor gene, to chromosome 9q22. Deletions in the same region are noted in as many as three fourths of sporadic BCCs. Studies to further localize the NBCCS gene are reported.

Methods.—The study included 4 Swedish families with NBCCS, each with at least 2 affected members. All affected patients had at least 2 major features of NBCCS, or 1 major and 2 minor features with an affected first-degree relative. Clinical and radiologic analyses were performed in 13 affected and 35 nonaffected family members. Linkage and haplotype analysis were performed in each kindred.

Findings.—Most patients had multiple NBCCS signs and symptoms. The patients’ mean age was 18 years at the onset of odontogenic kerato-cysts and 29 years at the onset of BCCs. However, 3 children aged 4 to 14 years at the onset of BCCs were identified. Eighty percent of patients had pitting, usually of both the palms and soles. All adults but no children had calcification of the falx cerebri. The only non-BCC tumor was a cardiac fibroma in 1 patient. One patient died of multiple untreated BCCs. The new mutation rate appeared to be 50%. Previous reports localized the NBCCS gene region to 9q22.3, between the microsatellite markers D9S180 and D9S196. The new genetic studies suggested a minimal candidate region of no more than 1 Mb, located between markers D9S280 and D9S287.

Conclusions.—This study significantly narrows the possible localization of the NBCCS gene on chromosome 9q22.3. The authors are testing new markers to further refine the location of this gene. Data on the clinical traits of families with NBCCS are presented as well.

Through linkage analysis, the gene for NBCCS has been mapped to chromosome 9q22.3-31. This gene is believed to function as a tumor sup-pressor gene and is deleted in 50% to 75% of sporadic BCCs, suggesting that it plays an important role in the development of the majority of these tumors. In this study the authors set out to refine the localization of this gene. By various methods of gene analysis they were able to localize the gene between markers D9S280 and D9S287 in the 9q22.3 area. In addition to reviewing current knowledge of the nevoid BCC gene, this article also succinctly reviews the clinical features of this syndrome.