Somatic mosaicism: a common cause of classic disease in tumor-prone syndromes? Lessons from type 2 neurofibromatosis

Blood samples from 125 families with classic type 2 neurofibromatosis with bilateral vestibular schwannomas were analyzed for mutations in the NF2 gene. Causative mutations were identified in 52 families. In five families, the first affected individual in the family (the index case) was a mosaic for a disease-causing mutation. Only one of nine children from the three mosaic cases with children are affected. Four of these nine children inherited the allele associated with the disease-causing mutation yet did not inherit the mutation. NF2 mutations were identified in only 27/79 (34%) of sporadic cases, compared with 25/46 (54%) of familial cases (P<.05). In 48 families in which a mutation has not been identified, the index cases have had 125 children, of whom only 29 are affected with NF2 and of whom only a further 21 cases would be predicted to be affected by use of life curves. The 50/125 (40%) of cases is significantly less than the 50% expected eventually to develop NF2 (P<.05). Somatic mosaicism is likely to be a common cause of classic NF2 and may well account for a low detection rate for mutations in sporadic cases. Degrees of gonosomal mosaicism mean that recurrence risks may well be <50% in the index case when a mutation is not identified in lymphocyte DNA.     

Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado-Joseph disease

Glucocorticoids (GC) are widely used for anti-inflammatory and immunosuppressive therapy. Thirty to 50% of GC-treated patients develop osteoporosis. Potential mechanisms of GC-induced osteoporosis (GC-OP) include abnormalities in calcium balance, vitamin D metabolism, parathyroid hormone release and activity, prostaglandin E2 and cytokine synthesis, interference with c-fos and p-53 expression in osteoblasts, and hypogonadism. Early diagnosis and detection of patients at risk are accomplished with rapid, safe and non-invasive bone density measurements. Preventive measures include maintaining a positive calcium balance, vitamin D supplementation (if indicated) and treatment of hypogonadism. The shortest duration and the smallest doses possible of GC for a particular condition are advisable. For high-risk patients and those with established GC-OP calcitonin or bisphosphonate therapy is recommended.     

Cortical dysgenesis in a patient with Turner mosaicism

BACKGROUND: Although there is increasing interest in the use of glycolic acid in the treatment of photoaged skin, to our knowledge, no controlled study has been done to assess the efficacy or the mode of this agent. OBJECTIVE: The purpose of this study was to determine whether 50% glycolic acid can improve photoaged skin and to study the histological basis for this improvement. METHODS: Forty-one volunteers were recruited into this double-blind vehicle-controlled study. Glycolic acid (50%) or vehicle was applied topically for 5 minutes to one side of the face, forearms, and hands, once weekly for 4 weeks. Punch biopsies were taken at pretherapy and at 5 weeks for histologic study. RESULTS: Significant improvement noted included decrease in rough texture and fine wrinkling, fewer solar keratoses, and a slight lightening of solar lentigines. Histology showed thinning of the stratum corneum, granular layer enhancement, and epidermal thickening. Some specimens showed an increase in collagen thickness in the dermis. CONCLUSION: The results of this study demonstrate that the application of 50% glycolic acid peels improves mild photoaging of the skin.     

Peripheral retinal vascular occlusive disorder in a young patient with neurofibromatosis 1

The mosquitos collected in Smolensk and Kaluga provinces in 1985 by the expedition team of the D. I. Ivanovski? Institute of Virology were identified by V. N. Danilov in 1986. Among the females of mosquitos collected in Smolensk Province four genera and 16 species were recorded; two genera (Culiseta, Mansonia) and 9 species were new ones for this region. Taking in account the reference data (excluding Anopheles hircanus and Aedes behningi, the presence of which here is doubtful) there 22 species of mosquitos of five genera (Anopheles--3, Aedes--16, Mansonia, Culiseta, Culex--one of each) are recently known in Smolensk Province. Among the females of mosquitos collected in Kaluga Province, two genera and 8 species were found including one genus (Mansonia) and three species being a new ones for this region. Together with the reference data, there 17 species of mosquitos of four genera (Anopheles--2, Aedes--13, Mansonia, Culex--one of each) are known now for Kaluga Province.     

Cognitive control in adolescents with neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a genetic disorder characterized by partial loss of growth control that affects the central nervous system. NF1 has been consistently associated with cognitive dysfunction, although there is no consensus on the cognitive profile in NF1 or on brain-cognition relationships. To clarify the pattern of cognitive dysfunction, performance of 16 NF1 patients and 16 age- and sex-matched controls (mean age = 14.5 years, SD = 1.3) was compared on computerized tasks measuring perception, executive functioning (inhibitory control, cognitive flexibility, and working memory), and motor control. A further aim of this study was to contrast performance on tasks or task parts requiring varying levels of cognitive control to find out whether this could explain potential difficulties experienced by this population in different cognitive domains or at different stages of information processing. Repeated measures analyses of variance showed that group differences, indicating poorer performance of NF1 patients, varied as a function of the level of cognitive control required. Evidence was also found for more basic motor skill problems in NF1 patients. Furthermore, NF1 patients were generally slower than controls. Results are discussed in the context of what is known about brain-cognition relationships in NF1. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Unusual form of recurrent giant cell granuloma of the mandible and lower extremities in a patient with neurofibromatosis type 1

The high resolution of capillary zone electrophoresis/mass spectrometry (CZE/MS) offers a promising technique to characterize biomolecules in pharmaceutical and biotechnology industries. A novel capillary zone electrophoresis/electrospray ionization time-of-flight mass spectrometry (CZE/ESI-TOFMS) interface was designed in this study to successfully integrate ESI-TOFMS, nanospray, and CZE for biomolecular identification. The interface offers a novel way to take advantage of the high resolution separation achieved during CZE and the detection sensitivity of nanospray ESI-MS. The results showed mixtures of peptides were highly resolved within a few minutes (each CZE electropherogram of a peptide is 2-3 seconds). The novel CZE/ESI-TOFMS interface may simultaneously provide sensitivity, data acquisition speed, mass range, and mass resolution while maintaining resolution of the CZE separation.     

NF1 (neurofibromatosis type 1)

Several distinct Ras GTPase activating proteins (GAPs) from mammals, including Ras GAP of 120 kDa (GAP1) and NF1, stimulate the intrinsic GTPase activity of normal Ras, but not oncogenic Ras mutants (Trahey and McCormick, 1987). That is the reason why normal Ras remains predominantly in the inactive GDP-bound form (D-Ras), whereas oncogenic Ras remains constitutively in the active GTP-bound form (T-Ras). NF1 is a tumor suppressor of 2818 amino acids whose disruption or deletion causes brain tumors called neurofibromatosis type 1 by elevating the T-Ras level. T-Ras activates several distinct oncogenic effectors, including Ser/Thr kinase Raf, GAP1, P1-3 kinase, PKC-zeta and Ra1 GDS. Interestingly, the binding of T-Ras to either GAPs or these oncogenic effectors requires the same effector domain I (residues 32-40) of T-Ras molecule. In other words, these GAPs and effectors compete for binding to T-Ras. Using a series of N- and C-terminal deletion mutants of NF1, we identified a 78 amino acid fragment (NF78, residues 1441-1518) as the minimum GAP domain, and a 56 amino acid fragment (NF 56, residues 1441-1496) as the minimum Ras-binding domain. Furthermore, we identified the Raf fragment of 81 amino acids (Raf81, residues, 51-131) as the minimum Ras-binding domain with a high affinity. We found that (i) these NF1 fragments and Raf81 compete for binding to T-Ras, and that (ii) over-expression of these NF1 or Raf fragments strongly suppresses the malignant transformation caused by oncogenic Ras mutants. Thus, these agents offer a unique opportunity to control the proliferation of T-Ras-associated tumors that represent more than 30% of all human carcinomas including neurofibromatosis type 1.     

Dysembryoplastic neuroepithelial tumors in two children with neurofibromatosis type 1

The quality of clinical trials in Japan has been improving through clear protocol preparation, improvements in methodology, coordinating systems, and so forth. In order to further improvement, the following are discussed: 1) dilemmas regarding adherence of treatment determined by protocol, 2) hospital policy and physician's discretion, 3) systems to support randomized controlled trials in hospital, and 4) systems to help obtain informed consent from subjects.     

Turner's syndrome--case report of a female patient with chromosome mosaicism

A 45-year old woman with the typical Turner's phenotype (short stature, short and broad neck, shield chest and low hairline) and signs of ovarian failure started at the age of 37 with menopause at the age of 44, is presented. The cytogenetic analysis showed the presence of three different cell lines with 45,X, 46,XX and 47,XXX karyotypes. It is a rare type of mosaicism, combining Turner's and triple-X syndrome. Interestingly, the became pregnant and gave birth to a healthy child. Second pregnancy resulted in a miscarriage in the first trimester.     

Intraosseous malignant peripheral nerve sheath tumor in a patient with neurofibromatosis

Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon sarcomas that almost always arise in soft tissue. They can develop in pre-existing neurofibromas or schwannomas, de novo from peripheral nerves, or following radiation therapy. Primary intraosseous MPNST is rare and has been reported most frequently in the mandible. Of the reported cases involving the long bones, none has been associated with neurofibromatosis type 1 (NF-1). We report a case of MPNST arising in the femur in a patient with NF-1.     

Magnetic resonance imaging lesion analysis in neurofibromatosis type 1

The purpose of this prospective study was to investigate the clinical outcome and marginal bone resorption of three different endosseous implants placed in the anterior mandibles of 15 elderly patients. Eleven women and 4 men (ranging from 65 to 80 years, mean 71 years) had three different endosseous implants placed in the anterior mandible; one titanium plasma-sprayed cylinder implant (4-mm diameter), one titanium cylinder implant with hydroxyapatite coating (4-mm diameter), and one standard threaded titanium implant (3.75-mm diameter). Three months later, at the second-stage surgical procedure, ball abutments were connected and an overdenture was placed. At 12, 24, and 36 months, marginal bone resorption and Periotest values were recorded. None of the implants was lost in this period. An analysis of variance with repeated measurement was performed annually to test the existence of significant differences between the implants. When differences appeared, paired t tests were used to identify which differences were significant. Bonferroni multipliers were used to adjust for multiple testing. When marginal bone resorption was concerned, threaded titanium and hydroxyapatite-coated implants had significantly better scores than titanium plasma-sprayed cylinder implants. Periotest values for hydroxyapatite-coated implants were significantly better than test values for the other implants after 2 years. After 3 years significance was obtained between hydroxyapatite and screw-shaped implants only (P < .05). It was concluded that titanium plasma-sprayed cylinder implants have a less favorable prognosis than the other implants used in this study.     

Disappearing enhancing brain lesion in a child with neurofibromatosis type I

Neurofibromatosis type 1 (NF1) in children can produce a variety of parenchymal signal abnormalities on cranial MR. Areas of abnormal signal in these patients may represent regions of disordered myelination, "hamartomatous" change or frank neoplasia. The presence of contrast enhancement in intracranial lesions in patients with NF1 is usually strongly suggestive of tumor. We report the case of a child with NF1 and a focal enhancing brain parenchymal lesion which spontaneously resolved without specific therapy.     

Intrathoracic vagus nerve neurofibroma and sudden death in a patient with neurofibromatosis

A 21 year old man with type 1 neurofibromatosis was found dead in the middle of the night. Postmortem examination revealed a large neurofibroma arising from the right intrathoracic vagus nerve, which might have contributed to his sudden death.     

Somatic mosaicism of p(CTG)n expansion in a case of myotonic dystrophy with parotid tumor

Myotonic dystrophy (MD) is an autosomal dominant systemic disorder with an unstable expansion of the CTG triplet repeat in the 3'-untranslated region of the gene encoding myotonine protein kinase (DMPK) which maps to chromosome 19q13.3. Somatic mosaicism of CTG repeats in MD has been reported; and it has been observed that CTG repeats in tumor tissues associated with MD are more expanded than the other tissues. It is not rare that parotid tumors are found in patients with MD. We performed Southern blot analysis for tissues from the parotid tumor, the normal parotid gland, the skeletal muscles, and the leukocyte from a 60-year-old patient with MD. CTG repeat was most expanded in the parotid tumor, and the normal parotid gland had longer expansion of CTG repeat than the skeletal muscles. The leukocyte had the shortest expansion of CTG repeat. The expansion of CTG repeat in the parotid tumor may be related to active cell division and may underlie the occurrence of tumors in MD.     

A cytogenetic deletion, del(17)(q11.22q21.1), in a patient with sporadic neurofibromatosis type 1 (NF1) associated with dysmorphism and developmental delay

Pure primary ovarian carcinoid tumors are uncommon and only 21 cases have been recorded in the literature. In the past 15 years, we have seen two cases. One was a strumal carcinoid and the other, the case presented here, was a primary ovarian carcinoid tumor arising from the left ovary of a 25-year-old woman who had no carcinoid syndrome. The tumor was made up of pure carcinoid tumor without other teratomatous elements. On light microscopy the neoplasm, composed of uniform tumor cells, was arranged in solid nests or a trabecular pattern. The differential diagnosis included granulosa cell tumor. However, the strongly argyrophilic, chromogranin staining and ultrastructural presence of neurosecretory granules confirmed the diagnosis of primary ovarian carcinoid tumor. After a careful survey of the contralateral ovary and the gastrointestinal tract, the patient underwent a left oophorectomy. Her postoperative course was uneventful. The literature and the pathologic findings are reviewed and discussed, along with the differential diagnosis and treatment of primary ovarian carcinoid tumor.     

Cutaneous manifestations of type 1 neurofibromatosis and their treatment

After recalling the frequency and pathophysiology of type 1 neurofibromatosis, or Von Recklinghausen disease, the authors report the various cutaneous manifestations: café-au-lait spots, lentigines, cutaneous neurofibromas, plexiform neurofibromas. Treatment must be multidisciplinary, as surgery is difficult and often gives disappointing results. The various surgical treatments are considered according to the type and site of the lesions to be treated, with particular emphasis on the treatment plan, which must be discussed with the patient.