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A 60-year-old white woman with generalized neurofibromatosis and multiple melanocytic hamartomas of the iris developed an unusual choroidal mass, with secondary sensory retinal separation in the left eye. Ophthalmoscopically the tumor had a peculiar donut configuration that was caused by a large focus of central necrosis within a spindle B melanoma.
Two patients with coexisting neurofibromatosis and hyperparathyroidism are described, bringing the total number of such cases in the world literature to seven. Other more classic examples of the association of tumorous conditions of neuroectodermal and entodermal origin are discussed to support the suggestion that the association of these two diseases may be another variant of multiple endocrine neoplasia type 2 (MEN2b). It may be clinically profitable to investigate all patients with either disease in order to uncover their coexistence.
Cellular fractionation of GTPase activating protein (GAP) activity using bovine cerebral cortex revealed that about half of GAP activity was found in membrane fraction. GAP activity of membrane was not solubilized with 0.5% (v/v) triton X-100 and was immunoprecipitated with antibody against carboxy-terminus of neurofibromatosis type 1 (NF1) gene product. In contrast, soluble GAP activity was precipitated with antibody against GAP but not with anti-NF1. These results suggest that NF1 gene product is a GTPase activating protein toward ras p21 with completely different intracellular distribution from that of GAP.
Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder. A part of the gene for NF1 was cloned and its deduced protein has a domain functionally related to mammalian ras GTP-ase-activating protein (GAP). Human tissues examined express two types of NF1 mRNAs: an originally identified species of NF1 mRNA (type I) and another one containing the 63 base insert in the region coding for GAP-related domain (type II). However relative levels of both mRNAs seem to change under certain conditions. Human brain expresses type I mRNA predominantly, while type II is preferentially expressed in most primary brain tumors (13/16 tumors analyzed). We suggest that higher levels of type II mRNA may be related to the genesis of brain tumors.
A second NF1 messenger differing in the GAP domain was recently described. This type II transcript contains an internal additional sequence consisting of an open reading frame, in phase with the preceding and the following sequences and predicts a 21 amino acid addition in the catalytic domain of NF1 protein. In this report we present analysis of the two forms of NF1 transcripts in several normal human tissues and in primary neurofibromatosis tumors. Our results indicate (i) that the type II NF1 messenger displaying the additional exon is very widely expressed in all the normal adult tissues tested, (ii) that it is the form of NF1 messenger expressed in peripheral nerve and neurofibromas, and (iii) that the additional sequence could encode for a peptide related to a nucleoside triphosphatase.
Experience with surgical management of cranio-orbital neurofibromatosis in 11 patients is reported. The surgery has a relatively high complication rate compared with craniofacial procedures for other conditions. The presence of an eye which is to be preserved in the orbit introduces difficulties in producing improved appearance without compromising corneal cover. A two-stage approach is recommended when an eye is present. The cosmetic improvements have been disappointing to the surgical team but generally worthwhile to the patients and their families.
The critical function of the neurofibromatosis type 1 (NF1) gene product (neurofibromin) is not well defined except that neurofibromin has homology with a family of the GTPase-activating proteins (GAPs). In this study, we confirmed that neurofibromin is constitutively phosphorylated and detected kinase activities which specifically phosphorylate the cysteine/serine-rich domain and the C-terminal domain of the neurofibromin in cell lysate. In vitro and in-gel kinase assays strongly indicated that cAMP-dependent protein kinase (PKA) is a candidate for the neurofibromin kinase. THe biological significance of the phosphorylation of neurofibromin is unclear at present, but we speculate that neurofibromin plays a crucial role in cellular function since it links the two major cellular pathways which are the GAP-ras and PKA-associated signals.
Liver involvement by neurofibromatosis is rare. This report describes a young man with von Recklinghausen's disease and hepatic neurofibromas who developed a large right hepatic lobe malignancy and died of massive intratumor hemorrhage. Postmortem examination showed the tumor to be composed of both malignant schwannoma and angiosarcoma and to have arisen from contiguous neurofibromas in portal tracts. Widespread pulmonary metastases consisted of the angiosarcomatous elements alone. The expression of malignant schwannoma and angiosarcoma phenotypes in this tumor may be related to a common histogenesis from cells of the neural crest.
An infant is reported in whom severe malabsorptive symptoms developed shortly after birth associated with intermittent episodes of intestinal obstruction. Plexiform neurofibromatosis involving the terminal ileum was found at laparotomy at the age of 6 mo. The infant died from gastrointestinal functional impairment at the age of 1 yr.
We report a case of clitoral and renovascular involvement of neurofibromatosis resulting in an enlarged phallus with juvenile hypertension. The patient was successfully treated by removal of the clitoral tumor and nephrectomy. This is the first of 15 reported cases with clitoral involvement, that showed concurrent renovascular hypertension.
Intellectual problems are a recognized feature of neurofibromatosis 1 (NF1) but their aetiology is unknown. We investigated the frequency, nature, severity and cause of intellectual impairment in NF1. We undertook neurological and psychometric assessments on 103 patients with NF1 and 105 controls equated for age, sex and socio-economic status. The mean full scale IQ was significantly lower in the NF1 than the control group, 88.6 (SD 14.6) compared with 101.6 (SD 14.2). However, the degree of intellectual impairment was mild and only 8% of NF1 patients had an IQ < 70. The NF1 patients also had significantly poorer reading skills and impaired short term memory. On a computerized performance test battery of complex tasks, the NF1 group had significantly slower mean reaction times and higher error rates than the controls. Overall the patients displayed impaired attention and were slow to develop and adapt strategies for complex and unfamiliar tasks. A particular profile of intellectual deficit did not emerge. The presence of neurological and/or medical complications was weakly associated with a lower mean full scale IQ in NF1 patients. Socio-demographic factors, age or sex differences and the presence of macrocephaly did not contribute to neurocognitive deficit in NF1.
Oral manifestations of multiple neurofibromatosis are not rare; manifestations in the facial skeleton have been reported. However, radiographic changes of the alveolar bone are rare. A review of the literature and an interesting case are presented.
One of the most feared complications of neurofibromatosis type I (NF-I) is development of cancer, which is estimated to occur in about 5% of cases. The most common associated malignancy is the neurofibrosarcoma (NFS). HOwever, oral NFS in association with NF-I has rarely been reported. We report two cases of oral NFS arising in patients with NF-I. Both patients died of their tumors. Oral NFS arising in association with NF-I appears to have an extremely poor prognosis, as do these tumors at other sites of the body.
The ocular and systemic manifestations of von Recklinghausen's neurofibromatosis are reviewed. A case is presented illustrating widespread involvement and the typical histopathologic changes of the eye and the ocular adnexa. The ophthalmologist should be aware of broad scope of this disorder so that a complete evaluation of the patient can be made.
With an occurrence of approximately 1 in 3000 births, von Recklinghausen neurofibromatosis (NF) is one of the most common inherited human disorders. NF is considered a neurocristopathy, a disorder of neural crest derived cells. One of the complications of NF is the development of neural crest derived malignancies such as malignant schwannoma, pheochromocytoma, and malignant melanoma of the skin and choroid. The case history of a patient with NF and conjunctival malignant melanoma which developed in an eye with primary acquired melanosis is yet another example of a neural crest malignancy developing in a NF patient.
A 14-year-old male adolescent presented with progressive enlargement of the forehead and a history of familial neurofibromatosis. Plain x-ray films of the skull, computed tomography scanning, and carotid angiography were performed prior to removal of the tumor. Pathologic verification of an ectopic subgaleal meningioma prompted the report of this rare tumor.
A review of 158 cases of multiple meningiomas reported in the literature and 7 additional cases are presented. The average incidence of multiple meningiomas is 2.5% of all meningiomas. In the absence of cutaneous manifestations of von Recklinghausen's disease, it is extremely difficult to distinguish between cases associated with central neurofibromatosis and those representing true multiple meningiomas. There are no specific pathognomonic features that distinguish true multiple meningiomas as a separate disease entity.
A case of primary intracranial malignant melanoma of the left gasserian ganglion associated with temporal lobe gliosis in a patient suffering from von Recklinghausen's disease is reported. The association of primary malignant melanoma of the trigeminal nerve and neurofibromatosis is discussed.