Vincent M. Riccardi

Von Recklinghausen Neurofibromatosis

Neurofibromatosis is of great importance not only to the thousands of affected patients and their physicians but also to researchers concerned with genetics, melanin synthesis, neural-crest embryol...

Deletions of Chromosome 15 as a Cause of the Prader–Willi Syndrome

THE Prader–Willi syndrome consists of muscular hypotonia, obesity, short stature, small hands and feet, hypogonadism, and mental retardation. Although an autosomal-recessive mode of inheritance has...

von Recklinghausen Neurofibromatosis: II. Incidence of Optic Gliomata

The association of optic glioma with von Recklinghausen neurofibromatosis (NF) is well established. However, the incidence of these tumors in a large population of NF patients, prospectively evaluated with modern radiologic techniques, has not been established. We investigated the ophthalmic and intracranial features of NF in 217 patients aged 4 weeks to 69 years, in whom the diagnosis was based on stringent criteria. Tumors at various locations along the anterior visual pathway occurred in 15% of patients and were occasionally bilateral. The mean age of patients with chiasmal tumors was approximately 15 years less than patients with tumors of the optic nerve only. Two-thirds (67%) of all tumors were neither suspected historically nor detected by ophthalmologic examination. Neither the ophthalmoscopic absence of optic atrophy nor the normal results of roentgenograms of the optic foramina were reliable predictors of tumors detected by CT scan. The presence of optic glioma is not correlated to other ocular, skeletal, neurologic, or anamnestic risk factors.

An Absence of Cutaneous Neurofibromas Associated with a 3-bp Inframe Deletion in Exon 17 of the NF1 Gene (c.2970-2972 delAAT): Evidence of a Clinically Significant NF1 Genotype-Phenotype Correlation

Neurofibromatosis type 1 (NF1) is characterized by cafe-au-lait spots, skinfold freckling, and cutaneous neurofibromas. No obvious relationships between small mutations (<20 bp) of the NF1 gene and a specific phenotype have previously been demonstrated, which suggests that interaction with either unlinked modifying genes and/or the normal NF1 allele may be involved in the development of the particular clinical features associated with NF1. We identified 21 unrelated probands with NF1 (14 familial and 7 sporadic cases) who were all found to have the same c.2970-2972 delAAT (p.990delM) mutation but no cutaneous neurofibromas or clinically obvious plexiform neurofibromas. Molecular analysis identified the same 3-bp inframe deletion (c.2970-2972 delAAT) in exon 17 of the NF1 gene in all affected subjects. The Delta AAT mutation is predicted to result in the loss of one of two adjacent methionines (codon 991 or 992) ( Delta Met991), in conjunction with silent ACA-->ACG change of codon 990. These two methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. Our data represent results from the first study to correlate a specific small mutation of the NF1 gene to the expression of a particular clinical phenotype. The biological mechanism that relates this specific mutation to the suppression of cutaneous neurofibroma development is unknown.

Malignant peripheral nerve sheath tumors in neurofibromatosis 1

One of the most clinically aggressive cancers associated with neurofibromatosis 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST). To determine the incidence and relative risk (RR) of MPNSTs in individuals with NF1, 1,475 individuals with NF1 were included from a cohort of patients examined by a single experienced geneticist from 1977 to 1996. The end points were incidence of MPNST, relative risk of MPNST, and relative risk associated with specific NF1 physical findings. Thirty-four individuals were identified with MPNST (2%). The relative risk of MPNST was higher than expected with an RR value of 113 (95% confidence interval [CI] = 78-158). The average 10-year annual incidence of MPNST between the second and fifth decade of life was roughly the same with a range of 0.0013 and 0.0068 MPNST per patient year. Most lesions occurred in the limbs (n = 18; 53%), and those with limb lesions survived longer than those with nonlimb MPNSTs. Pain associated with a mass was the greatest risk factor associated with MPNST development (RR = 31.4; 95% CI = 13.2-75.1). Further biological and epidemiological studies are needed to determine other factors that influence the risk of MPNST development in individuals affected with NF1. Am. J. Med. Genet. 93:388-392, 2000. Published 2000 Wiley-Liss, Inc.

von Recklinghausen Neurofibromatosis: Incidence of Iris Hamartomata

The results of a prospective survey of the ophthalmic manifestations of neurofibromatosis (NFT) have never been published. We studied the ocular features of NFT in 77 patients (ages 5 weeks to 69 years) among whom the diagnosis was made by nonophthalmic parameters. Of subjects ages 6 years and older, 92% had hamartomatous lesions of the iris, termed Lisch nodules, as distinguished from common iris nevi in nonaffected individuals. The presence of Lisch nodules is correlated to age, but not to number of cafe-au-lait spots, number of neurofibromata, or severity of disease. Lisch nodules appear among prepubertal children and are apparently unique to NFT. They are a valuable criterion by which to diagnose NFT in problematic cases.

The aniridia-Wilms tumor association: The critical role of chromosome band 11p13

Abstract The role of del (11)(p13) as a cause of aniridia, with and without Wilms tumor, is strengthened by demonstration of this chromosome aberration in 3 patients: monozygous twin girls, both of whom have aniridia and mental retardation and one of whom has a Wilms tumor; and an unrelated boy with aniridia and ambiguous genitalia. The break points defining the interstitial deletion for the twins are 11p13 and 11p15.1, while for the boy they are 11p1302 and 11p14.1. These patients and their karyotypes substantiate the critical importance of chromosome band 11p13 (or its hemizygous representation) in the development of aniridia and an associated Wilms tumor diathesis, as had been suggested previously (Riccardi VM, Sujansky E, Smith AC, Francke U, (1978): Pediatrics 61, 604-610).

Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes

SummaryAn interesting feature of neurofibromatosis type 1 (NF1) is its high mutation rate of 1×10−4 per gamete per generation. The molecular basis for frequent NF1 mutation in unknown; the gene is not deletion prone. We have found that in all ten families examined, the apparent new NF1 mutation occurred on the paternally-derived chromosome. The probability of observing this result by chance is less than 0.001 assuming an equal frequency of mutation of paternal and maternal NF1 genes. We hypothesize a role for genomic imprinting that may either enhance mutation of the paternal NF1 gene or confer protection from mutation to the maternal NF1 gene.

Neurofibro matosis: Oral and radiographic manifestations

Oral manifestations of neurofibromatosis have been reported in only 4% to 7% of affected persons. All oral tissues, hard and soft, have been reported to be affected with tumors, but the tongue has been the most common site. We report on the oral and radiographic findings in twenty-two patients with neurofibromatosis. The prevalence of oral and radiographic findings in our sample was 72%, which is much higher than previously reported. The five most common findings are oral neurofibromas, enlarged fungiform papillae, intrabony lesions, wide inferior alveolar canals, and enlarged mandibular foramina.

Pathophysiology of neurofibromatosis: IV. Dermatologic insights into heterogeneity and pathogenesis***

A systematic, uniform evaluation of 102 patients with, or at risk for, neurofibromatosis has shown that café au lait spots (CLS), even in large numbers, may not be sufficient to diagnose this disorder, and that several other dermatologic features may provide clues to its pathogenesis. These features include pruritus associated with high concentrations of cutaneous neurofibromas, hyperpigmentation overlying plexiform neurofibromas, two levels of hyperpigmentation in some CLS, hypopigmentation in surgical scars through CLS, and areolar neurofibromas in postpubertal females. Iris Lisch nodules (hamartomas) are present in 97% of postpubertal patients.