Familial cafe au lait spots: a variant of neurofibromatosis type 1.

Abeliovich, Dvorah; Gelman-Kohan, Z; Silverstein, Shira; Lerer, Israela; Chemke, Juan; Merin, Saul; Zlotogora, Joël

doi:10.1136/jmg.32.12.985

Cited by 48 publications

(34 citation statements)

References 5 publications

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“…In general, little evidence has been found of allele-phenotype correlations in NF1, although a more or less consistent phenotype occurs in association with deletions involving the entire NF1 gene (Tonsgard et al 1997;Dorschner et al 2000). Similar clinical features have been observed among affected members of a few families with the NF1 variants Watson syndrome (Allanson et al 1991), familial cafe-au-lait spots (Abeliovich et al 1995) or familial spinal neurofibromas (Pulst et al 1991;Poyhonen et al 1997;Ars et al 1998). This observation is consistent with an allele-phenotype correlation, but no consistent kind of NF1 mutation has been found in families with these or other phenotypic variants.…”

Section: Introductionsupporting

confidence: 52%

Statistical Methods for Analysis of NF Clinical Data

Joe¹

2001

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Section: Introductionsupporting

confidence: 52%

Statistical Methods for Analysis of NF Clinical Data

Joe¹

2001

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“…Consistent with this hypothesis, prior NF1 mutation testing, linkage studies argued for genetic heterogeneity of this phenotype. 18,19 Successively, studies allowed to identify a 3-bp deletion in exon 22 of the gene (c.2970_2972delAAT, p.Met992del) as responsible for a mild form of NF1 with multiple CaLS and SF as cardinal signs, in the absence of CNFs. 7 Genetic heterogeneity for familial CaLS in association with SF without LN, NFs or other features of NF1, was confirmed by the identification of inactivating mutations in SPRED1 8 as the molecular event underlying the NF1 clinically related LS.…”

Section: Discussionmentioning

confidence: 99%

p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas

et al. 2014

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Analysis of 786 NF1 mutation-positive subjects with clinical diagnosis of neurofibromatosis type 1 (NF1) allowed to identify the heterozygous c.5425C4T missense variant (p.Arg1809Cys) in six (0.7%) unrelated probands (three familial and three sporadic cases), all exhibiting a mild form of disease. Detailed clinical characterization of these subjects and other eight affected relatives showed that all individuals had multiple cafè-au-lait spots, frequently associated with skinfold freckling, but absence of discrete cutaneous or plexiform neurofibromas, Lisch nodules, typical NF1 osseous lesions or symptomatic optic gliomas. Facial features in half of the individuals were suggestive of Noonan syndrome. Our finding and revision of the literature consistently indicate that the c.5425C4T change is associated with a distinctive, mild form of NF1, providing new data with direct impact on genetic counseling and patient management.

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“…In the NFl autopsy series examined by Salyer and Salyer (12), 5 of 8 individuals over 25 years of age, but only 2 of 10 patients who were younger than this, had lesions of NFl vasculopathy. Development of new vascular lesions and progression of previously existing ones have been demonstrated in NFl patients (37,38).…”

Section: Theories Of Pathogenesis For Nf1 Vasculopathymentioning

confidence: 99%

“…These include Watson syndrome (characterized by pulmonic stenosis, cafe-au-lait spots, short stature, and cognitive impairment) (34,35); familial multiple cafe-au-lait spots (without other NF1 features) (36)(37)(38); familial spinal neurofibromatosis (characterized by spinal tumors and, sometimes, cafe-au-lait spots, but not by other features of NF1) (39,40); and encephalocraniocutaneous lipomatosis (characterized by unilateral lipomatous growths, ipsilateral ophthalmologic and brain malformations, mental retardation, and seizures) (41). It appears that these variants may be allelic to NF1, at least in some families.…”

Section: Associationsmentioning

confidence: 99%

Analysis of Phenotypic Variability in Neurofibromatosis Type I (NF1)

Friedman¹

2001

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and This project was designed to characterise the sources of phenotypic variability in neurofibromatosis 1 (NF1) by a combination of clinical, statistical, epidemiological, and molecular genetic methods. We have analysed associations found in clinical and genetic data from the NNFF International Database and two other databases with logistic regression and generalized estimating equations. We then extended these methods to use multivariate probit models on familial data. These are novel statistical techniques that have not been used in this way before and yielded interesting results about the sources of phenotypic variability. We were able to determine that the presence of some features of NF1 are more influenced by variability in the NF1 allele, others by the normal NF1 allele and still others by unlinked modifying genes. We have set up, and tested the screening protocol to identify the constitutional mutations of NF1 and have obtained a number of blood samples. We have results for one of our phenotypic subgroups and are completing the analysis at the present time.14. SUBJECT TERMS Neurofibromatosis Body 5 Key Research Accomplishments 26 Reportable Outcomes 27Conclusions 31 Appendices 32 INTRODUCTIONThe natural history of neurofibromatosis 1 (NF1) is incompletely understood. It exhibits extreme clinical variability and is progressive over the course of an affected individual's life. However, the rate of progression and the occurrence of serious complications vary greatly between different patients of the same age, different affected members of a single family, and even a single affected individual at different times in life. This variability and concomitant uncertainty greatly increases the burden for affected families.The purpose of this project is to characterize the sources of phenotypic variability in NF1. The studies were performed on the world's largest NF clinical databases, together including over 5000 individuals, and used a variety of statistical and genetic epidemiological methods. Our goal was to determine if a set of clinical phenotypes exists for which allelic differences at the NF1 locus appear to be important determinants of phenotype. The molecular component of this study (undertaken by Dr. D. Viskochil, University of Utah) was to develop a molecular screening process to enable us to identify the nature of the mutations within these putative phenotypes. BODY Data used in these studies:Most of the initial analy...

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Familial cafe au lait spots: a variant of neurofibromatosis type 1.

Cited by 48 publications

References 5 publications

Statistical Methods for Analysis of NF Clinical Data

Statistical Methods for Analysis of NF Clinical Data

p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas

Analysis of Phenotypic Variability in Neurofibromatosis Type I (NF1)

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