Jaffe–Campanacci syndrome, revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations, or a distinct disorder

Stewart, Douglas R.; Brems, Hilde; Gomes, Alicia; Ruppert, Sarah L.; Callens, Tom; Williams, Jennifer; Claes, Kathleen; Bober, Michael B.; Hachen, Rachel K.; Kaban, Leonard B.; Li, Hua; Lin, Angela E.; McDonald, Marie; Mélancon, Serge B.; Ortenberg, June; Radtke, Heather B.; Samson, Ignace; Saul, Robert A.; Shen, Joseph; Siqveland, Elizabeth; Toler, Tomi L.; Maarle, Merel van; Wallace, Margaret R.; Williams, Misti; Legius, Eric; Messiaen, Ludwine

doi:10.1038/gim.2013.163

Cited by 36 publications

(47 citation statements)

References 42 publications

(40 reference statements)

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“…In Jaffe-Campanacci syndrome, overlapping manifestations include non-ossifying fibromas of the long bones, mandibular giant cell granulomas, and caf e-au-lait macules. The cause is mutation of NF1, thus this condition is allelic to or a variant form of neurofibromatosis type 1 [Stewart et al, 2014]. Evidence for mosaic KRAS alterations as the genetic etiology of OES is presented here, with alteration frequencies falling well below 40% regardless of tissue context.…”

Section: Discussionmentioning

confidence: 81%

“…Two individuals with SFMS were recently found to harbor mosaicism for mutations in HRAS (c.37G>C,p. The cause is mutation of NF1, thus this condition is allelic to or a variant form of neurofibromatosis type 1 [Stewart et al, 2014]. Sun et al [2013] also described a patient with SFMS and mosaicism for a mutation in HRAS, which was also a c.37G>C mutation.…”

Section: Discussionmentioning

confidence: 99%

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Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations

Peacock

Dykema

Toriello

et al. 2015

American J of Med Genetics Pt A

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Oculoectodermal syndrome (OES) is a rare disease characterized by a combination of congenital scalp lesions and ocular dermoids, with additional manifestations including non-ossifying fibromas and giant cell granulomas of the jaw occurring during the first decade of life. To identify the genetic etiology of OES, we conducted whole-genome sequencing of several tissues in an affected individual. Comparison of DNA from a non-ossifying fibroma to blood-derived DNA allowed identification of a somatic missense alteration in KRAS NM_033360.3(KRAS):c.38G>A, resulting in p.Gly13Asp. This alteration was also observed in the patient's other affected tissues including the skin and muscle. Targeted sequencing in a second, unrelated OES patient identified an NM_033360.3(KRAS):c.57G>C, p.Leu19Phe alteration. Allelic frequencies fell below 40% in all tissues examined in both patients, suggesting that OES is a mosaic RAS-related disorder, or RASopathy. The characteristic findings in OES, including scalp lesions, ocular dermoids, and benign tumors, are found in other mosaic and germline RASopathies. This discovery also broadens our understanding of the spectrum of phenotypes resulting from KRAS alterations. Future research into disease progression with regard to malignancy risk and investigation of RAS-targeted therapies in OES is warranted. KRAS sequencing is clinically available and may also now improve OES diagnostic criteria.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations

Peacock

Dykema

Toriello

et al. 2015

American J of Med Genetics Pt A

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“…This syndrome describes the complex of multiple nonossifying fibromas (NOFs) of the long bones, giant cell granulomas (GCG) of the jaw, and CAL macules. It has been demonstrated that the majority of patients with these symptoms harbored a pathogenic germline NF1 mutation, 16 and that inactivation of the NF1 gene may contribute to the development of GCG, 17 suggesting that many Jaffe-Campanacci Two of our NF1 patients, brothers and sisters, are both carriers of a neomutation. Interestingly, the two mutations found are not the same.…”

Section: Atypical Casesmentioning

confidence: 90%

Phenotype–Genotype Correlation in Children with Neurofibromatosis Type 1

et al. 2018

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Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with an incidence of ∼1 in 4,000 live births. Neurofibromin, the gene product, is ubiquitously expressed at high levels in the nervous system and functions as a tumor suppressor. Haploinsufficiency of neurofibromin through mutation leads to an increased risk of developing benign and malignant tumors in affected individuals. Although NF1 has complete penetrance, it displays considerable inter- and intrafamilial variability in phenotypic expression which poses disease prediction and management problems. Some NF1 genotype-phenotype correlations have been described. To evaluate the genetic component of variable expressivity in NF1, we examined the phenotypic correlations between affected relatives in 52 NF1 patients from 45 families.

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“…CGCG of the jaws, cutaneous café‐au‐lait macules, and non‐ossifying fibromas of the long bones have been described in patients without neurofibromas in the so‐called Jaffe–Campanacci syndrome. However, recent evidence suggests that many of those patients may represent cases of NF1, as a pathogenic germline NF1 gene mutation was found. Multiple giant cell lesions of the jaws are a diagnostic feature of cherubism, an autosomal dominant disease also associated with NF1 or NS.…”

Section: Discussionmentioning

confidence: 99%

“…A linkage between “Rasopathies” and CGCG has not been established, but a deregulated Ras/MAPK pathway may be involved in the pathogenesis of CGCG. Recently, mutations in the NF1 gene were detected in cases of giant cell lesions of the jaws in NF1 patients.…”

Section: Discussionmentioning

confidence: 99%

Multiple osteolytic lesions of the jaws in a patient with neurofibromatosis type I. A case report and focused literature review

2018

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We describe the case of a patient diagnosed with neurofibromatosis type 1 (NF1) where unusually extensive and multiple osteolytic lesions of both jaws consistent with central giant cell granulomas (CGCG) caused massive bone destruction and left her almost "jawless." The patient was a 58-year-old woman who at the age of 15 years was diagnosed with NF1 and at the age of 53 years underwent radiation therapy for nasal obstruction due to CGCG. The most significant intraoral findings were brown tumors on the maxillary gingiva; bilateral expansion of the hard palate; and a yellow mass on the floor of the mouth. Head and neck examination revealed mandibular asymmetry and features consistent with NF1. Panoramic radiograph and cone beam computed tomography disclosed multiple radiolucent masses. Although the occurrence of multiple CGCG of the jaws in patients with NF1 is rare, early diagnosis, regular follow-up and proper therapeutic intervention may limit the extent of bone destruction.

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Jaffe–Campanacci syndrome, revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations, or a distinct disorder

Cited by 36 publications

References 42 publications

Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations

Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations

Phenotype–Genotype Correlation in Children with Neurofibromatosis Type 1

Multiple osteolytic lesions of the jaws in a patient with neurofibromatosis type I. A case report and focused literature review

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