Neurofibromatosis Type 1 With Cherubism-like Phenotype, Multiple Osteolytic Bone Lesions of Lower Extremities, and Alagille-syndrome: Case Report With Literature Survey

Abstract

Background/Aim: Neurofibromatosis type 1 (NF) is an autosomal dominant hereditary disease. The cardinal clinical findings include characteristic skeletal alterations. Difficulties in diagnosis and therapy can arise if an individual has further illnesses. Case Report: This is a case report of a 16-year-old patient affected by NF1. She also suffered from Alagille syndrome and the consequences of fetal alcohol exposure. The patient's facial phenotype showed findings that could be assigned to one or more of the known diseases. The patient was referred for treating a cherubismlike recurrent central giant cell granuloma (CGCG) of the jaw. The patient developed bilateral, multilocular nonossifying fibromas (NOF) of the long bones of the lower extremity. Treatment of the skeletal lesions consisted of local curettage. While NOF regressed after surgery, the CGCG of the jaw remained largely unchanged. Extensive genetic tests confirmed a previously unknown germline mutation in the JAG1 gene, the germline mutation of the NF1 gene, and the somatic mutation in the NF1 gene in the diffuse plexiform neurofibroma, but not in the CGCG. Conclusion: Assigning facial findings to a defined syndrome is ambiguous in many cases and especially difficult in patients who have multiple diseases that can affect the facial phenotype. Surgical therapy should be adapted to the individual findings.Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder (1). The disease has a high penetrance (about 100%). However, the phenotype is extremely variable (2). The NF1 gene is located on chromosome 17q11.2 (3, 4). NF1 is a tumor suppressor gene syndrome (5) and the most common monogenetic disease predisposing to cancer (1). NF1 is primarily characterized by multiple skin tumors. The tumors are of neurogenic origin termed neurofibroma. Somatic mutations of NF1 gene in neurofibroma arise in Schwann cells or precursors of Schwann cells. Since Schwann cells originate from the neural crest, NF1 is rated among the diseases that are characterized by mutations in neural crest cells (6). The frequent and numerous neoplasms of NF1 patients arise primarily from the connective soft tissues. Genetic studies show that many of the different neoplasms arising in NF1 patients meet the criteria of somatic allelic loss of NF1 gene according to Knudson's two-hit hypothesis of tumor development (7). However, the unusual variety of symptoms and findings in NF1 patients go far beyond the spectrum of neoplastic lesions (1). Most cases are diagnosed by clinical examination (Table I). Diagnosis and treatment of NF1 patients can be made more difficult if other diseases develop in the same individual and 1711 This article is freely accessible online.

Giant Cell Lesions of the Jaws Involving RASopathy Syndromes

“…Following comprehensive review of the English language literature in PubMed, a total of 124 syndromic CGCGs, in 56 patients, were identified in the following RASopathy syndromes ( Table 1 ): Noonan syndrome /77/ ( 15 - 37 ), neurofibromatosis type I /22/, ( 38 - 47 ), oculoectodermal syndrome /11/ ( 48 , 49 ), Schimmelpenning syndrome /6/ ( 50 - 52 ), cardio-facio-cutaneous syndrome /5/ ( 53 ), and osteoglophonic dysplasia /3/ ( 54 , 55 ). In light of a recent systematic review of 2270 CGCG published in the literature by Chrcanovic et al, 5.1% (121/2391) of all published CGCG have occurred syndromically, though this presumably reflects substantial publication bias since sporadically occurring CGCG are no longer commonly reported, and the proportion is likely much smaller ( 2 ).…”

“…First reported in 1982, rare patients have presented with a characteristic triad of café-au-lait macules, non-ossifying fibromas of the long bones, and CGCG, termed Jaffe-Campanacci syndrome ( 47 ). The relationship between this presentation and NF1 has been uncertain due to overlapping features with NF1 but a uniform absence of neurofibromas, though most reported cases have been in young individuals and neurofibromas typically appear in early adolescence ( 71 ).…”

Case Report: Non-ossifying fibromas with pathologic fractures in a patient with NONO-associated X-linked syndromic intellectual developmental disorder

“…Multiple NOFs, with atypical location and fracture propensity, have been previously described in patients with neurofibromatosis type 1, and multifocal NOF have also been reported in patients with Jaffe-Campanacci syndrome and Oculoectodermal Syndrome (Peacock et al, 2015;Vannelli et al, 2020;Friedrich et al, 2021). All these disorders are known as RASopathies and are caused by germline or post-zygotic mosaic mutations in genes encoding RAS/ MAPK signaling pathways components.…”

“…The principal locations of NOF are metaphysis of the distal femur, proximal and distal tibia, but can also be found in the proximal humerus, fibula and distal radius ( Mankin et al, 2009 ; Sakamoto et al, 2017 ). Pathologic fractures may occur with non-physiological loading or low-impact injuries and have been reported to occur in up to 20% of NOFs ( Friedrich et al, 2021 ; Emori et al, 2022 ).…”