A Computed Tomography-Based Comparison of Abnormal Vertebrae Pedicles Between Dystrophic and Nondystrophic Scoliosis in Neurofibromatosis Type 1.

OBJECTIVE: To explore the prevalence and distribution of abnormal vertebral pedicles in scoliosis secondary to neurofibromatosis type 1 (NF1-S) and to compare the abnormal vertebrae pedicles between dystrophic and nondystrophic scoliosis. METHODS: Using computed tomography images, we carefully measured 2652 vertebral pedicles from 56 patients with NF1-S with dystrophic scoliosis and 22 patients with NF1-S with nondystrophic scoliosis. Pedicle morphology was classified as follows: type A, a cancellous channel of >4 mm; type B, a cancellous channel of 2 to 4 mm; type C, a cancellous channel of <2 mm with an entirely cortical channel of ≥2 mm; type D, a cortical channel of <2 mm; or type E, absent pedicle. Types B, C, D, and E were defined as abnormal. RESULTS: The total prevalence of abnormal vertebral pedicles in patients with NF1-S was as high as 67%, with type B comprising 39%, type C comprising 22%, type D comprising 4%, and type E comprising 2%. A significantly greater rate of abnormal pedicles was found in dystrophic scoliosis compared with nondystrophic scoliosis (70% vs. 59%, P < 0.0001). The upper thoracic spine (87%) is the most concentrated region of abnormal pedicles compared with the lower thoracic (73%) and lumbar spine (34%). CONCLUSIONS: There is a significantly high prevalence of abnormal pedicles in patients with NF1-S and an increased rate of abnormal pedicles in dystrophic scoliosis compared with nondystrophic ones. The described pedicle classification system could serve as an objective tool to guide preoperative assessment.

Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview.

Patients with neurofibromatosis 1 (NF1) develop multiple neurofibromas, with 8% to 15% of patients experiencing malignant peripheral nerve sheath tumor (MPNST) during their lifetime. Prediction of transformation, typically from plexiform neurofibroma, is clinically and histologically challenging. In this overview, after a consensus meeting in October 2016, we outline the histopathologic features and molecular mechanisms involved in the malignant transformation of neurofibromas. Nuclear atypia alone is generally insignificant. However, with atypia, loss of neurofibroma architecture, high cellularity, and/or mitotic activity >1/50 but <3/10 high-power fields, the findings are worrisome for malignancy. We propose the term "atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP)" for lesions displaying at least 2 of these features. This diagnosis should prompt additional sampling, clinical correlation, and possibly, expert pathology consultation. Currently, such tumors are diagnosed inconsistently as atypical neurofibroma or low-grade MPNST. Most MPNSTs arising from neurofibromas are high-grade sarcomas and pose little diagnostic difficulty, although rare nonnecrotic tumors with 3-9 mitoses/10 high-power fields can be recognized as low-grade variants. Although neurofibromas contain numerous S100 protein/SOX10-positive Schwann cells and CD34-positive fibroblasts, both components are reduced or absent in MPNST. Loss of p16/CDKN2A expression, elevated Ki67 labeling, and extensive nuclear p53 positivity are also features of MPNST that can to some degree already occur in atypical neurofibromatous neoplasms of uncertain biologic potential. Complete loss of trimethylated histone 3 lysine 27 expression is potentially more reliable, being immunohistochemically detectable in about half of MPNSTs. Correlated clinicopathological, radiologic, and genetic studies should increase our understanding of malignant transformation in neurofibromas, hopefully improving diagnosis and treatment soon.

Dissecting Clinical Heterogeneity in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder in which affected children and adults are predisposed to the development of benign and malignant nervous system tumors. Caused by a germline mutation in the NF1 tumor suppressor gene, individuals with NF1 are prone to optic gliomas, malignant gliomas, neurofibromas, and malignant peripheral nerve sheath tumors, as well as behavioral, cognitive, motor, bone, cardiac, and pigmentary abnormalities. Although NF1 is a classic monogenic syndrome, the clinical features of the disorder and their impact on patient morbidity are variable, even within individuals who bear the same germline NF1 gene mutation. As such, NF1 affords unique opportunities to define the factors that contribute to disease heterogeneity and to develop therapies personalized to a given individual (precision medicine). This review highlights the clinical features of NF1 and the use of genetically engineered mouse models to define the molecular and cellular pathogenesis of NF1-associated nervous system tumors.

Multiple non-ossifying fibromas as a cause of pathological femoral fracture in Jaffe-Campanacci syndrome.

BACKGROUND: Jaffe-Campanacci is a rare syndrome characterised by the association of café-au-lait spots, axillary freckles, multiple non-ossifying fibromas of the long bones and jaw, as well as some features of type 1 neurofibromatosis. There are less than 30 reported cases, and a genetic profile has not yet been determined. Furthermore, it has not been clarified whether it is a subtype of type 1 neurofibromatosis or a separate syndrome. The risk of pathological fracture is over 50%, due to substantial cortical thinning of the weight-bearing bones. CASE PRESENTATION: A 17-year-old female patient, known for type 1 neurofibromatosis, presented with a low-energy distal femoral fracture due to disseminated large non-ossifying fibromas. Investigations revealed all of the distinctive signs of Jaffe-Campanacci syndrome. Both her distal femurs and proximal tibias exhibited multiple non-ossifying fibromas. The fracture was treated by open reduction and internal plate fixation. Some of the bony lesions were biopsied to confirm the diagnosis. The fracture healed eventless, as did the lesions biopsied or involved in the fracture. The other ones healed after curettage and bone grafting performed at the time of plate removal. CONCLUSION: Jaffe-Campanacci is a rare syndrome having unclear interactions with type 1 neurofibromatosis, which still needs to be characterised genetically. It is associated with a high risk of pathological fracture, due to the presence of multiple large non-ossifying fibromas of the long bones, with an expected normal healing time. Curettage and bone grafting promote healing of the lesions and should be considered to prevent pathological fracture. We agree with other authors that all patients with newly-diagnosed type 1 neurofibromatosis should undergo an osseous screening to detect disseminated non-ossifying fibromas, and evaluate the inherent risk of pathological fracture.

Gastrointestinal stromal tumors (GIST): lesser known facts.

In an era of molecular targeted therapy, patients with advanced gastrointestinal stromal tumor (GIST) are living longer and are often followed with imaging. Therefore, it is important for the radiologists to be aware of the atypical subtypes of GIST, implications of molecular makeup, its behavior, and the uncommon metastatic sites. The aim of this pictorial review is to illustrate the lesser-known aspects of GIST including histological and molecular classifications, syndromes associated with GIST, and uncommon metastatic sites.

The adverse influence of attention-deficit disorder with or without hyperactivity on cognition in neurofibromatosis type 1.

AIM: A substantial proportion of patients with neurofibromatosis type 1 (NF1) have attention-deficit disorder with or without hyperactivity (AD[H]D). This study explored the influence of AD(H)D symptoms on the intellectual profile of patients with NF1. METHOD: We retrospectively analysed neuropsychological data from 114 children (66 males, 48 females; age range 6-16y; mean age 9y 3mo [SE 3mo]) with NF1 from an NF1 outpatients department. Assessment included psychiatric diagnosis of AD(H)D (DSM-IV-TR criteria) and intelligence testing (Wechsler Intelligence Scale for Children, German version). Magnetic resonance images were available for all patients, intracranial findings being an exclusion criterion. The effects of AD(H)D symptoms on intelligence and on the cognitive profile were tested by analyses of variance. RESULTS: Patients with AD(H)D symptoms performed significantly worse than those without AD(H)D symptoms on all intelligence measures (main effects for Full-scale, Verbal, and Performance IQ; p<0.005). Subtests typically impaired in patients with NF1 (visuospatial skills and arithmetic) were not specifically influenced by AD(H)D symptoms. There were no differences between AD(H)D subtypes. INTERPRETATION: AD(H)D symptoms have a negative impact on the intellectual development of children with NF1. This impact seems to be of an unspecific nature, with a general attenuation of the cognitive profile.

Caracterización clínica de pacientes con neurofibromatosis segmentaria / Clinical characterization of patients suffering from segmental neurofibromatosis

La neurofibromatosis tipo 1 es la enfermedad monogénica más frecuente en la especie humana. En su clasificación se describe la variante segmentaria como forma clínica especial, poco frecuente, caracterizada por máculas "café con leche" o neurofibromas cutáneos que se extienden por sectores bien delimitados. En el estudio, se reportan seis casos con neurofibromatosis segmentaria evaluados en el Servicio de Genética Clínica de Pinar del Río, desde el año 2001. El diagnóstico en la edad pediátrica se efectuó en el 67 por ciento de los casos, no encontrando una distribución preferencial según el sexo. Las manchas café con leche y las pecas en la axila o ingle se presentaron en la totalidad de los pacientes, al tiempo que los nódulos de Lisch fueron identificados en el 50 por ciento de la muestra. Se reportaron además, anomalías óseas y trastornos del aprendizaje en 33 por ciento de los pacientes estudiados. El 67 por ciento de los casos se debieron a nuevas mutaciones y el 33 por ciento restante heredó la enfermedad de uno de sus progenitores. Se concluye que la neurofibromatosis segmentaria, hasta ahora definida como benigna requiere un estrecho seguimiento clínico pues las posibilidades de compromiso sistémico no son nulas y aunque raro puede darse la situación en que el diagnóstico se herede de progenitores con otras variantes de la enfermedad(AU)

Neurofibromatosis type-1 (NF-1) is the most frequent monogenic disease in human being. In its classification a segmental variant is described as a clinical special form, not frequent characterized by “café au lait spots” or cutaneous neurofibromas extended to well-limited sectors. Six cases of segmental neurofibromatosis have been evaluated in the Service of Clinical Genetics in Pinar del Rio province since 2001. The diagnosis in pediatric ages was carried out in 67 per cent of the cases, where no preferential distribution regarding sex was found. The “café au lait spots” and freckles in the axilla or the groin were present in the totality of patients, and 50 per cent of the sample suffered from Lisch nodules. Besides; osseous anomalies and learning disorders were reported in 33 per cent of the patients included in the study. 67 per cent of the cases resulted in new mutations and 33 per cent inherited the disease from one of the parents. Segmental neurofibromatosis, defined as a benign entity needs a close clinical follow up, given that the systemic compromise is not null, although rare, in some situations it can be inherited from parents having other variants of the disease(AU)

Segmental neurofibromatosis.

A 59-year-old man presented for evaluation and excision of non-tender, fleshy nodules that were arranged in a dermatomal distribution from the left side of the chest to the left axilla. A biopsy specimen of a nodule was consistent with a neurofibroma. Owing to the lack of other cutaneous findings, the lack of a family history of neurofibromatosis, and the dermatomal distribution of the neurofibromas, this patient met the criteria for a diagnosis of segmental neurofibromatosis (SNF) according to Riccardi's definition of SNF and classification of neurofibromatosis. Because the patient has no complications of neurofibromatosis 1 no medical treatment is required.

Application of the International Classification of Functioning, Disability and Health in children with neurofibromatosis type 1: a review.

AIM: The World Health Organization's International Classification of Functioning, Disability and Health adapted for children and young people (ICF-CY) is a framework for describing and classifying health and health-related states. The aim of the present study was to review literature on neurofibromatosis type 1 (NF1) using ICF-CY guidelines and to highlight findings about the quality of life of children with NF1. METHOD: Electronic databases were searched to identify studies involving children with NF1. Eligible studies were classified according to ICF-CY categories. RESULTS: Children with NF1 have a variety of cognitive and other deficits. However, very little information is available on the impact of these deficits on their daily life. INTERPRETATION: Despite the broad range of functional and structural deficits in children with NF1, the functional assessment of these children remains largely unexplored. Future studies should aim at evaluating the participation of children with NF1 in various situations, using tools with high real-world validity.

Perception of disease severity in adolescents diagnosed with neurofibromatosis type 1.

PURPOSE: To examine the relationship between adolescents' families' perception of the severity of neurofibromatosis (NF1) and the clinical severity of NF1, a genetic condition with variable manifestations. METHODS: The Perception of Severity of Chronic Illness (PSCI) questionnaire was administered to 56 parents of 47 adolescents with NF1. Each participant was asked one open-ended question regarding the challenges of living with NF1. Scores assessing the clinical severity of NF1 were assigned by health care providers in the NF Clinic. Correlation coefficients and paired t-test were used to evaluate the relationship between the clinical severity and the families' perceptions. Qualitative data were reviewed and grouped into themes. RESULTS: Parental perceptions were correlated with the degree of medical (r = 0.3116, p <.05), cognitive (r = 0.4911, p <.0001), and behavioral (r = 0.3341, p <.05) impairment of the adolescent. Adolescent perception was correlated with the degree of cognitive impairment (r = 0.5429, p <.0001). Parental and adolescent perceptions were correlated (r = 0.6724, p <.0001); however, adolescents viewed the condition's impact as being less than their parents (p <.001). The qualitative data provide additional insight into the concerns of these families. CONCLUSIONS: Families dealing with more medical, cognitive, and behavioral complications of NF1 perceive the impact of the condition on daily life as being greater than those families with fewer complications. The quantitative and qualitative results of this study have several implications for the clinical care of adolescents with NF1 and their families.

Comparative pathology of nerve sheath tumors in mouse models and humans.

Despite the progress made in our understanding of the biology of neurofibromatosis (NF), the long-term clinical outcome for affected patients has not changed significantly in the past decades, and both NF1 and NF2 are still associated with a significant morbidity and a decreased life span. A number of NF1 and NF2 murine models have been generated to aid in the study of NF tumor biology and in the development of targeted therapies for NF patients. A single, universal pathological classification of the lesions generated in these murine models is essential for the validation of the models, for their analysis and comparison with other models, and for their future effective use in preclinical treatment trials. For the formulation of a pathological classification of these lesions, the WHO classification of human tumors was used as a reference. However, it was not adopted for the classification of the GEM lesions because of some important differences between the human and murine lesions. A novel classification scheme for peripheral nerve sheath tumors in murine models was therefore devised.

Jaw malformations plus displacement and numerical aberrations of teeth in neurofibromatosis type 1: a descriptive analysis of 48 patients based on panoramic radiographs and oral findings.

AIM: The aim of this study was to analyse jaw malformations and tooth displacement in patients with neurofibromatosis type 1 (NF1). MATERIAL AND METHODS: Forty-eight patients were included in the study (male or female 24 each). All fulfilled the current NIH diagnostic criteria for NF1. The age range was 2.5-66 years. The type of neurofibroma was histologically proven in surgically treated patients. Patients with disseminated cutaneous neurofibromata and those with the plexiform type were distinguished. The analysis was based on physical investigation, photographs, panoramic radiographs and dental casts. RESULTS: With the emphasis on alterations of tooth position, deformities of the adjacent bones and malocclusion, the majority of these patients (26) were affected by plexiform neurofibromata. In the other 22 patients with disseminated neurofibromata, malformations of the alveolar ridge were absent and individual oral symptoms were rarely found and were mild, and in all cases were unimpaired. Numerical aberrations and retention of molars was exclusively associated with a trigeminal nerve affected by plexiform neurofibroma. Aplasia of a second lower molar was recognized in four of these plexiform-neurofibroma patients. CONCLUSION: It is widely accepted that malformations of the facial skeleton are often of genetic origin. However, in this study these malformations were strongly associated with plexiform neurofibromata originating from the trigeminal nerve. Thus, in addition to presently unknown genetic factors, the pattern of skeletal malformation can be caused by tumour invasion and local destruction, e.g. the neuromuscular unit or prenatal development of the plexiform neurofibroma in the inferior alveolar nerve. It is further concluded that epidemiologic studies on the incidence and severity of NF1 in the oral and maxillofacial region have to distinguish between patients with or without plexiform neurofibroma, especially when analysing alterations and deformities of the jaws, teeth and malocclusion. Aplasia of second inferior molars is an additional (dental) finding associated with plexiform neurofibromata in NF1.

[Neurofibromatoses. Types, classification and diagnostic criteria]. / Nevrofibromatozi. Vidove, klasifikatsiia i diagnostichni kriterii.

According to the worldwide-accepted classification of the neurofibromatoses only neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are well defined. Other described forms of neurofibromatosis are rare. The aim of this paper is to review the contemporary classification and diagnostic criteria of the different types of neurofibromatoses.

Neurofibromatosis type 1.

Neurofibromatosis 1 (NF1) is an autosomal dominant neurocutaneous disorder with an incidence of approximately 1 in 4000. Cognitive deficits and academic learning difficulties are the most common neurological 'complication' of NF1 in childhood and can be responsible for significant lifetime morbidity. The NF1 gene is usually classified as a tumor suppressor gene, but it is not yet known how NF1 gene mutations cause many of the non-tumor manifestations of the disorder. The NF1 protein, neurofibromin is expressed early during embryonic development with high levels of expression in the brain, suggesting that it plays an important role in regulating the orderly differentiation of central nervous system neurons. The mouse model for NF1 demonstrates behavioral abnormalities which bear striking similarity to the cognitive phenotype observed in humans with NF1. This review summarises our current understanding of the function of the NF1 gene, the nature of cognitive deficits in this disorder and correlations between neuroradiological, pathological and neuropsychological findings and animal studies which provide an insight into the pathogenesis.