Clinical characteristics and healthcare burden of neurofibromatosis type 1 in Saudi Arabia: a single centre experience

INTRODUCTION Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder characterized by variable clinical expression and a predisposition to tumor development. Plexiform neurofibromas (PNs), a hallmark and often debilitating feature, contribute significantly to morbidity. This study presents a retrospective, single-center analysis of NF1 patients at King Faisal Specialist Hospital & Research Centre (KFSHRC) in Riyadh, Saudi Arabia, focusing on the distribution of PNs and associated comorbidities. METHODS We retrospectively reviewed the records of all patients diagnosed with NF1 at KFSHRC between 2020 and 2025. Data were extracted from electronic medical records, including demographics, family history, NF1 diagnostic criteria, PN presence and distribution, associated comorbidities, and additional tumor types. RESULTS Fifty-one NF1 patients were identified (28 females, 54.9%; 23 males, 45.1%). The most common clinical features included café-au-lait macules (n = 46, 90.2%) and cutaneous neurofibromas (n = 31, 60.8%), with PNs present in 25 patients (49.0%). Other features included skinfold freckling (33.3%), Lisch nodules (21.6%), skeletal abnormalities (13.7%), and optic pathway gliomas (11.8%). Parental consanguinity was noted in 21.6%, and a family history of NF1 in 60.8%. The mean age at NF1 diagnosis was 4.8 years, with PNs typically emerging by 8.2 years. Among PN patients, 44% had multiple tumors. PN distribution involved the extremities (56%), trunk (48%), head (24%), orbit (24%), neck (20%), face (8%), and other regions (12%). Common comorbidities included headache (13.7%), scoliosis (11.8%), epilepsy (9.8%), visual impairment (9.8%), cognitive delay (3.9%), and malignant peripheral nerve sheath tumors (3.9%). Additional tumors included gliomas (n = 5), schwannomas (n = 3), and rhabdomyosarcoma (n = 1). CONCLUSION This cohort of NF1 patients exhibited a high prevalence of plexiform and cutaneous neurofibromas, along with diverse comorbidities and tumor manifestations. These findings underscore the need for early diagnosis, multidisciplinary management, and sustained surveillance to optimize outcomes in this complex patient population.

NF1 Tumor Suppressor Gene Function: Narrowing the GAP

1. Mustafa Tekin, MD* 2. Joann N. Bodurtha, MD, MPH† 3. Vincent M. Riccardi, MD‡ 1. 2. *Clinical Genetics Fellow. 3. 4. †Associate Professor of Human Genetics, Pediatrics, Obstetrics and Gynecology, Virginia Commonwealth University/Medical College of Virginia Hospitals, Richmond, VA. 5. ‡President, The Neurofibromatosis Institute, La Crescenta, CA. Objectives After completing this article, readers should be able to: 1. Define cafe au lait spots typical of neurofibromatosis type 1 (NF1) and describe their frequency and variability in the normal population. 2. List three or more genetic disorders other than NF1 that are associated with cafe au lait spots. 3. Summarize three or more clinical manifestations and molecular bases of NF1 and NF2. 4. List the diagnostic criteria for NF1. 5. Summarize clinical findings of genetic disorders other than NF1 associated with cafe au lait spots. Every pediatrician faces the challenge of deciding if a patient who has cafe au lait (CAL) spots has an underlying genetic condition. CAL spots typical of neurofibromatosis type 1 (NF1) are discrete, round or oval, uniformly hyperpigmented skin patches. Their color varies from light to dark brown, and the border may be smooth or irregular. They usually are smaller in newborns, enlarge as children get older, and are less prominent in adults. The histologic basis of CAL spots is increased melanin content, with the presence of giant melanosomes in both melanocytes and basal keratinocytes and no melanocytic proliferation. The giant melanosomes in CAL spots are not unique to NF1; they can be seen in unaffected skin of adults who have NF1 and occasionally in normal skin of healthy individuals. Therefore, the presence of giant melanosomes is not helpful for diagnosing NF1. The frequency and number of CAL spots vary in the general population according to ethnic background and age. Sometimes otherwise healthy children who have red hair and often are of Irish or Welsh background have multiple areas of patchy hyperpigmentation. Similarly, multiple patchy areas of hyperpigmentation can occur in healthy children who have mixed ethnic backgrounds in which two parents have very different skin colors. CAL spots were noted in 0.3% of Caucasians and 18% of African-Americans …

Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only

Background Neurofibromatosis type 1 (NF1) is the most common tumor predisposition syndrome, with an incidence of 1/3500. Plexiform neurofibromas (PN) are benign tumors that can occur along the nerve sheath throughout the body, with unpredictable growth and with risk of malignant transformation. Symptoms will depend on their size and location, and include pain, deformity and functional impairment. There is a great variability in the PN severity and impact on quality-of-life (QOL). An unknown percentage of NF1 patients may need treatment, either medical and/or surgical. Objectives To assess the frequency of PN in a NF1 population followed in a comprehensive cancer center. Material and Methods Retrospective study. All patients with NF1 and PN followed in our center, between 31/12/2000 and 31/12/2021. Results Of 438 NF1 patients, 185 had PN (42%). 52 NF1 patients with PN were children (≤ 18). The most common symptoms were pain in 71 people (38,4%), deformity in 70 (37,8%) and functional impairment in 69 (37,3%). Several patients had a combination of these symptoms. Different treatment modalities were used for PN: medical, surgical or both. In this study, 54 patients (29,1%) were treated with MEK inhibitors (selumetinib), 74 patients (40%) were treated surgically and 12,4% (23) needed a combined approach (medical and surgical treatment). Conclusion PN are frequent in NF1 patients. A significant percentage is symptomatic and will require treatment, surgical, medical or both. There is no standard of care for PN NF1. The timing and sequence of medical and surgical treatment is yet to be defined.

We present a case of Von-Recklinghausen disease with malignant transformation of a plexiform neurofibroma over her left leg. The proposita is a 35-year-old female with typical clinical features of neurofibromatosis type 1 (NF1) including cafe-au-lait spots, Lisch nodule and multiple fibromas. The major problem is a rapid growing mass within her left calf and ankle with resultant limb deformation, walking difficulties and debilitating pain. Besides that, there exists the great concern of malignant change of the lesion, therefore we elect to perform below-knee amputation for her. The pathologic examination confirmed our suspicion and the patient made an uneventful recovery and fares well during the follow-up period eversince.

Huge plexiform neurofibroma of the head and liver--case report.

BackgroundNeurofibromatosis type-1 (NF1) is caused by mutations of the NF1 gene at 17q11.2. In 95% of non-founder NF1 patients, NF1 mutations are identifiable by means of a comprehensive mutation analysis. 5-10% of these patients harbour microdeletions encompassing the NF1 gene and its flanking regions. NF1 is characterised by tumours of the peripheral nerve sheaths, the pathognomonic neurofibromas. Considerable inter- and intra-familial variation in expressivity of the disease has been observed which is influenced by genetic modifiers unrelated to the constitutional NF1 mutation. The number of plexiform neurofibromas (PNF) in NF1 patients is a highly heritable genetic trait. Recently, SNP rs2151280 located within the non-coding RNA gene ANRIL at 9p21.3, was identified as being strongly associated with PNF number in a family-based association study. The T-allele of rs2151280, which correlates with reduced ANRIL expression, appears to be associated with higher PNF number. ANRIL directly binds to the SUZ12 protein, an essential component of polycomb repressive complex 2, and is required for SUZ12 occupancy of the CDKN2A/CDKN2B tumour suppressor genes as well as for their epigenetic silencing.MethodsHere, we explored a potential association of PNF number and PNF volume with SNP rs2151280 in 29 patients with constitutional NF1 microdeletions using the exact Cochran-Armitage test for trends and the exact Mann–Whitney–Wilcoxon test. Both the PNF number and total tumour volume in these 29 NF1 patients were assessed by whole-body MRI. The NF1 microdeletions observed in these 29 patients encompassed the NF1 gene as well as its flanking regions, including the SUZ12 gene.ResultsIn the 29 microdeletion patients investigated, neither the PNF number nor PNF volume was found to be associated with the T-allele of rs2151280.ConclusionOur findings imply that, at least in patients with NF1 microdeletions, PNF susceptibility is not associated with rs2151280. Although somatic inactivation of the NF1 wild-type allele is considered to be the PNF-initiating event in NF1 patients with intragenic mutations and patients with NF1 microdeletions, both patient groups may differ with regard to tumour progression because of the heterozygous constitutional deletion of SUZ12 present only in patients with NF1 microdeletions.

A lateral cephalometry study of patients with neurofibromatosis type 1

Neurocutaneous syndromes (phakomatosis) represent a group of central nervous system disorders associ-ated with lesions in the skin, eye, and possibly other visceral organs. They include Neurofibromatosis 1 and 2, Tuberous sclerosis complex, and Sturge-Weber Syndrome [1].Neurofibromatosis is an autosomal dominant disorder with variable penetrance and varied presentation. Neurofi-bromatosis is further divided into NF1 and NF 2 based on genetic and specific features. Neurofibromatosis 1 is more common. Clinical diagnosis of neurofibromatosis 1 requires the presence of at least two of the following seven criteria [2]:Six or more cafe au lait spots or hyperpigmented mac-ules greater than or equal to 5 mm in diameter in children younger than 10 years and equal to 15 mm in adults • Axillary or inguinal freckles• Two or more typical neurofibromas or one plexiform neurofibroma• Optic nerve glioma• Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp examination.• Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis• First-degree relative (eg, mother, father, sister, brother) with NF1Our patient had cafe au lait spots and plexiform neu-rofibroma of lumbar region which was confirmed by histo-pathology. The next best step in diagnosis would be to use slit lamp examination as lisch nodules are pathognomonic of NF1. NF 1 can be differentiated from NF 2 by the presence of bilateral acoustic schwannoma. Pure tone audiometry would help in identifying lesions in NF2 rather NF1.Tuberous sclerosis (Bournveville’s disease) is character -ized by hamartoma of many organs, including the skin, brain, eyes and kidney. It is manifested by the clinical triad of seizure, mental retardation and adenoma sebaceum. MRI of the brain would be useful in detecting subependymal nodule(tuber). Intracerebral calcification are the most common and pathognomonic findings in tuberous scle-rosis. Hence MRI/CT of the brain would be used in cases of tuberous sclerosis [3].Sturge-Weber Syndrome presents with a typical ipsilat-eral port wine facial nevus in the distribution of trigeminal nerve (V1) with neurological features.

Neurofibromatosis type 1. Part I. Clinical and central nervous system manifestations

The molecular basis of a number of inherited diseases that affect the eyelids has been elucidated over the last two decades. Due to the vast number of these diseases, a clinician may become overwhelmed by the volume of data, making it difficult to incorporate newer information into his or her clinical practice. This article intends to review the recent developments of inherited diseases that affect the eyelids that a typical oculoplastic surgeon will encounter. This review proposes categorizing genetic diseases affecting the eyelids on rarity and whether the disease manifests itself at birth or later in life. Based on this classification system the following 10 diseases (the first five manifesting at birth, the last five later in life) are considered more likely to be encountered by the typical oculoplastic surgeon and reviewed in detail: blepharophimosis-ptosis-epicanthus inversus syndrome, congenital fibrosis of the extraocular muscles, lymphedema-distichiasis syndrome, neurofibromatosis type 1, congenital myasthenic syndrome, oculopharyngeal muscular dystrophy, chronic progressive external ophthalmoplegia, myotonic dystrophy, neurofibromatosis type 2, and basal cell nevus syndrome. The remaining known genetic disorders that affect the eyelids are considered less likely to be encountered by the typical oculoplastic surgeon and are listed in tabular form. It is prudent for the oculoplastic surgeon to be knowledgeable of inherited disorders that affect the eyelids to aid in accurate diagnosis, counseling, and treatment. The development of future therapies may at some point make treatment of these diseases no longer surgical. http://links.lww.com/COOP/A4.

신경섬유종증의 안과적 소견방재순․양홍석․안재홍․국경훈․장윤희 아주대학교 의과대학 안과학교실 목적: 신경섬유종증의 안과적 소견과 그 빈도에 대하여 알아보고자 한다.대상과 방법: 2001년 11월에서 2008년 1월까지 본원 안과를 방문한 환자 중 신경섬유종증의 진단 기준을 충족하는 153명을 대상으로 후향적 연구를 시행하였다.결과: 남자 77명, 여자 76명이며 평균 나이는 20.44±14.34세이고신경섬유종증 제1형 112명, 제2형 6명, 분절 제 1형 35명이었다.신경섬유종증 제1형에서는 리쉬소결절(52

This set of guidelines is designed to assist the pediatrician in caring for the child in whom the diagnosis of neurofibromatosis has been made. Although the pediatrician's first contact with the child is usually during infancy, occasionally the pregnant woman who has been given the prenatal diagnosis of neurofibromatosis will be referred for advice. Therefore, these guidelines offer advice for this situation as well. At least two distinct types are recognized—neurofibromatosis 1, or NF-1 (previously known as von Recklinghausen disease or generalized neurofibromatosis), and neurofibromatosis 2, or NF-2 (previously known as bilateral acoustic neurofibromatosis). This discussion addresses only issues concerning the diagnosis and management of NF-1.1-8 Neurofibromatosis 1 is a progressive, multisystem disorder affecting about 1 in 3,000 individuals.9 A National Institutes of Health (NIH) Consensus Development Conference10 regarding NF-1 demarcated seven features, of which two or more are required to establish firmly the diagnosis of NF-1: 1. Six or more cafe-au-lait spots (CLS) or macules, greater than or equal to 5 mm in diameter in prepubertal patients and 15 mm in diameter in postpubertal patients; 2. Two or more neurofibromata of any type, or one plexiform neurofibroma; 3. Freckling in the axillary or inguinal region; 4. Optic glioma; 5. Two or more Lisch nodules (iris hamartomas); 6. A distinctive osseous lesion such as sphenoid dysplasia or cortical thinning of long bones, with or without pseudarthrosis; or 7. A first-degree relative (parent, sibling, or child) with NF-1 according to the preceding criteria. Diagnosis in nonfamilial pediatric cases may be difficult because certain clinical features are age-pendent.

We assessed the accuracy of semi-automated tumor volume maps of plexiform neurofibroma (PN) generated by a deep neural network, compared to manual segmentation using diffusion weighted imaging (DWI) data. NF1 Patients were recruited from a phase II clinical trial for the treatment of PN. Multiple b-value DWI was imaged over the largest PN. All DWI datasets were registered and intensity normalized prior to segmentation with a multi-spectral neural network classifier (MSNN). Manual volumes of PN were performed on 3D-T2 images registered to diffusion images and compared to MSNN volumes with the Sørensen-Dice coefficient. Intravoxel incoherent motion (IVIM) parameters were calculated from resulting volumes. 35 MRI scans were included from 14 subjects. Sørensen-Dice coefficient between the semi-automated and manual segmentation was 0.77 ± 0.016. Perfusion fraction (f) was significantly higher for tumor versus normal tissue (0.47 ± 0.42 vs. 0.30 ± 0.22, p = 0.02), similarly, true diffusion (D) was significantly higher for PN tumor versus normal (0.0018 ± 0.0003 vs. 0.0012 ± 0.0002, p < 0.0001). By contrast, the pseudodiffusion coefficient (D*) was significantly lower for PN tumor versus normal (0.024 ± 0.01 vs. 0.031 ± 0.005, p < 0.0001). Volumes generated by a neural network from multiple diffusion data on PNs demonstrated good correlation with manual volumes. IVIM analysis of multiple b-value diffusion data demonstrates significant differences between PN and normal tissue.