Epilepsy in Legius syndrome: Coincidence or causation?

Legius syndrome is a rare genetic disorder, caused by heterozygous SPRED1 pathogenic variants, which shares phenotypic features with neurofibromatosis type 1 (NF1). Both conditions typically involve café-au-lait macules, axillary freckling, and macrocephaly; however, patients with NF1 are also at risk for tumors, such as optic nerve gliomas and neurofibromas. Seizure risk is known to be elevated in NF1, but there has been little study of this aspect of Legius syndrome. The reported epilepsy incidence is 3.3%-5%, well above the general population incidence of ~0.5%-1%, but the few reports in the literature have very little data regarding epilepsy phenotype. We identified two unrelated individuals, both with Legius syndrome and epilepsy, and performed thorough phenotyping. One individual's mother also had Legius syndrome and now-resolved childhood epilepsy, as well as reports of more distant relatives who also had multiple café-au-lait macules and seizures. Both probands had experienced childhood-onset focal seizures, with normal brain MRI. In one patient, EEG later showed apparently generalized epileptiform abnormalities. Based on the data from this small case series and literature review, seizure risk is increased in people with Legius syndrome, but the epilepsy prognosis appears to be generally good, with patients having either self-limited or pharmacoresponsive courses.

Genetically confirmed coexistence of neurofibromatosis type 1 and Cherubism in a pediatric patient.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder typified by various combination of numerous Café-au-lait macules, cutaneous and plexiform neurofibromas, freckling of inguinal or axillary region, optic glioma, Lisch nodules and osseous lesions. Cherubism is a rare genetic syndrome described by progressive swelling of the lower and/or upper jaw due to replacement of bone by fibrous connective tissue. Patients are reported in the literature with NF1 and cherubism-like phenotype due to the NF1 osseous lesions in the jaws. The purpose of this case report is the description of a young male genetically diagnosed with both NF1 and cherubism. METHODS AND RESULTS: A 9 years and six month old patient with clinical findings of NF1 and cherubism in whom both diseases were genetically confirmed, is presented. The patient was evaluated by a pediatrician, a pediatric endocrinologist, an ophthalmologist, and an oral and maxillofacial surgeon. A laboratory and hormonal screening, a histological examination, a chest X-ray, a magnetic resonance imaging (MRI) of the orbit and a digital panoramic radiography were performed. Genetic testing applying Whole Exome Sequencing was conducted. CONCLUSIONS: A novel and an already reported pathogenic variants were detected in NF1 and SH3BP2 genes, respectively. This is the first described patient with coexistence of NF1 and cherubism. The contribution of Next Generation Sequencing (NGS) in gene variant identification as well as the importance of close collaboration between laboratory scientists and clinicians, is highlighted. Both are essential for optimizing the diagnostic approach of patients with a complex phenotype.

Pathogenesis and treatment of a giant occipital bone defect with meningoencephalocele in an NF1 child: case report and review of the literature.

Autosomal dominantly inherited neurofibromatosis type I (NF1) is a systemic disorder caused by a mutation of a gene on chromosome 17q11.2 and characterized by multiple café-au-lait spots, lentiginous macules, Lisch nodules of the iris, and tumors of the nervous system. Bony manifestations such as scoliosis, dysplasia of the greater sphenoidal wing, tibial pseudoarthrosis, short stature, and macrocephaly have been reported in approximately 50% of patients. However, calvarial bone defects are rare. After screening 324 articles, 23 cases (12 adult and 11 pediatric patients) of occipital bone defects in NF1 patients were selected. All patients had a single/multiple bone defect over the lambdoid suture. Adjacent benign plexiform neurofibromas were observed in 14 patients (60.8%, 7 adults and 7 children); one adult patient was diagnosed with neurofibrosarcoma. Meningoencephalocele over the occipital defect was noted in 8 cases (34.78%, all adults). Cranioplasty was performed in only 17.39% of patients. Histologic examination was performed in 7 of the 15 patients with associated neurofibromas/neurofibrosarcomas. Biopsy of the bone margins surrounding the defect was performed in only one case. Pathologic examination of the herniated parieto-occipital or cerebellar tissue was not performed in any of the patients studied. We report the case of a 9-year-old girl with NF1 and a significant occipital bone defect and performed a systematic review of the relevant literature to highlight the challenges in treating this condition and to investigate the underlying mechanisms contributing to bone defects or dysplasia in NF1.

Neurofibroma: Case Series with Clinical Features and Recommendations.

Neurofibroma is an autosomal benign disorder. It can be localized, diffuse or invasive like plexiform neurofibroma that involves the nerves, muscle, tissues, skeleton. It represents itself as a destructive variant of neurofibroma, mostly present as orbital or periorbital neurofibroma or may be associated with autosomal dominant disease. Clinical diagnosis of neurofibromatosis (NF) according to National Institutes of Health (NIH) criteria should have more than two of the seven features including lisch nodules, cafe'- au-lait spots, plexiform neurofibroma, optic glioma, freckling, first degree relative with NF or dysplasia of cortical bones. However, proper early diagnosis is still crucial due to its various presentation such as cheek mass, painless swelling on skin, chalazion, intratracheal tumor, genital swelling or ptosis. It is reported that neurofibroma often represents as ocular or facial swelling. Here we are presenting features of neurofibroma of eight cases of patients from Civil Hospital, Karachi. These cases had main complain of overhanging skin mass mainly on orbital or periorbital region that damage the area and with poor daily activities. Multiple nodules on face and body along with them Cafe'-au-lait spots and lisch nodules were main signs. While, other signs i.e. ptosis, pterygium, telecanthus and muddy discoloration of conjunctiva need further evaluation for correlation with neurofibromatosis. Debulking surgery was planned for most of the cases but the huge disfigurement caused by overhanging skin mass and nodules made it a challenge for plastic surgeons to provide good outcomes with minimum damage. Keywords: neurofibroma; lisch nodules; ptosis; Cafe'-au-lait spot; periorbital; overhanging skin.

[McCune-Albright syndrome: a case report and literature review]. / Syndrome de McCune-Albright : à propos d'un cas et revue de la littérature.

McCune-Albright syndrome is an inherited disease characterized by the association of fibrous dystrophy of bone, café-au-lait skin spots and precocious puberty revealing endocrine hyperactivity. Genetically, this disease is due to a mutation of the Gs protein responsible for activation of adenylate cyclase with excessive production of cAMP. The particular morphology of café-au-lait spots should suggest early diagnosis. Its treatment depends on the endocrinopathy from which the patient suffers and the extent of the fibrous dysplasia. Bisphosphonates have proven their effectiveness on bone pain and the limitation of fibrous dysplasia. Surgery retains its place in complicated forms. We report a rare case of McCune-Albright syndrome complicated by a femur fracture in a 12-year-old girl and we discuss the clinical and paraclinical characteristics of this pathological entity.

Fatal Retroperitoneal Bleeding in Neurofibromatosis Type 1: A Clinically Occult Complication.

ABSTRACT: Neurofibromatosis type 1 (NF1) is a common, autosomal dominant neurocutaneous syndrome. The most frequent clinical manifestations include multiple neurofibromas, café-au-lait spots, dystrophic scoliosis, benign and malignant peripheral nerve sheath tumors, and paragangliomas. Neurofibromatosis type 1 vasculopathy is a less well-recognized constellation of vascular pathologies that can cause significant medical complications in patients with NF1. A rare manifestation of this process is neurofibroma infiltration of vasculature with resultant bleeding. The case presented herein illustrates a rare example of a massive fatal hemorrhage due to disruption of a large paraspinal artery in the setting of a diffuse, infiltrative neurofibroma. This case highlights the potential of benign neurofibromas to infiltrate major blood vessels, leading to extensive bleeding and death.

[Clinical aspects of Neurofibromatosis type 1 seen in the Department of Dermatology at University Hospital Antananarivo, Madagascar]. / Aspects cliniques de la Neurofibromatose de type 1 vue au service de Dermatologie Du Centre Hospitalier Universitaire Antananarivo, Madagascar.

Introduction: Neurofibromatosis 1 (NF1) is an inherited disease, in an autosomal dominant manner, with complex multi-system involvements. Prevalence varies from one country to another. However, little is known about neurofibromatosis in African countries, particularly in Madagascar. Methodology: A descriptive retrospective study from 2014 to 2019 was conducted at the service of dermatology at University Hospital Joseph Raseta Befelatanana in Antananarivo, including all patients with neurofibromatosis according to National Institutes of Health Consensus Conference criteria for whom genealogical investigation could be made. Results: Among 32 cases of NF1 seen during 6 years, 28 cases were included with a sex ratio M/F of 0.87. The mean age was 24 years ranging from 11 to 54 years. Seventeen patients presented sporadic forms. All patients had "café au lait" spots and cutaneous neurofibromatosis. Three cases presented plexiform neurofibromas which cause significant cosmetic and functional problems by their size and their displayed topography. Fifteen patients had Lisch nodules but no case of optic glioma was identified. Neurological symptoms such as learning difficulties, epilepsy and headache were frequent in our case series. However, access to medical imaging was very limited. Scoliosis was the most common orthopedic complication. Conclusion: The clinical manifestations of NF1 are extremely variable. Although the possibility of systemic complications seems to be low, patients must be followed up.

Bone deformities in patients with neurofibromatosis type 1: Single-center experience.

BACKGROUND: Neurofibromatosis type 1 (NF-1) is the most common neurocutaneous syndrome with an autosomal dominant inheritance. However, half of the cases are de novo mutations. Involvement of bone, skin (cafe au lait macules), as well as ocular and tumoral formations is also associated with NF-1. Here, we present our case series of patients with bone deformities. METHODS: The medical files of patients with NF-1 who were followed up by the same doctor in the pediatric neurology outpatient clinic over 2 years were retrospectively analyzed. RESULTS: Overall, 19 girls and 13 boys were diagnosed with NF-1. Of these 32 patients, 12 (nine girls, three boys) were found to have bone pathologies. The average age was of these patients with bone pathology was 7.5 and 9.5 years. Scoliosis, bowing, short stature, and long bone cysts were found in descending order of frequency. Severe adhesions in the hands and feet as well as phalangeal hypoplasia were noted in one patient. CONCLUSION: NF-1 requires a multidisciplinary approach. Routine follow-up is very important as it is known that deformities that affect different systems may appear or increase with age. Severe hand and foot anomalies seen in one of our patients did not seem to be associated with NF-1.

An unusual case of pediatric embryonal rhabdomyosarcoma with subsequent diagnosis of neurofibromatosis type 1.

A 10-month-old girl presented with a 4-month history of a rapidly growing lesion on the lower lip. Initial assessment and Doppler ultrasound supported a diagnosis of pyogenic granuloma. However, emergent biopsy revealed an embryonal rhabdomyosarcoma, a highly malignant tumor commonly associated with cancer-susceptible syndromes including neurofibromatosis type 1 (NF1). Despite having no apparent clinical features of NF1 at initial presentation, she was later found to have multiple café-au-lait spots and a subsequent diagnosis of NF1 was made.

[Neurofibromatosis type 1 initially presented with glaucoma in the Department of Ophthalmology: a case report].

An eleven-year-old boy visited the Department of Ophthalmology due to visual acuity loss accompanied by high intraocular tension in the left eye for one year. Besides glaucoma, the typical ocular manifestations of neurofibromatosis type 1 such as bilateral Lisch nodules of the iris, multiple patchy choroidal nodules and retinal microvascular abnormalities were identified, and Cafe-au-lait macules appeared on the body skin. Based on the medical history, clinical presentation and auxiliary examination results, the diagnosis of neurofibromatosis type 1 with secondary glaucoma in the left eye was confirmed.

Value of a café-au-lait macules screening clinic: Experience from The Hospital for Sick Children in Toronto.

BACKGROUND/OBJECTIVES: Café-au-lait macules (CALMs) are a characteristic feature of neurofibromatosis type 1 (NF1), but also occur in other genetic disorders. Differential diagnosis of CALMs remains challenging and can be stressful for families. We sought to examine the role of an established CALMs screening clinic in diagnosing CALMs-related disorders. METHOD: We retrospectively reviewed patients seen between July 2012 and January 2019 in a CALMs screening clinic at The Hospital for Sick Children, a tertiary pediatric hospital in Toronto, Canada. Pediatric patients were referred because of multiple CALMs or suspected NF1. Selection was based on a chronological referral sample with no exclusions. A pediatric dermatologist examined all patients for CALMs and NF1 manifestations. Genetic testing was offered to confirm a clinical diagnosis or when clinical findings were inconclusive. RESULTS: Three hundred patients, of which 152 (50.7%) were female and had a mean age of 5.6 ± 4.8 years were seen during the study period. NF1 was diagnosed in 76 (25.3%) patients, mosaic NF1 in 38 (12.7%) patients, and 8 (2.7%) patients received other genetic diagnoses. One hundred and twelve (37.3%) patients were diagnosed with isolated CALMs not associated with an underlying genetic disease. Furthermore, 36 (12%) of our patients did not have CALMs. CONCLUSIONS: The CALMs screening clinic aided in the early diagnosis of genetic disorders such as NF1 and distinguished CALMs from other hyperpigmented lesions. We encourage the adoption of this clinic model in referral centers to streamline and optimize care of patients with presumptive diagnosis of CALMs.

[Neurofibromas in Type I Neurofibromatosis. Description of a clinical case and literature review]. / Neurofibromas en la Neurofibromatosis tipo I. Descripción de caso clínico y revisión de la literatura.

Neurofibromatosis type 1 (NF1) is the most frequent genodermatosis. Its cutaneous findings are key for early diagnosis, as they usually appear at early age. Café-au-lait macules are the most known cutaneous findings. Neurofibromas are the most frequent cutaneous tumors in patients with NF1, showing multiple clinical manifestations. They are classified as superficial and deep lesions, and su perficial neurofibromas are subdivided in cutaneous or subcutaneous. Some neurofibromas may be present since birth; however, most appear during adolescence. Neurofibromas constitute 2 out of 7 of the NIH criteria of Neurofibromatosis type 1. Most of them are benign, do not require treatment and their recognition allows an early diagnosis of the disease. OBJECTIVE: To describe and classify neu rofibromas associated with NF1 through a clinical case. CLINICAL CASE: 18-year-old male diagnosed since childhood with NF1 presents with multiple oval nodules on his face, occipital area, and wrist, multiple blue-red macules on his back and an asymptomatic pink plaque in his thigh. Ultrasound of the nodules was suggestive of neurofibromas and a skin biopsy of the lesions in the back and thigh were consistent with cutaneous neurofibromas. CONCLUSION: This case illustrates the varied clinical manifestations of neurofibromas in adolescence. Recognition of neurofibromas by the pediatrician, pediatric neurologist and/or dermatologist is crucial for the early diagnosis of NF1.

Extent of Extraskeletal Manifestations of Fibrous Dysplasia/McCune-Albright Syndrome in Patients with Mazabraud's Syndrome.

Mazabraud's syndrome (MZB) is a rare condition in which fibrous dysplasia of bone/the McCune-Albright syndrome (FD/MAS) co-exists with intramuscular myxomas. Both FD and the myxomas harbor the GNAS-mutation. Recent studies have shown that extraskeletal, GNAS-related features are associated with a more severe phenotype of FD/MAS. However, patients with MZB are often only seen by orthopedic surgeons. We therefore evaluated MZB patients seen in tertiary referral centers from the Netherlands (LUMC), USA (National Institutes of Health) and France (INSERM UMR 1033 (Lyos), Hôpital Edouard Herriot). All FD/MAS patients known in these centers with an additional diagnosis of a myxoma were included. Demographic information and data on disease extent and extraskeletal manifestations of FD/MAS such as precocious puberty (PP) or café-au-lait patches (CAL) were retrieved from patient's medical records. Thirty MZB patients were included: 20 women (67%) and 10 men (33%). Patients received a diagnosis of MZB (median 42 years, range 16-19) significantly later than the diagnosis of FD/MAS (median 30 years, range 0-60), p < 0.01. Twenty-six patients were diagnosed with polyostotic disease (87%). In 97% the myxoma was located near the skeletal FD lesion. The combination of MZB and MAS was made in 13 patients in whom PP (n = 7), CAL (n = 7), GH-excess (n = 3) and hyperthyroidism (n = 3) were present. Other extraskeletal features were (multinodular) goiter (n = 2) and thyroid cysts (n = 1). Furthermore, in this cohort of patients with MZB several (pre-)malignant tumors were observed; ductal carcinoma in situ of the breast in 3 patients (10%), breast cancer in 1 patient (3.3%), intra pancreatic mucinous neoplasms in 3 patients (10%) and liver adenomas in 2 patients (6.6%). A total of 47% of patients with MZB had an additional extraskeletal feature such as an endocrinopathy. In MZB, 87% of patients suffer from polyostotic FD, 43% of patients have extraskeletal GNAS-features such as an hyperfunctioning endocrinopathy and 30% (pre-)malignant tumors. We therefore advocate that MZB patients should undergo a complete screening and long-term follow-up for extent of bone disease, but also extraskeletal GNAS features of FD/MAS.

Transdisciplinary Approach in Type I Neurofibromatosis - Review of Psychiatric Disorders.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant a multisystem genetic disorder that primarily involves the skin and the nervous system. The incidence of the disease is 1:3000-4000 live-born children, equally in both sexes. The diagnosis of NF1 is determined individually with any two of the following clinical features: café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic glioma, distinctive bone lesions and first-degree family relative with NF1. NF1 is a disease most commonly diagnosed and treated by neuropediatricians. RESULTS: Cognitive and behavioral disorders affect between 50-80% of all children with NF1. Children with NF1 show impairments in attention, visual perception, language, executive function, academic skills, and behavior. This requires a multidisciplinary approach to the treatment s as seen in the case we present. Furthermore, NF1 is often associated with psychiatric disorders, which are more frequent in this disease than in general population, according to some studies even up to 33% patients. Psychiatric disorders are more frequent in NF1 than in the general population, particularly in children. They include dysthymia, depressive mood, anxiety, and personality disorders. Bipolar mood disorders or schizophrenia are rather rare. The majority of studies have focused on physical health and neurocognitive function in NF1, whereas psychiatric disorders associated with this disease remain unclear and poorly documented. CONCLUSIONS: We present a case of an eight-year-old boy with behavioural and learning disabilities referred for psychological and psychiatric evaluation as well as an overview of NF-related psychiatric illnesses described in the literature.

Moyamoya syndrome in a child with Legius syndrome: Introducing a cerebral vasculopathy to the SPRED1 phenotype?

Legius syndrome is a disorder of the RAS and mitogen-activated protein kinase (MAPK) pathway first described in 2007 by Eric Legius, et al., that has been considered a milder phenotype than reported in the RASopathy neurofibromatosis type 1 (NF1). However, with approximately 200 cases reported in the literature, the Legius syndrome phenotype remains to be fully characterized. We report a child who presented with moyamoya syndrome and who has Legius syndrome due to a pathogenic variant in SPRED1. Vascular complications such as moyamoya syndrome have been reported in NF1. However, this association has not been reported in Legius syndrome. This child's case may represent an expansion of the clinical phenotype of Legius syndrome, and further study is needed. We emphasize the importance of obtaining neuroimaging studies in patients with Legius syndrome who present with new neurologic deficits.

Coincidental Expression of Classic Hodgkin Lymphoma and Neurofibromatosis Type I and Literature Review.

Neurofibromatosis Type 1 (NF1) is a genetic disorder with an incidence of 1 in 2600 to 3000 individuals. It is a clinical diagnosis characterized by café-au-lait macules, neurofibromas, and axillary and/or groin freckling. Because of genetic mutations in the NF1 gene affecting the Ras/mitogen-activated protein kinase pathway, there is also risk of associated soft tissue sarcomas and hematologic malignancies. However, reports of classic Hodgkin lymphoma in patients with NF1 are sparse. We report an adolescent with NF1 who developed classic Hodgkin lymphoma. Although there is an unclear association between mutations in the NF1 gene and classic Hodgkin lymphoma, further studies are warranted.

Constitutional Mismatch Repair Gene Defect Syndrome Presenting With Adenomatous Polyposis and Cafe au Lait Spots: A Case Report.

INTRODUCTION: Adenomatous polyps in the gastrointestinal system rarely occur in childhood and are accompanied by syndromes such as Familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MUTYH-associated polyposis, Gardner and Turcot syndrome, and also mismatch repair (MMR) gene defects. In this article, we want to present a rare patient who had adenomatous polyposis and in situ carcinoma and was detected biallelic MMR gene defect. CASE: A 16-year-old female patient admitted with painless rectal bleeding, chronic abdominal pain, and anorexia for 1 year. Her physical examination was notable for multiple cafe au lait spots. The colonoscopic and histopathologic examination revealed multiple adenomatous polyps that one of them contains low-high grade dysplasia and in situ carsinoma. Genetic analysis revealed a homozygous mutation in the PMS2 gene [c.1164delT (p.H388Qfs*10) (p.His388GInfsTer10)] and she was diagnosed with constitutional MMR gene defect syndrome. Polypectomy was performed 4 times in 2 years period. Then, the patient's last colonoscopic examination revealed a large broad polyp in the rectum and multiple polyps in the other colon segments, and she underwent colectomy because of high risk of colorectal cancer. CONCLUSIONS: Adenomatous polyps are very important in childhood because of rarity. In particular, the presence of cafe au lait spots and a history of malignancy detected in relatives at an early age must be considered for CMMRD.