RESUMEN

Sturge-Weber syndrome (SWS) type III, a rare neurocutaneous disorder, presents diagnostic challenges due to its variable clinical manifestations. The present study focuses on enhancing the understanding of this syndrome by conducting a detailed analysis of two pediatric cases and providing a comprehensive review of the existing literature. The cases, managed at the Children's Hospital Affiliated to Shandong University (Jinan, China), highlight the diverse clinical presentations and successful management strategies for SWS type III. In the first case, a 4-year-old male patient exhibited paroxysmal hemiplegia, epileptic seizures and cerebral angiographic findings indicative of left pia mater and venous malformation. The second case involved a 2.5-year-old male patient presenting with recurrent seizures and angiographic findings on the right side. Both cases underscore the importance of considering epileptic seizures, acquired and transient hemiplegia and cognitive impairments in the diagnosis of SWS type III. The present study provides insights into the effective use of both pharmacological and surgical interventions, drawing from the positive outcomes observed in these cases. The findings emphasize the need for heightened awareness and a meticulous approach in diagnosing and treating SWS type III, contributing to the better management and prognosis of this condition.

RESUMEN

Neurocutaneous disorders, also known as phakomatoses, are congenital and acquired syndromes resulting in simultaneous neurologic and cutaneous involvement. In several of these conditions, the genetic phenomenon is understood, providing a pivotal role in the development of therapeutic options. This review encompasses the discussion of the genetic and clinical involvement of neurocutaneous disorders, and examines clinical management and treatment options. With the current advances in genetics, the role of precision medicine and targeted therapy play a substantial role in addressing the management of these conditions. The interconnectedness between therapeutic options highlights the importance of precision medicine in treating each disorder's unique molecular pathway. This review provides an extensive synthesis of ongoing and current therapeutics in the management of such clinically unique and challenging conditions.

RESUMEN

PURPOSE: Tethered spinal cord syndrome (TCS) is characterized by cutaneous attachments on the filum terminale that stretch the spinal cord, leading to musculoskeletal and urogenital sequelae. While the neurocutaneous associations with TCS remain undefined, a recent study reports a high incidence of TCS among a pediatric neurofibromatosis (NF) cohort. This present study utilizes a population-level database to estimate TCS incidence among pediatric patients with neurofibromatosis types 1 and 2 (NF1, NF2). METHODS: The TriNetX Research Network was queried to identify patients diagnosed with NF and/or TCS before the age of 21. Symptomatic TCS requiring surgical intervention was identified using corresponding procedural codes within 12 months following TCS diagnosis. Odds ratios (OR) were calculated to measure the associations of NF1/NF2 with TCS. RESULTS: 19,426 pediatric NF patients were evaluated (NF1: 18,383, NF2: 1042). The average ages of TCS diagnosis among NF1, NF2, and non-NF patients were 12, 16, and 9 years, respectively. The incidence of TCS was 1.2% in NF1 patients and 7.3% in NF2 patients, compared to 0.074% in the general population. The associations of NF incidence with TCS were significantly increased in both NF1 (OR 16.42; 14.38-18.76) and NF2 (OR 105.58; 83.56-133.40) patients compared to the general population. Symptomatic TCS requiring surgical intervention was not significantly associated with NF1/NF2 patients compared to the general TCS population. CONCLUSION: This analysis demonstrates a high incidence of TCS but delayed intervention in pediatric NF patients. Considering TCS counseling, spinal MRI, and earlier intervention may be warranted for NF patients experiencing musculoskeletal symptomatology.

Asunto(s)

RESUMEN

PHACE (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac anomalies, eye anomalies) association has many recognized clinical features. A link between PHACE and non-vascular intracranial lesions has not been well-described. We report three pediatric patients with PHACE and non-vascular intracranial lesions.

Asunto(s)

RESUMEN

BACKGROUND: Spine abnormalities are a common manifestation of Neurofibromatosis Type 1 (NF1); however, the outcomes of surgical treatment for NF1-associated spinal deformity are not well explored. The purpose of this study was to investigate the outcome and risk profiles of multilevel fusion surgery for NF1 patients. METHODS: The National Inpatient Sample was queried for NF1 and non-NF1 patient populations with neuromuscular scoliosis who underwent multilevel fusion surgery involving eight or more vertebral levels between 2004 and 2017. Multivariate regression modeling was used to explore the relationship between perioperative variables and pertinent outcomes. RESULTS: Of the 55,485 patients with scoliosis, 533 patients (0.96%) had NF1. Patients with NF1 were more likely to have comorbid solid tumors (P < 0.0001), clinical depression (P < 0.0001), peripheral vascular disease (P < 0.0001), and hypertension (P < 0.001). Following surgery, NF1 patients had a higher incidence of hydrocephalus (0.6% vs. 1.9% P = 0.002), seizures (4.9% vs. 5.7% P = 0.006), and accidental vessel laceration (0.3% vs.1.9% P = 0.011). Although there were no differences in overall complication rates or in-hospital mortality, multivariate regression revealed NF1 patients had an increased probability of pulmonary (OR 0.5, 95%CI 0.3-0.8, P = 0.004) complications. There were no significant differences in utilization, including nonhome discharge or extended hospitalization; however, patients with NF1 had higher total hospital charges (mean -$18739, SE 3384, P < 0.0001). CONCLUSIONS: These findings indicate that NF1 is associated with certain complications following multilevel fusion surgery but does not appear to be associated with differences in quality or cost outcomes. These results provide some guidance to surgeons and other healthcare professionals in their perioperative decision making by raising awareness about risk factors for NF1 patients undergoing multilevel fusion surgery. We intend for this study to set the national baseline for complications after multilevel fusion in the NF1 population.

Asunto(s)

RESUMEN

BACKGROUND: Wyburn-Mason syndrome (WMS) is a neurocutaneous disorder consisting of vascular malformations of the brain, eye, and skin. These include characteristically high-flow intracranial and intraorbital arteriovenous malformations (AVMs) that present commonly with visual deterioration, headache, and hemiplegia. Complete removal of these lesions is challenging. Most patients are followed closely, and intervention occurs only in the setting of worsening symptoms secondary to AVM growth or hemorrhage. Here the authors present the first known case of a patient with WMS and a pituitary macroadenoma. OBSERVATIONS: A 62-year-old man with a 30-year history of WMS with right basal ganglia and orbital AVMs and right eye blindness presented for new-onset left-sided vision loss. A pituitary adenoma was identified compressing the optic chiasm and left optic nerve. Magnetic resonance imaging and digital subtraction angiography studies were obtained for surgical planning, and the patient underwent an endoscopic transnasal transsphenoidal resection, with significant postoperative vision improvement. LESSONS: Given the variable presentation and poor characterization of this rare syndrome, patients with WMS presenting with new symptoms must undergo evaluation for growth and hemorrhage of known AVMs, as well as new lesions. Further, in patients undergoing intracranial surgery, extensive preoperative imaging and planning are crucial for safe and successful procedures.

RESUMEN

Background: Neurofibromatosis (NF) is an umbrella term that refers to three distinct disease entities: NF Type 1, Type 2, and schwannomatosis. Here, we reviewed the scientific performance and the most influential publications on NF. Methods: A keyword-based search was performed using the Scopus database. The top 100 articles were grouped based on NF types and the studied entities. The differences between the articles, authors, and journals were quantified based on certain parameters. Other parameters were collected for the complete citational analysis. Results: The top 100 articles were published between 1961 and 2020. The most trending period of research was in the 1990s and articles studying the clinical aspect and the underlying genetic correlation made up 84% of all articles from the list. The United States of America (USA) had the highest number of contributions (69 articles, 69%). The top institute of contribution to the list was the Howard Hughes Medical Institute, USA (14 articles, 14%). Author-based analysis reveals that the neurologist D. H. Gutmann from St. Louis Children's Hospital, USA, was the most active and authored 11 articles (11%) on the list. Conclusion: The publication trends show that articles studying medical and surgical management were of little interest. The top 100 articles did not include any randomized control trials, and the highest level of evidence was obtained from reviews of pooled knowledge as well as population-based and longitudinal studies.

RESUMEN

OBJECTIVE: Sturge-Weber syndrome (SWS) is a rare neurocutaneous disorder presenting mostly with a facial port-wine stain and leptomeningeal angiomatosis. More than 85% of the patients are affected by epilepsy by the age of 2 years. Seizure and symptom control is the focus of SWS treatment, since no causal therapy exists yet. For pharmacologically intractable epilepsy, surgery is a treatment option. The aim of this systematic review and meta-analysis was to provide an overview of the literature regarding lesionectomy in SWS with a focus on seizure outcome, complications, and motor and cognitive development. METHODS: The PubMed and Embase databases were searched using a systematic search strategy to identify studies on SWS from their inception until 2021. Two independent researchers assessed the studies for inclusion and quality. Outcome measures were seizure outcome, postoperative complications, and motor and cognitive development. Thereafter, a systematic review was conducted, and a meta-analysis was performed for all included cohort studies. Risk of bias was assessed using the Newcastle-Ottawa Scale. Forest plots have been generated for all outcomes; risk ratio was used for pooled outcomes. A p value < 0.05 was considered as statistically significant. RESULTS: After removal of duplicates, the authors screened 439 articles, of which 9 articles with 150 patients were included. Our case and 5 case reports and 4 retrospective cohort studies were included for systematic review. The latter 4 studies qualified for the meta-analysis. In these 4 articles, 144 patients received surgical treatment: 81 (56%) underwent focal lesionectomy and 63 (44%) hemispherectomy. Pooled outcome analysis for postoperative favorable seizure outcome showed a nonsignificant difference between lesionectomy and hemispherectomy (69.2% vs 87.3%; RR 0.73, 95% CI 0.50-1.08; t = -2.56, p = 0.08). Lesionectomy showed a significantly lower rate for developmental delay and postoperative hemiparesis in comparison with hemispherectomy (29.8% vs 76.3%; RR 0.41, 95% CI 0.28-0.59; z = -4.77, p < 0.0001 and 18.1% vs 100%; RR 0.11, 95% CI 0.06-0.21; z = -6.58, p < 0.0001, respectively). CONCLUSIONS: Based on the limited literature available, lesionectomy leads to a nonsignificant lower seizure control rate, while postoperative developmental or motor deficits are significantly lower compared with hemispherectomy. Therefore, focal lesionectomy remains a valid alternative to hemispherectomy in SWS with a clearly localized epileptogenic area; however, individual case-based decisions in a specialized multidisciplinary team are of paramount importance.

Asunto(s)

RESUMEN

PURPOSE OF REVIEW: Tuberous sclerosis complex (TSC) and neurofibromatosis (NF) are neurocutaneous disorders often encountered by neurologists in clinical practice. This article aims to familiarize adult and pediatric neurologists with common features of these disorders and headache specific evaluation and management. RECENT FINDINGS: Non-malignant intracranial tumors in TSC include cortical tubers (glioneuronal hamartomas), subependymal nodules or subependymal giant-cell astrocytomas (SEGA). Headache disorders in TSC are largely secondary and can cause headaches due to increased intracranial pressure, mass effect, obstructive hydrocephalus, or hemorrhage. Neurosurgical intervention is typically required for management of large SEGAs; however, in patients with increased surgical risk, newer treatment modalities may be offered such as neoadjuvant therapy with an mTOR inhibitor (mTORi). Newer studies indicate headache disorders are more prevalent in neurofibromatosis type 1 (NF1). Primary headache disorders can include migraine and tension-type headache, while secondary headache disorders can be due to associated neoplasms such as optic pathway gliomas or brainstem gliomas, or less commonly vasculopathies such as moyamoya syndrome. Selumetinib is an oral, small molecule mitogen-activated protein kinase (MEK) agent with antineoplastic activity which is in ongoing trials for treatment of NF1-associated pediatric low-grade gliomas. NF1 stands out as having a higher association with primary headache disorders such as migraine. This association may be related to effects of mutation of the neurofibromin gene on pathways involved in pain and migraine genesis, however, warrants future study. Care should be taken when formulating a headache treatment plan to address comorbidities and avoid medications that may be contraindicated.

Asunto(s)

RESUMEN

Sjögren-Larsson syndrome (SLS) is a rare, autosomal recessive neurocutaneous disorder. It is caused by the inheritance of sequence variants in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH). Universal signs of the condition are congenital ichthyosis, spastic paresis of the lower and upper limbs, and reduced intellectual ability. In addition to this clinical triad, patients with SLS experience dry eyes and decreased visual acuity caused by a progressive retinal degeneration. Examination of the retina in patients with SLS often reveals glistening yellow crystal-like deposits surrounding the fovea. This crystalline retinopathy often develops in childhood and is considered pathognomonic for the disease. The metabolic disorder typically shortens lifespan to half that of the unaffected population. However, now that patients with SLS live longer, it becomes increasingly important to understand the natural course of the disease. Our case describes a 58-year-old woman with advanced SLS whose ophthalmic examination illustrates the end-stage of the retinal degeneration. Optical coherence tomography (OCT) and fluorescein angiography confirm the disease is restricted to the neural retina with dramatic thinning of the macula. This case is unique since it is among the most advanced both in terms of chronological age and severity of retinal disease. While the accumulation of fatty aldehydes, alcohols, and other precursor molecules is the probable cause of retinal toxicity, a more complete understanding of the course of retinal degeneration may aid in the development of future treatments. The aim of our presentation of this case is to increase awareness of the disease and to foster interest in therapeutic research which may benefit patients with this rare condition.

Eye issues in Sjogren-Larsson Syndrome Sjögren-Larsson syndrome (SLS) is a rare, inherited condition that affects the skin and nervous system. It is caused by variations in a gene that controls the way fats are broken down in the body. The three key signs of the disease are (1) peeling, dry skin; (2) muscle stiffness and impaired movement of the arms and legs; and (3) reduced intellectual ability. Most signs of the condition appear shortly after birth. Genetic testing and counseling services can help patients and their families to understand what to expect with SLS. Caring for people with SLS requires teamwork by specialists like neurologists and physical therapists. Because eye problems are common, the early consultation of an eye doctor is also important. An eye examination can also confirm the diagnosis of SLS. SLS often causes the eyes to appear red, feel dry, or become irritated. This can make it hard to see in bright light. Decreased vision at night is also common. This is caused by the progressive loss of the central part of the retina which is needed to see fine details. Because SLS shortens lifespan, it is rare for anyone to reach the final stages of the disease. As patients with SLS are living longer, as illustrated by the individual in our case study, it becomes important to understand how the disease progresses. Unfortunately, treatments to restore vision are not yet available. Nevertheless, some protective measures can be taken. Eye examinations in early childhood are important for preventing damage to the eyes. Wearing glasses can improve vision, as well as protect eyes from accidental injury or falls. Eye drops can provide relief from dry eyes, and sunglasses can reduce glare and sensitivity to light. In the future, gene therapy may be used to treat SLS.

RESUMEN

Café au lait macules (CALMs) are a normal and frequent finding in the general population, but multiple CALMs raise the possibility of an underlying neurocutaneous disease like neurofibromatosis type I. Certain features of CALMs like number, size, shape, and distribution are important in identifying children at higher risk of having a neurocutaneous disorder or another genetic disorder. Genetic testing can be especially helpful in establishing a diagnosis in atypical presentations, or when the child is young and other features of the disease aside from CALMs have not manifested.

Asunto(s)

RESUMEN

Neurocutaneous melanocytosis (NCM) is characterized by melanocyte deposition in the leptomeninges and brain parenchyma, primarily occurring in children with large or giant congenital melanocytic nevi (LCMN) or multiple congenital melanocytic nevi. Patients with NCM may develop hydrocephalus and increased intracranial pressure, which can be managed with ventriculoperitoneal (VP) shunting. We present the case of a 16-month-old girl who developed peritoneal carcinomatosis and malignant ascites following VP shunting for hydrocephalus secondary to NCM to increase awareness of this rare, but serious, complication of cerebrospinal fluid diversion.

Asunto(s)

RESUMEN

The Dutch ophthalmologist, Jan van der Hoeve, first introduced the terms phakoma/phakomata (from the old Greek word "ϕαχοσ" = lentil, spot, lens-shaped) to define similar retinal lesions recorded in tuberous sclerosis (1920) and in neurofibromatosis (1923). He later applied this concept: (a) to similar lesions in other organs (e.g. brain, heart and kidneys) (1932) and (b) to other disorders (i.e. von Hippel-Lindau disease and Sturge-Weber syndrome) (1933), and coined the term phakomatoses. At the same time, the American neurologist Paul Ivan Yakovlev and psychiatrist Riley H. Guthrie (1931) established the key role of nervous systems and skin manifestations in these conditions and proposed to name them neurocutaneous syndromes (or ectodermoses, to explain the pathogenesis). The Belgian pathologist, Ludo van Bogaert, came to similar conclusions (1935), but used the term neuro-ectodermal dysplasias. In the 1980s, the American paediatric neurologist Manuel R. Gomez introduced the concept of "hamartia/hamartoma" instead of phakoma/phakomata. "Genodermatoses" and "neurocristopathies" were alternative terms still used to define these conditions. Nowadays, however, the most acclaimed terms are "phacomatoses" and "neurocutaneous disorders", which are used interchangeably. Phacomatoses are a heterogeneous group of conditions (mainly) affecting the skin (with congenital pigmentary/vascular abnormalities and/or tumours), the central and peripheral nervous system (with congenital abnormalities and/or tumours) and the eye (with variable abnormalities). Manifestations may involve many other organs or systems including the heart, vessels, lungs, kidneys and bones. Pathogenically, they are explained by interplays between intra- and extra-neuronal signalling pathways encompassing receptor-to-protein and protein-to-protein cascades involving RAS, MAPK/MEK, ERK, mTOR, RHOA, PI3K/AKT, PTEN, GNAQ and GNA11 pathways, which shed light also to phenotypic variability and overlapping. We hereby review the history, classification, genomics, clinical manifestations, diagnostic criteria, surveillance protocols and therapies, in phacomatoses: (1) predisposing to development of tumours (i.e. the neurofibromatoses and allelic/similar disorders and schwannomatosis; tuberous sclerosis complex; Gorlin-Goltz and Lhermitte-Duclos-Cowden syndromes); (2) with vascular malformations (i.e. Sturge-Weber and Klippel-Trenaunay syndromes; megalencephaly/microcephaly-capillary malformation syndromes; CLOVES, Wyburn-Mason and mixed vascular nevus syndromes; blue rubber bleb nevus syndrome; hereditary haemorrhagic telangiectasia); (3) with vascular tumours (von Hippel-Lindau disease; PHACE(S)); (4) with pigmentary/connective tissue mosaicism (incontinentia pigmenti; pigmentary/Ito mosaicism; mTOR-related megalencephaly/focal cortical dysplasia/pigmentary mosaicism; RHOA-related ectodermal dysplasia; neurocutaneous melanocytosis; epidermal/papular spilus/Becker nevi syndromes; PENS and LEOPARD syndromes; encephalocraniocutaneous lipomatosis; lipoid proteinosis); (5) with dermal dysplasia (cerebellotrigeminal dermal dysplasia); and (6) with twin spotting or similar phenomena (phacomatosis pigmentovascularis and pigmentokeratotica; and cutis tricolor).

Asunto(s)

RESUMEN

Encephalocraniocutaneous lipomatosis "ECCL" is a rare, sporadic neurocutaneous disorder that results from a lethal autosomal mutation surviving by somatic mosaicism. It is characterized by unilateral involvement of skin, eyes and central nervous system in addition to a propensity for mesenchymal tumors. A 30-year-old male with previously controlled epilepsy presented with recurrent seizures. Brain imaging revealed a left parietal parasagittal enhancing tumor, in addition to left sided gyriform calcifications, and bilateral cerebral atrophy and ventricular dilatation more prominent on the left side. He also presented multiple left sided sebaceous nevi and abundant subcutaneous lipomas in addition to left mandibular condylar cysts. The brain tumor was excised, and cytopathology revealed a WHO grade I fibrous meningioma. After a thorough evaluation and exclusion of alternative diagnoses, the patient was diagnosed with definite encephalocraniocutaneous lipomatosis as per Moog's criteria. Several cases of ECCL recently presented with different intracranial neoplasms. Here we report the first case of ECCL in association with meningioma.

RESUMEN

OPINION STATEMENT: Though the majority of nervous system tumors are sporadic, several clinically relevant genetic syndromes are associated with a predisposition to tumors of the central and peripheral nervous system including neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis (SWN). These represent prototypical tumor suppressor syndromes where loss of a tumor suppressor gene-protein impairs the cell's ability to regulate cell proliferation. While clinical manifestations vary widely for each of these syndromes, tumors arising in the peripheral nerve sheath are a unifying feature. Clinical clues should prompt the clinician to recognize the underlying genetic syndrome and screen for associated tumors including, among others, plexiform neurofibromas and gliomas in NF1 and vestibular schwannomas, meningiomas, and spinal ependymomas in NF2. Improvements in mechanistic understanding of how the genetic mutations that underlie these syndromes contribute to tumor formation have led to new advances in targeted therapies. MEK inhibitors have shown promise for treating progressive plexiform neurofibromas in NF1. Bevacizumab has been shown to improve hearing and treat vestibular schwannomas in NF2. This article reviews the currently available data on management of tumors associated with these three syndromes.

Asunto(s)

RESUMEN

Postzygotic mutations of the PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha] gene constitutively activate the PI3K/AKT/mTOR pathway in PIK3CA-related overgrowth spectrum (PROS) patients, causing congenital mosaic tissue overgrowth that even multiple surgeries cannot solve. mTOR inhibitors are empirically tested and given for compassionate use in these patients. PROS patients could be ideal candidates for enrolment in trials with PI3K/AKT pathway inhibitors, considering the "clean" cellular setting in which a unique driver, a PIK3CA mutation, is present. We aimed to assess the effects of blocking the upstream pathway of mTOR on PROS patient-derived cells by using ARQ 092, a potent, selective, allosteric, and experimental orally bioavailable and highly selective AKT-inhibitor with activity and long-term tolerability, currently under clinical development for treatment of cancer and Proteus syndrome. Cell samples (i.e., primary fibroblasts) were derived from cultured tissues obtained from six PROS patients [3 boys, 3 girls; aged 2 to 17 years] whose spectrum of PIK3A-related overgrowth included HHML [hemihyperplasia multiple lipomatosis; n = 1], CLOVES [congenital lipomatosis, overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies, scoliosis; n = 1], and MCAP [megalencephaly capillary malformation syndrome; n = 4]. We performed the following: (a) a deep sequencing assay of PI3K/AKT pathway genes in the six PROS patients' derived cells to identify the causative mutations and (b) a pathway analysis to assess the phosphorylation status of AKT [Ser473 and Thr308] and its downstream targets [pAKTS1 (Thr246), pRPS6 (Ser235/236), and pRPS6Kß1 (Ser371)]. The anti-proliferative effect of ARQ 092 was tested and compared to other PI3K/AKT/mTOR inhibitors [i.e., wortmannin, LY249002, and rapamycin] in the six PROS patient-derived cells. Using ARQ 092 to target AKT, a critical node connecting PI3K and mTOR pathways, we observed the following: (1) strong anti-proliferative activity [ARQ 092 at 0.5, 1, and 2.5 µM blunted phosphorylation of AKT and its downstream targets (in the presence or absence of serum) and inhibited proliferation after 72 h; rapamycin at 100 nM did not decrease AKT phosphorylation] and (2) less cytotoxicity as compared to rapamycin and wortmannin. We demonstrated the following: (a) that PROS cells are dependent on AKT; (b) the advantage of inhibiting the pathway immediately downstream of PI3K to circumventing problems depending on multiple classes a PI3K kinases; and (c) that PROS patients benefit from inhibition of AKT rather than mTOR. Clinical development of ARQ 092 in PROS patients is on going in these patients.

Asunto(s)

RESUMEN

The neurocutaneous disorders (NCDs) embrace an extensive group of developmental disorders associated with involvement of the skin, central nervous system (CNS), and/or the peripheral nervous system (PNS). The neurocutaneous manifestations relate to the common ectodermal origin of these organs. This review intended for the practicing clinical neurologist focuses on selected aspects of the NCDs primarily those associated with cerebrovascular disease. Our emphasis is primarily on those NCDs with genetic heterogeneity and their neurological manifestations.

Asunto(s)

RESUMEN

Children with neurodevelopmental disorders are at increased risk for sleep issues, which affect quality of life, cognitive function, and behavior. To determine the prevalence of sleep problems in children with the common neurodevelopmental disorder neurofibromatosis type 1, a cross-sectional study was performed on 129 affected subjects and 89 unaffected siblings, age 2 to 17 years, using the Sleep Disturbance Scale for Children questionnaire. Children with neurofibromatosis type 1 were significantly more likely to have disturbances in initiating and maintaining sleep, arousal, sleep-wake transition, and hyperhidrosis, but not problems with abnormal sleep breathing, or excessive somnolence. Although the overall sleep scores were higher in children with neurofibromatosis type 1, this was not related to a coexisting attention deficit disorder, cognitive impairment, or stimulant medication use. Collectively, these results demonstrate that children with neurofibromatosis type 1 are more likely to have sleep disturbances, and support the use of appropriate interventions for this at-risk population.