Skinfold Freckling Research Articles

Type 1 Neurofibromatosis Sans Neurofibroma: A Case Report Emphasizing the Role of Ocular Examination

Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders and is inherited in an autosomal dominant fashion. NF1 is a member of the RASopathies, a class of congenital disorders brought on by mutations in the Ras/mitogen-activated protein kinase pathway. Dermatologic manifestations are typically prevalent in NF1 individuals. Multiple café-au-lait macules (CALMs) may be present at birth or develop in the 1st year of life. Other cutaneous manifestations like freckles in the skinfolds appear in early childhood. Neurofibromas are present in almost all adult patients and may be cutaneous, subcutaneous, or along the peripheral nerves, but their appearance may be delayed till adulthood. CALMs and skinfold freckling are not specific for NF1, and we may need to consider other differential diagnoses like Legius syndrome. A recent modification of the diagnostic criteria includes the identification of the genetic abnormality to facilitate diagnosis in children who may not have cutaneous neurofibromas. This emphasizes the added value of genetic analysis in a condition which is generally a clinical diagnosis. Lisch nodules generally occur by about 7 years of age and are present in 90% of cases. Their presence can help differentiate from Legius syndrome with its more benign course without genetic analysis. We report the case of a 14-year-old male with NF1 who had no cutaneous neurofibromas to reiterate the importance of ophthalmic evaluation in all cases of NF1, especially in resource-poor settings where genetic studies may not be possible.

Translated article] Neurofibromatosis Type 1: Diagnostic Timelines in Children

Background and objectivesDiagnosis of neurofibromatosis 1 (NF1) diagnosis is challenging in young children without a family history of NF1. The aims of this study were to estimate diagnostic delays in children without a family history of NF1 and to examine the effects of considering café-au-lait macules and skinfold freckling as a single diagnostic criterion. Patients and methodsRetrospective, descriptive, observational study of all patients diagnosed with NF1 before the age of 18 years who were seen at our hospital. The medical records of those included were reviewed to identify the date on which the diagnostic criteria of NF1 were objectified. The patients were categorized into 2 groups: those with a known parental history of NF1 and those without. Café-au-lait macules and skinfold freckling were assessed as a single diagnostic criterion, and genetic evidence was considered to confirm highly suspicious cases. ResultsWe studied 108 patients younger than the age of 18 years with a diagnosis of NF1. Mean (SD) age at diagnosis was 3.94 (±3.8) years for the overall group, 1 year for patients with a parental history of NF1, and 4 years and 8 months for those without. Diagnosis was therefore delayed by 3 years and 8 months in patients without a family history. ConclusionSkin lesions were the first clinical manifestation of NF1 in most patients. We believe that the National Institutes of Health's diagnostic criteria for NF1 should be updated to aid diagnosis in young children.

The NF1 microdeletion syndrome: early genetic diagnosis facilitates the management of a clinically defined disease.

Neurofibromatosis type-1 (NF1) is a genodermatosis frequently encountered in general dermatology. In many patients, the diagnosis of NF1 is made clinically based on the presence of café-au-lait macules and skinfold freckling, as well as plexiform neurofibromas detectable during early childhood. Later in life, cutaneous neurofibromas often represent important diagnostic features. NF1 is characterized by extreme clinical variability and a broad heterogeneity of NF1 gene mutations which impede genotype/phenotype correlations. Notable exceptions are NF1 microdeletions observed in 5-11% of all NF1 patients. Patients with NF1 microdeletions frequently exhibit facial dysmorphic features and a tall stature as rather specific clinical signs. Furthermore, cutaneous and subcutaneous neurofibromas present at an early age, severe global developmental delay and cognitive disability are pathognomonic for the "NF1 microdeletion syndrome". Importantly, NF1 microdeletions are associated with an approximately twofold higher risk for malignant peripheral nerve sheath tumors than intragenic NF1 gene mutations. The severe clinical manifestations of patients with NF1 microdeletions require early multidisciplinary clinical care and frequent tumor surveillance. Therefore, when red flag features for the "NF1 microdeletion syndrome" are present in a patient, genetic testing is necessary to confirm or exclude an NF1 microdeletion.

A CASE REPORT ON NEUROFIBROMATOSIS TYPE 1 IN CHILDREN

Neurofibromatosis1 is an autosomal dominant neurocutaneous disorder occurs due to mutation of NF1 gene on chromosome 172. It affects 1 in 3000 births.There is no sex or racial predilection. It is a multiorgan disease affecting nervous system ,skin and bones. Most cases with NF1 develop hyperpigmented cutaneous macule (café au lait macules),skinfold freckling,lisch nodules and dermal neurofibroma1 Here, we present a case of 4 year old boys with NF1. He was seen by many ophthalmologist outside and was diagnosed with congenital ptosis and reffered to our institute for ptosis management. Ptosis and deterioration of vision is an uncommon presentation.He presented with multiple cutaneous macules,plexiform neurofibroma, ptosis and sphenoid wing dysplasia on imaging. Here, we present a cse report on neurofibrmatosis(NF1) in a four year old child presenting in this mode. The diagnosis of NF1 was made according to the diagnostic criteria laid by National Institute of Health Consensus Development Conference1.

Sudden bilateral lower limb paralysis with dural ectasia in Neurofibromatosis type 1

Abstract Introduction: Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder characterized by pigmented lesions (café-au-lait macules, skinfold freckling, and Lisch nodules), and dermal neurofibromas. In some subjects, NF-1 presents with complications such as brain tumors, skeletal abnormalities, peripheral nerve tumors, and behavioral abnormalities. Patient concerns: We report the case of a 30-year-old man who presented with sudden bilateral lower limb paralysis and acute-onset lower back pain following a fall while rising from a seated position. He denied a history of back pain or muscle weakness before the index event. On examination, the patella and Achilles tendon reflexes were absent bilaterally. The patient presented with a power grade of 0 in all lower limb muscle groups and normal muscle bulk. Diagnosis: Bilateral lower limb paralysis was associated with sensory loss in the T11 dermatome. X-ray, computed tomography, and magnetic resonance imaging (MRI) showed vertebral canal enlargement (dural ectasia) at multiple levels suggestive of a lateral meningocele associated with neurofibromatosis. After repeated MRI studies, herniation of nerve root sleeves was noted, with marked compression of the traversing nerve roots. Notably, there was no evidence of cord compression on either the computed tomography or MRI. The cerebrospinal fluid studies were unremarkable. Interventions: No particular intervention was performed to address specific NF symptoms. In the hospital, the patient received analgesics and antibiotics (gentamicin and cefuroxime) for a urinary tract infection, lactulose for constipation and enoxaparin as anticoagulant prophylaxis. Outcomes: The patient experienced a clinical decline unrelated to his initial symptoms and succumbed to sepsis 6 weeks after admission. The cause of death was not directly linked with NF-1. Conclusion: We report a case of NF-1 with dural ectasia presenting with sudden bilateral lower limb paralysis and lower back pain following mild trauma. Although 70% of dural ectasia cases are associated with NF-1, there are few reports of NF-1 patients with dural ectasia and associated orthopedic complications. Here, we note that dystrophic changes in NF-1 may lead to rapidly aggravating neurological symptoms even after trivial trauma.

Severe Phenotype in Patients with Large Deletions of NF1.

Simple SummaryNeurofibromatosis type 1 (NF1) is a genetic disorder caused by pathogenic variants in the NF1 tumor suppressor gene. In 5–10% of NF1 patients, a large heterozygous deletion of the whole NF1 gene is identified, leading to the commonly called “NF1 microdeletion syndrome”. NF1-deleted patients were previously reported to develop a particularly severe form of the disease with frequent cognitive impairment and an increased risk of benign and malignant tumors. Here, we performed a comprehensive clinical assessment of the largest NF1-deleted cohort to date, including 126 NF1 patients with a deletion of the NF1 gene. This work provides new insights into the specific phenotype associated with NF1 deletions and may contribute to improve the follow-up care of NF1 patients. Complete deletion of the NF1 gene is identified in 5–10% of patients with neurofibromatosis type 1 (NF1). Several studies have previously described particularly severe forms of the disease in NF1 patients with deletion of the NF1 locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. NF1-deleted patients were enrolled and phenotypically characterized with a standardized questionnaire between 2005 and 2020 from a large French NF1 cohort. Statistical analyses for main NF1-associated symptoms were performed versus an NF1 reference population. A deletion of the NF1 gene was detected in 4% (139/3479) of molecularly confirmed NF1 index cases. The median age of the group at clinical investigations was 21 years old. A comprehensive clinical assessment showed that 93% (116/126) of NF1-deleted patients fulfilled the NIH criteria for NF1. More than half had café-au-lait spots, skinfold freckling, Lisch nodules, neurofibromas, neurological abnormalities, and cognitive impairment or learning disabilities. Comparison with previously described “classic” NF1 cohorts showed a significantly higher proportion of symptomatic spinal neurofibromas, dysmorphism, learning disabilities, malignancies, and skeletal and cardiovascular abnormalities in the NF1-deleted group. We described the largest NF1-deleted cohort to date and clarified the more severe phenotype observed in these patients.

Giant mediastinal mass in a 3-year-old boy: A rare presentation of neurofibromatosis type I.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease diagnosed with the presentation of café-au-lait macules, skinfold freckling, iris Lisch nodules, neurofibromas, osseous lesion, and optic gliomas. Mediastinal mass as the first presentation of NF1 is very rare, with a frequency of about 2.7%. Here, we present a rare case of NF1 in a 3-year-old boy admitted with respiratory distress and superior vena cava syndrome.

Clinical spectrum of neurofibromatosis type 1 among children in a tertiary care center.

Objectives:To identify the clinical and neuroradiological features of neurofibromatosis type 1 and the risk of malignancy in a pediatric age group.Methods:This observational retrospective cohort study was conducted at King Saud University Medical City, Riyadh, Kingdom of Saudi Arabia, for the patients with neurofibromatosis type 1 who were seen and had follow up from January 2000 to January 2019.Results:A total of 50 children were included. Approximately 90% of patients presented with café-au-lait macules, and 34% had skin-fold freckling. Moreover, 42% of the participants had a first-degree relative with neurofibromatosis type 1, and about a quarter presented with associated epilepsy. About 90% of the neuroradiological features were consistent with those of neurofibromatosis type 1. About 52% of the patients had one or multiple types of tumors, and 34% presented with optic pathway glioma.Conclusion:This study described clinical spectrum of neurofibromatosis type 1 among children. It showed also a higher percentage of tumors than previous studies.

Nerwiakowłókniakowatość typu I — obraz kliniczny i diagnostyka

Disorders in the embryonic development affecting three germ layers result in the formation of skin-muscular syndromes — phakomatoses. Type 1 neurofibromatosis (NF-1) is the most common phakomatosis. NF-1, also known as Recklinghausen’s disease, occurs at a frequency of 1:2500–1:3000, with equal distribution in males and females regardless of race, and is caused by mutations of the NF1 gene on the long arm of chromosome 17q11.2. This is an autosomal dominant disease with variable gene expression and incomplete penetration, resulting in variable clinical picture. Over 70% of patients are diagnosed between 5th and 18th year of age. Cafe-au-lait spots, neurofibromas, plexiform neurofibromas, skinfold freckling, optic nerve glioma, Lisch nodules and skeletal abnormalities are the most common symptoms. Cafe-au-lait spots occur in 99% of patients, but neurofibromas, which are tumors of the peripheral nerve sheaths, are the hallmark of this disease.

Genetic basis of neurofibromatosis type 1 and related conditions, including mosaicism.

Neurofibromatosis type 1 (NF1) is a frequent autosomal dominant disorder characterised by café-au-lait maculae (CALM), skinfold freckling, iris Lisch nodules and benign peripheral nerve sheath tumours (neurofibromas). The NF1 gene is a tumour suppressor gene and NF1 individuals have an increased risk for a long list of tumours, all resulting from a second hit in the normal copy of the NF1 gene. Remarkably, some non-tumour phenotypes such as CALM and pseudarthrosis are also caused by a "second hit". Germline mutations inactivating the NF1 gene show a large variability in genetic mechanisms ranging from single-nucleotide substitutions and somatic mosaicism to large deletions affecting neighbouring genes. Molecular confirmation of the clinical diagnosis is becoming increasingly more important to differentiate NF1 from other syndromes such as Legius syndrome, to investigate genotype-phenotype correlations relevant in 10% of cases and to detect somatic mosaicism. Some degree of learning difficulties, attention deficit and social problems are observed in most children and affect quality of life. There is a large individual variability in complications and the evolution of the disease is difficult to predict. Specialised outpatient clinics for children have been widely established and are important for surveillance and guidance. Regular surveillance is also important for adolescents and adults because many tumour complications can be detected by whole-body MRI and treated even before symptoms develop and irreversible damage occurs. Recent data on nodular plexiform neurofibromas with continued growth in adolescents and young adults show that many of these tumours are premalignant lesions called atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP). Specific surveillance and timely local resection of these benign peripheral nerve sheath tumours might be important to prevent malignant degeneration. In the last years, targeted therapy with MEK inhibitors has shown promise to treat unresectable and symptomatic plexiform neurofibromas. Many more challenges remain to find the best way to monitor children and adults for potential complications and to find a satisfying cure for many complications in this disorder.

Hypopigmented macules in neurofibromatosis type 1: A case control study

To the Editor: Neurofibromatosis type 1 (NF1) is an autosomal dominant, neurocutaneous disorder. In most cases, cutaneous pigmentary manifestations are the main diagnostic clue. NF1 is characterized by hyperpigmentation—café au lait macules (CALMs), skinfold freckling, and melanotic plexiform neurofibromas. However, hypopigmented lesions have received little attention in patients with NF1. Riccardi1Riccardi V.M. Neurofibromatosis and Albright's syndrome.Dermatol Clin. 1987; 5: 193-203Abstract Full Text PDF PubMed Google Scholar described the presence of hypopigmented macules (HMs) in approximately 2% to 3% of patients with NF1 in 1987. Studies regarding the physiopathology of HM in NF1 are lacking. This study aimed to characterize the prevalence of HMs in our pediatric patients diagnosed with NF1. A case-control prospective study design was used to compare the prevalence of HMs in 108 patients diagnosed with NF1 (younger than 18 years) and 137 healthy age-matched control individuals. All patients included in the cases cohort had a confirmed diagnosis of NF1. We required a third National Institutes of Health criterion or genetic testing in children who exclusively showed CALMs and skinfold freckling. The patients were enrolled from October 2014 to January 2017. We also assessed the number, location, size, and morphology of HMs in our patients. Well-circumscribed lesions, those with early onset in life, and stable hypomelanosis were considered HMs. Patients with postinflammatory hypomelanosis and other possible causes of hypopigmentation as well as vitiligo or nevus anemicus (NA) were excluded. All HMs became erythematous after rubbing, unlike NA. All participants signed informed consent. We observed that 13.9% (n = 15) of patients showed HMs. In the control group 4.4% (n = 6) children presented with HMs. The prevalence of HMs in the cases group was significantly higher than in the control group (Pearson chi-square test P value = .008). Demographic and clinical characteristics are shown in Table I. The HM sizes ranged from 0.5 to 9 cm, and all presented with well-defined or sharp margins (Fig 1 and Supplemental Fig 1; available via Mendeley at https://doi.org/10.17632/6w3g76nyxr.2). Parents recalled the presence of HMs from birth in 4 (22.2%) children.Table IDemographic and clinical characteristicsClinical featuresPatients with NF1 (N = 108)Control individuals (N = 137)HMs, n (%)15 (13.9)6 (4.4)Age when HMs first noticed, y Mean4.24.7 Range0-103-13Sex, n (%)P = .132P = 1 Male9 (60)3 (50) Female6 (40)3 (50)Distribution Solitary, n (%)12 (80)6 (100) Range1-2 Mean ± SD1.2 ± 0.41Location, n (%) Thorax6 (40)3 (50) Legs5 (33.3)1 (16.6) Abdominal3 (20)0 Arms2 (13.3)1 (16.6) Lumbar1 (6.6)1 (16.6) Neck1 (6.6)0Size, cm, n (%) <14 (22.2)2 (33.3) 1-513 (72.2)4 (66.6) >51 (5.6)0Morphology, n (%) Ash-leaf6 (33.3)0 Rounded5 (27.8)3 (50) Oval5 (27.8)3 (50) Polygonal2 (11.1)0HM, Hypopigmented macule; SD, standard deviation. Open table in a new tab HM, Hypopigmented macule; SD, standard deviation. Although CALMs are present in almost all patients with NF1, the prevalence of circumscribed hypomelanosis has not been characterized. The differential diagnosis for HMs included tuberous sclerosis complex (TSC) hypomelanotic macules, NA, vitiligo, pityriasis alba, postinflammatory hypopigmentation, and piebaldism. The simultaneous occurrence of NF1 and TSC in a single individual is extremely rare,2Samanta D. Bosanko K.B. Zarate Y.A. An infant with ash-leaf and café au lait spots: a case of double phakomatosis.Acta Neurol Belg. 2016; 117: 323-324Crossref PubMed Scopus (1) Google Scholar and our patients did not show other signs of TSC. The HMs observed in patients with NF1 fulfilled the Coupe clinical diagnostic criteria and could be considered nevus depigmentosus (ND).3Coupe R.L. Unilateral systematized achromic naevus.Dermatology. 1967; 134: 19-35Crossref Scopus (40) Google Scholar,4Kim S.K. Kang H.Y. Lee E.S. Kim Y.C. Clinical and histopathologic characteristics of nevus depigmentosus.J Am Acad Dermatol. 2006; 55: 423-428Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar ND is the best characterized congenital, stable throughout life, well-circumscribed hypopigmented lesion.3Coupe R.L. Unilateral systematized achromic naevus.Dermatology. 1967; 134: 19-35Crossref Scopus (40) Google Scholar ND occurs in approximately 0.4% to 0.7% of infants,5Baselga E. Disorders of hypopigmentation.in: Schachner L.A. Hansen R.C. Pediatric Dermatology. 4th ed. Mosby Elsevier, Philadelphia, PA2012: 719-722Google Scholar so the HM prevalence in our series (13.9%) was higher than expected. Thus, our results suggest a statistical relationship between NF1 and HMs (P < .008). However, the pathophysiologic explanation of the higher prevalence of HMs in the NF1 population remains unknown. We conclude that HMs are a common finding in NF1. This finding could be either a coincidence or truly associated with NF1. Basic research investigations are needed to achieve a better knowledge of HM physiopathology.

Legius Syndrome and its Relationship with Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is the most common disorder characterized by multiple café-au-lait macules. Most individuals with this autosomal dominant disorder also have other features, such as skinfold freckling, iris Lisch nodules and benign or malignant peripheral nerve sheath tumours. Legius syndrome is a less frequent autosomal dominant disorder with similar multiple café-au-lait macules and skinfold freckling. Legius syndrome is not characterized by an increased risk of tumours, and a correct diagnosis is important. In young children with a sporadic form of multiple café-au-lait macules with or without freckling and no other manifestations of NF1 these 2 conditions cannot be differentiated based on clinical examination. Molecular analysis of the NF1 and SPRED1 genes is usually needed to differentiate the 2 conditions. Other less frequent conditions with café-au-lait macules are Noonan syndrome with multiple lentigines, constitutional mismatch repair deficiency and McCune-Albright syndrome.

Ossifying Fibroma of Maxilla in a Female Affected by Neurofibromatosis Type 1

Ossifying fibroma is a benign fibro-osseous lesion found exclusively in jaws. It has a predilection for premolar-molar region in the mandible. The occurrence of OF as solitary lesions with no underlying disease is common in jaws. However its co-existence in patients with neurofibromatosis type 1 (NF1) has not been described in jaws. NF1, also known as von Recklinghausen's disease or peripheral neurofibromatosis, is an autosomal dominant multisystem disorder that approximately affects 1 in 2500-3000 births. The common manifestations of this disease include Café-au-lait macules, skinfold freckling, cutaneous neurofibromas, blue-red and pseudoatrophic macules on skin, plexiform neurofibroma, scoliosis, optic glioma. So far only one case of ossifying fibroma (OF) in such patients has been reported in the skull but not in the maxillofacial region. We report a case of OF of the maxilla in a 45year old female suffering from NF1. To the best of our knowledge this is the first case report where OF occurred in the maxilla in patient with NF1.

Novel and Recurring Disease-Causing NF1 Variants in Two Chinese Families with Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder primarily characterized by multiple café-au-lait macules, peripheral neurofibromas, skinfold freckling, and Lisch nodules. The causative genetic factor is the neurofibromin 1 gene (NF1), which encodes a Ras GTPase-activating protein called neurofibromin. NF1 variants may lead to loss of neurofibromin function and activation of downstream cell growth. This study aims to discover the disease-causing variants responsible for NF1 in two Han Chinese families by using exome sequencing combined with Sanger sequencing. A recurrent missense variant c.269T>C (p.Leu90Pro) and a novel nonsense variant c.2993dupA (p.Tyr998*) in the NF1 gene were identified. These variants co-segregated with the disorder in the pedigrees and were absent in the normal controls. The results broaden the NF1 mutation spectrum responsible for NF1. This may be helpful in genetic counseling, clinical management, and gene-targeted therapies for NF1.

Independent NF1 mutations underlie café-au-lait macule development in a woman with segmental NF1.

Segmental neurofibromatosis type 1 (NF1) is an under-recognized form of NF1 caused by postzygotic somatic loss-of-function NF1 gene mutations that affect a subset of cells in the body.1 This is in contrast to classic or generalized NF1, in which a germline NF1 gene mutation affects all diploid cells in the body. In the segmental NF1 variant, individuals typically exhibit clinical features characteristic of generalized NF1, such as café-au-lait macules (CALMs), skinfold freckling, and neurofibromas, restricted to one segment of the body. For this reason, establishing the diagnosis can be challenging because the underlying NF1 gene mutation is often not detected in the blood. Underscoring the challenges of caring for individuals with this variant of NF1, we describe a woman with segmental NF1 referred to us at 22 years of age for evaluation.

Clinical and molecular characterization of 112 single-center patients with Neurofibromatosis type 1

BackgroundThe aim of this retrospective study was to define clinical and molecular characteristics of a large sample of neurofibromatosis type 1 (NF1) patients, as well as to evaluate mutational spectrum and genotype-phenotype correlation. NF1 is a relatively common neurogenetic disorder (1:2500–1:3000 individuals). It is caused by mutations of the NF1 gene on chromosome 17ql1.2, with autosomal dominant pattern of inheritance and wide phenotypical variability. Café-au-lait spots (CALs), cutaneous and/or subcutaneous neurofibromas (CNFs/SCNFs), skinfold freckling, skeletal abnormalities, Lisch nodules of the iris and increased risk of learning and intellectual disabilities, as well as tumors of the nervous system and other organs are its main clinical features.MethodsThe preliminary group collected 168 subjects with clinical suspicion of NF1. They were evaluated following the National Institutes of Health (NIH) criteria for NF1, revised by Gutmann et al. 1997, integrated for 67 of them by molecular testing. According to these references, 112 of 168 patients were diagnosed as NF1. The sample was characterized by an equal sex ratio (57 males, 55 females) and age distribution ranging from 10 days to 60 years of age (mean age, 13 years).ResultsA wide spectrum of clinical features has been observed in our patients. Mutational analysis resulted positive in 51 cases (76%). Twenty-four mutations detected in our cohort have not been reported to date.ConclusionsThis study may contribute to a better definition of genotypic and phenotypic features of NF1 patients, with respect to further insights into the clinical characterization of the disease. In addition, an amplification of the spectrum of mutations in the NF1 gene has been documented.

AB118. Association between clinical phenotypes and neurodevelopmental outcomes in pediatric patients with neurofibromatosis type 1 at Siriraj hospital

Background: Neurofibromatosis type 1 (NF1) is characterized by multiple café-au-lait spots, skinfold freckling, cutaneous neurofibromas, and Lisch nodules. Additional signs and symptoms of NF1 include macrocephaly, skeletal abnormalities, hypertension, and learning disabilities. This study has objective to analyze the association between clinical phenotypes and neurodevelopmental outcomes in pediatric patients diagnosed with NF1 from 2005-2015 at Siriraj Hospital. The neurodevelopmental outcomes included intellectual disability (ID), developmental delay, epilepsy, attention deficit hyperactive disorder (ADHD), and learning disabilities (LD).

Neurofibromatosis type 1.

Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (café-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.

Neurofibromatosis Type 1 Molecular Diagnosis: The RNA Point of View

Neurofibromatosis Type 1 Molecular Diagnosis: The RNA Point of View

Segmental Neurofibromatosis with Visceral Neurofibromas.

Dear Editor: Segmental neurofibromatosis 1 (NF1) is generally accepted to be the result of somatic mosaicism for a NF1 mutation that occurs early in embryogenesis. Segmental NF1 is roughly 10 times less frequent than NF1. This condition is characterized by the typical features of NF1 that are limited to a specific body segment1. The distribution is usually unilateral; however, bilateral occurrences have been reported2. Although deep-seated neurofibromas have been occasionally reported in generalized NF1, extracutaneous manifestations in segmental NF1 have rarely been reported3. A 45-year-old Korean man visited the emergency department in our medical center with signs of an acute abdomen. The history and physical examination revealed a 35-year history of multiple, soft-to-firm, asymptomatic, flesh colored plaques and nodules on the left side of neck, shoulder and upper back (Fig. 1A, B). The plaques had gradually increased in size over time. He had several cafe-au-lait macules, but no skin-fold freckling. His medical history and family history were non-contributory. The ophthalmologic examination revealed Lisch nodules on both the irises. Fig. 1 A 35-year history of multiple, soft-to-firm, flesh colored plaques and nodules on the left side of neck, shoulder (A), and upper back (B). Computed tomography scan. Low attenuated masses in porta hepatis and small bowel mesentery (C, arrows). A contrast-enhanced computed tomography (CT) was performed of the chest and abdomen and revealed diffuse, infiltrative skin and subcutaneous masses. Furthermore, low attenuated masses were also seen in the retroperitoneal space, porta hepatis and small bowel mesentery, and mediastinum (Fig. 1C). The diagnostic laparoscopy revealed multiple nodules in the intraperitoneal space. A resection of the visible nodules in the mesentery of the small bowel was performed for biopsy. The brain CT revealed normal findings. The patient did not undergo any other additional therapy. The histological analysis of the nodules from the skin and the mesentery of the small bowel revealed nodular infiltration of fusiform cells and the presence of oval and fusiform shaped nuclei that formed strands crossing each other. The immunohistochemical examination showed positive staining with S-100 protein. In 1987, Roth et al.4 suggested that segmental neurofibromatosis should be separated into four different subtypes. Roth's classification type II was defined as non-familial and segmental neurofibromatosis with deep systemic involvement as in our case. The frequency of deep-seated neurofibromas in NF1 has been reported to be 44% in abdomen/pelvis and 20% in thorax, respectively1. In contrast to NF1, systemic involvement in segmental NF1 is uncommon3 and the incidence of visceral neurofibromas in segmental NF1 is unknown. Since gastrointestinal neurofibromas are rare, a high degree of suspicion is needed for timely diagnosis. Generally, delay and difficulty arises in the diagnosis of gastrointestinal neurofibromas, due to the presence of non-specific symptoms as well as the predominantly small bowel location5. In our case, the patient reported abdominal pain, but during the laparoscopy the physicians did not observe any other specific findings except for the intra-peritoneal neurofibromas. Consequently, we suspected that the patient had symptomatic intra-abdominal neurofibromas. Surgical excision is the treatment of choice for all symptomatic tumors occurring in patients with NF1, and it may be the same in segmental NF1. However, surgical excision of benign asymptomatic tumors is still controversial. In conclusion, we report a rare case of segmental NF1 with intra-thoracic and intra-abdominal neurofibromas. To our knowledge, this is the first such case report in Korea. If patient with segmental NF1 complains of non-specific abdominal pain, visceral neurofibromas should be considered.