제1형 신경섬유종증 환자들에서 관찰된 망막미세혈관이상 소견

최형준(Hyung Jun Choi),윤정현(Jung Hyun Yoon),손병재(Byeong Jae Son),황수경(Su Kyeong Hwang),전보영(Bo Young Chun) 대한안과학회 2021 대한안과학회지 Vol.62 No.2

목적: 제1형 신경섬유종증 환자에서 관찰되는 망막미세혈관이상의 양상과 빈도를 알아보고자 하였다. 대상과 방법: 제1형 신경섬유종증 환자 61명과 전신질환 및 안과적 이상이 없는 대조군 61명의 안저촬영사진을 후향적으로 비교 분석하였다. 단순혈관굴곡, 나선상의 망막혈관, 모야모야형 패턴 양상으로 나타나는 망막미세혈관이상 유무를 확인하였고, 제1형 신경섬유종증에 대한 진단민감도, 진단특이도, 양성예측도, 음성예측도 및 진단정확도를 분석하였다. 결과: 환자군 중 19.7% (12명)에서 망막미세혈관이상이 있었으며, 대조군에서는 해당되는 경우가 없어서, 환자군과 대조군 간 망막미세혈관이상 유무는 의미있는 차이를 보였다(p=0.0003). 망막미세혈관이상을 보이는 환자 12명 중 11명은 단순혈관굴곡 양상이, 1명은 나선상의 망막혈관 양상이 관찰되었으며 1명은 2가지 소견 모두 나타내었다. 제1형 신경섬유종증에 대한 망막미세혈관이상의 진단민감도는 23.53%, 진단특이도는 100%, 양성예측도는 100%, 음성예측도는 61%였다. 진단정확도는 65.18%로, 리쉬결절의 진단정확도인 79.5%보다 다소 낮았으나, 신경섬유종의 진단정확도인 68.03%와 필적하는 진단정확도를 보였다. 결론: 제1형 신경섬유종증 환자군의 19.7%에서 망막미세혈관이상이 관찰되었으며 이 중 단순혈관굴곡 양상이 가장 많았다. 망막미세혈관이상이 대조군에서는 전혀 없었고, 진단정확도가 65.18%임을 고려하면 이는 제1형 신경섬유종증의 새로운 안과적 임상양상에 포함될 수 있을 것이다 Purpose: To evaluate the findings and frequencies of retinal microvascular abnormalities observed in patients with type 1 neurofibromatosis. Methods: Fundus photographs of 61 patients with type 1 neurofibromatosis and 61 controls without systemic disease or ophthalmic abnormalities were retrospectively compared and analyzed. The presence or absence of retinal microvascular abnormalities in the form of simple vascular tortuosity, corkscrew retinal vessels, and moyamoya-like patterns was confirmed, and the diagnostic sensitivity, diagnostic specificity, positive predictive value, negative predictive value, and diagnostic accuracy for type 1 neurofibromatosis were analyzed. Results: Retinal microvascular abnormalities were found in 19.7% (12 patients) of the patient group, There was no cases in the control group, thus. The difference between the patient group and the control group was significant (p = 0.0003). Of the 12 patients with abnormalities, 10 exhibited simple vascular tortuosity, one had corkscrew retinal vessels, and one exhibited both findings. The diagnostic sensitivity of retinal microvascular abnormalities for type 1 neurofibromatosis was 23.53%, the diagnostic specificity was 100%, the positive predictive value was 100%, and the negative predictive value was 61%. The diagnostic accuracy was 65.18%, which was slightly lower than the 79.5% diagnostic accuracy for the Lisch nodule, but the diagnostic accuracy was comparable to that of neurofibroma (68.03%). Conclusion: Retinal microvascular abnormalities were observed in 19.7% of type 1 neurofibromatosis patients, of which simple vascular tortuosity was the most common. Considering that retinal microvascular abnormalities were not observed at all in the control group, and the diagnostic accuracy was 65.18%, this type of abnormality could be included as a new ophthalmic clinical feature of type 1 neurofibromatosis.

제1형 신경 섬유종증 (Neurofibromatosis Type 1)에 병합된 미세 변화성 신증후군

이정욱 ( Joung Wook Lee ),정현철 ( Hyun Chul Jung ),이수봉 ( Soo Bong Lee ),곽임수 ( Ihm Soo Kwak ),나하연 ( Ha Yeon Rha ) 대한신장학회 2002 Kidney Research and Clinical Practice Vol.21 No.6

Neurofibromatosis type 1 is the most common neurocutaneous disorders and affects between 1/2,000 and 1/4,500 people. This occurs at any age and is hereditary disease with autosomal dominant fashion.. Renovascular hypertension is major form of renal manifetation of the disease. There are few reported cases in Japan and Hungary of Recklinghausen`s neurofibromatosis with several glomerular lesions but their relationship is not apparent. A 21-year-old man was admitted to the hospital because of general edema. On admission, the blood pressure was 130/80 ㎜Hg and general edema was noted. He had a plexiform neuroma on right flank and multiple cafe-au-lait spots on chest and extremites. Laboratory findings were as follows; Hemoglobin 14.2 g/dL, AST 28 IU/L, ALT 12 IU/L, albumin 1.2 gm/dL, total cholesterol 533 ㎎/dL, urinary protein 4.0 gm/day, C3 86.6 ㎎/dL, C4 19.9 ㎎/dL, HBs Ag/Ab (+/-), HBe Ag/Ab (+/-), HCV Ab (-), HBV DNA probe 6,000 pg/mL. Renal biopsy was performed and the histological findings were compatible with minimal change disease. The immunohistochemical method revealed that HBsAg was negative. We experienced a case of minimal change disease concurrent with Neurofibromatosis type 1, but their relationship is not clear. We report this case with a brief review.

Correlation Between Unidentified Bright Objects on Brain Magnetic Resonance Imaging (MRI) and Cerebral Glucose Metabolism in Patients with Neurofibromatosis Type 1

Sohn, Young Bae,An, Young Sil,Lee, Su Jin,Choi, Jin Wook,Jeong, Seon-Yong,Kim, Hyon-Ju,Ko, Jung Min Korean Society of Medical Genetics and Genomics 2012 대한의학유전학회지 Vol.9 No.2

Purpose: Neurofibromatosis type 1 (NF1), which is caused by mutations of the NF1 gene, is the most frequent single gene disorder to affect the nervous system. Unidentified bright objects (UBOs) are commonly observed on brain magnetic resonance imaging (MRI) in patients with NF1. However, their clinical and pathologic significance is not well understood. The purpose of this study was to investigate the correlation between UBOs and cerebral glucose metabolism measured by $^{18}F$-2-Fluoro-2-deoxy-D-glucose ($^{18}F$-FDG) positron emission tomography (PET) in Korean patients with NF1. Materials and Methods: Medical records of 75 patients (34 males and 41 females) with NF1 who underwent brain MRI and PET between 2005 and 2011 were evaluated retrospectively. Clinical data including demographics, neurological symptoms, and brain MRI and PET findings, were reviewed. Results: UBOs were detected in the brain MRI scans of 31 patients (41%). The region most frequently affected by UBOs was the basal ganglia. The most frequent brain PET finding was thalamic glucose hypometabolism (45/75, 60%). Of the 31 patients with UBOs, 26 had thalamic glucose hypometabolism on brain PET, but the other 5 had normal brain PET findings. Conversely, of the 45 patients with thalamic glucose hypometabolism on brain PET, 26 showed UBOs on their brain MRI scans, but 19 had normal findings on brain MRI scans. Conclusion: UBOs on brain MRI scans and thalamic glucose hypometabolism on PET appear to be 2 distinctive features of NF1 rather than correlated symptoms. Because the clinical significance of these abnormal imaging findings remains unclear, a longitudinal follow-up study of changes in clinical manifestations and imaging findings is necessary.

신경섬유종증 1형: 두개의 새로운 돌연변이에 대한 보고

이호종,김웅전,김우신,고영진,박건,장숙진,강성호 대한진단검사의학회 2021 Laboratory Medicine Online Vol.11 No.2

Neurofibromatosis type 1 (NF1) is characterized by multiple café-au-lait spots, axillary and inguinal freckling, Lisch nodules in the iris, and fibromatous tumors of the skin. We performed direct sequencing of 58 exons comprising the NF1 gene along with the associated intronic regions in suspected cases of NF1. We have detected two different novel frameshift mutations in two cases, respectively. The first case involved a 59-year-old male presenting with neurofibromas and a positive family history of NF1. The patient presented with leiomyomas of the iliac bone and right adrenal gland, and an astrocytoma of the left cerebellum. The mutation in this patient was caused by heterozygous deletion of base A at nucleotide position 3108 (c.3108delA; p.Lys1036Asnfs*14). The second case involved a 25-month-old girl presenting with multiple café-au-lait spots and a positive family history of NF1. The mutation in this patient was caused by heterozygous deletion of base G at nucleotide position 7623 (c.7623delG;p.Ile2541Serfs*7). These novel mutations may be useful for advanced genetic counseling and clinical management of patients with NF1 and their families. 신경섬유종증 1형(NF1)은 피부에 나타나는 밀크커피색 반점, 겨드랑이와 서혜부의 주근깨, 홍채의 Lisch 결절, 신경섬유종 등을 특징으로 한다. 신경섬유종증 1형이 의심되는 환자에서 NF1 유전자의 58개의 엑손과 주변 인트론에 대하여 염기서열분석을 실시하였다. 이를 통해 2명의 환자에서 병원성으로 판단되는 이전에 보고되지 않은 틀이동돌연변이를 검출하였다. 환자1은 59세 남자 환자로 신경섬유종과 가족력이 있었고, 오른쪽 엉덩뼈에 양성 종양, 오른쪽 부신에 양성종양, 좌측 소뇌에 별아교세포종이 발견되었고, 3108번 핵산에 A염기의 이형 결실 돌연변이(c.3108delA; p.Lys1036Asnfs*14)가 발견되었다. 환자2는 25개월 여아로 가족력과 밀크커피색 반점이 있었고, 7623번 핵산에 G염기의 이형 결실돌연변이(c. 7623delG; p.Ile2541Serfs*7)의 틀이동돌연변이가 발견되었다. 새로운 변이의 보고를 통해 신경섬유종증 1형 환자와 가족의 유전상담과 임상관리에 유용하게 사용될 수 있겠다.

Clinical Characteristics of Epilepsy and Its Risk Factors in Neurofibromatosis Type 1: A Single-Center Study

Areum Shin,Jun Chul Byun,Su-Kyeong Hwang,Soonhak Kwon,Yun Jeong Lee 대한소아신경학회 2021 대한소아신경학회지 Vol.29 No.1

Purpose: This study investigated the clinical characteristics and risk factors of epilepsy in patients with neurofibromatosis type 1 (NF1) at a tertiary center. Methods: The medical records of 103 children diagnosed with NF1 from February 2009 to July 2019 were retrospectively reviewed. Demographic features, NF1-related features, seizure characteristics, treatment outcomes, and electroencephalography and brain magnetic resonance imaging (MRI) findings were compared between patients with and without epilepsy. Results: Among the 103 patients (median age, 11.5 years; age range, 1.0 to 34.8), 14 (13.6%) had epilepsy. The median age of seizure onset was 5.8 years (range, 1.1 to 18.9). Focal and generalized seizures were observed in nine (64.3%) and six (42.9%) patients, respectively. Five patients (35.7%) had a history of status epilepticus and one of them died of it. Two patients (14.3%) had drug-resistant epilepsy. On brain MRI obtained at the time of seizure onset, seven (50%) patients had unidentified bright objects and three (21.4%) had other structural abnormalities. Learning disability (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.17 to 17.5) and a family history of epilepsy (OR, 39.7; 95% CI, 3.78 to 416.53), but not structural abnormalities, were significant risk factors for epilepsy. Conclusion: Epilepsy was more common in NF1 patients than in the general population. NF1 patients with epilepsy had various seizure types, but exhibited relatively good outcomes. The types of brain abnormalities were not significantly different between patients with and without epilepsy. Our results suggest that mechanisms other than structural brain abnormalities should be considered epileptogenic in NF1 patients.

Surgical Outcomes and Complications Following All Posterior Approach for Spinal Deformity Associated with Neurofibromatosis Type-1

Park, Byoung-Joo,Hyun, Seung-Jae,Wui, Seong-Hyun,Jung, Jong-Myung,Kim, Ki-Jeong,Jahng, Tae-Ahn The Korean Neurosurgical Society 2020 Journal of Korean neurosurgical society Vol.63 No.6

Objectives : The purpose of this study was to evaluate surgical outcomes and complications of spinal deformity associated with neurofibromatosis type-1 (NF-1). Methods : From 2012 to 2018, patients suffering from spinal deformity associated with NF-1 who underwent surgical correction were identified. Demographic data and radiographic measures were retrospectively reviewed. Pre- and postoperative whole spine radiograph images were used to determine both coronal and sagittal Cobb angles. All of patients underwent 3-dimentional computed tomographic scan and magnetic resonance imaging scan to confirm dystrophic features. For evaluation of clinical outcomes, we surveyed the pre- and postoperative scoliosis research society-22r (SRS-22r) score. Results : Seven patients with spinal deformity associated with NF-1 were enrolled in this study. The mean age of patients was 29.5±1.2 years old. The mean follow-up period was 2.8±1.4 years. The apex of the deformity was located in cervicothoracic (n=1), thoracic (n=4), and lumbar region (n=2). Most patients have poor bone quality and decreased bone mineral density with average T-score of -3.5±1.0. All patients underwent surgical correction via posterior approach. The pre- and postoperative mean coronal and sagittal Cobb angle was 61.6±22.6° and 34.6±38.1°, 56.8±18.5° and 40.2±9.1°, respectively. Mean correction rate of coronal and sagittal angle was 44.7% and 23.1%. Ultimate follow-up SRS-22r score (average score, 3.9±0.4) improved comparing to preoperative score (average score, 3.3±0.9). Only one patient received revision surgery due to rod fracture. No serious complication occurred, such as neurological deficit, and viscerovascular injury. Conclusion : The surgical correction of patients having spinal deformity associated with NF-1 is challenging, however the radiographic and clinical outcomes are satisfactory. The all posterior approach can be a safe and effective surgical option for patients having dystrophic curves associated with NF-1.

Synchronous Gastrointestinal Stromal Tumor and Ampullary Neuroendocrine Tumor in Association with Neurofibromatosis Type 1: A Report of Three Cases

박은규,김희준,이윤호,고양석,허영회,조철균 대한소화기학회 2019 대한소화기학회지 Vol.74 No.4

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary disorder. The pathogenesis of NF1 is suggested to be an alteration of the NF-1 gene, which normally functions as a tumor suppressor. A mutation of NF-1 causes the development of viable tumors in various sites. On the other hand, the synchronous manifestation of a gastrointestinal stromal tumor (GIST) and neuroendocrine tumor (NET) in the background of NF1 is extremely rare. This paper reports three cases treated with surgical intervention along with the long-term follow-up results. Three patients showed synchronous ampullary NET and GIST in association with NF1 supported by postoperative histopathologic analysis. Surgical treatments, such as pancreatoduodenectomy and local excision were applied. No recurrence occurred during the postoperative follow-up period of 10, 9, and 2.7 years. Synchronous GIST and NET in the background of NF1 is extremely rare, but the possible coexistence of other tumors in NF1 patients is relatively higher than that in the general population. Furthermore, both NETs and GISTs occurring in NF1 patients tend to be smaller in size compared to that in the general population. Therefore, when NF1 patients present with vague abdominal discomfort, close attention must be paid to identifying the coexistence of other neoplasms.

The Role of RUNX1 in NF1-Related Tumors and Blood Disorders

Na, Youjin,Huang, Gang,Wu, Jianqiang Korean Society for Molecular and Cellular Biology 2020 Molecules and cells Vol.43 No.2

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. NF1 patients are predisposed to formation of several type solid tumors as well as to juvenile myelomonocytic leukemia. Loss of NF1 results in dysregulation of MAPK, PI3K and other signaling cascades, to promote cell proliferation and to inhibit cell apoptosis. The RUNX1 gene is associated with stem cell function in many tissues, and plays a key role in the fate of stem cells. Aberrant RUNX1 expression leads to context-dependent tumor development, in which RUNX1 may serve as a tumor suppressor or an oncogene in specific tissue contexts. The co-occurrence of mutation of NF1 and RUNX1 is detected rarely in several cancers and signaling downstream of RAS-MAPK can alter RUNX1 function. Whether aberrant RUNX1 expression contributes to NF1-related tumorigenesis is not fully understood. This review focuses on the role of RUNX1 in NF1-related tumors and blood disorders, and in sporadic cancers.

시상하부 과오종과 연관된 성조숙증을 동반한 신경섬유종증 1예

이신애(Shin Ae Lee),김진호(Jin Ho Kim),김선준(Sun Jun Kim) 대한소아신경학회 2018 대한소아신경학회지 Vol.26 No.1

신경섬유종증 1형은 흔히 보일 수 있는 신경피부증후군의 하나로, 담갈색 반점, 겨드랑이 주근깨 모양 색소반, 피부신경섬유종 그리고 Lisch 소결절 등을 특징적으로 나타내며, Neurofibromin을 발현하는 NF1 유전자의 변이가 이 질환의 원인으로 알려져있다. NF1 환아에게 있어서 성조숙증을 같이 동반하는 경우가 있으며, 이런 경우 대부분 시신경 종양과 연관되어있다. 저자들은 NF1에서 시상하부 과오종과 연관된 성조숙증을 동반한 케이스를 보고하고자 하며, 이 환아의 경우 지금까지 보고되지 않았던 NF1 exon 5의 14-bp 결실 돌연변이를 동반하고 있는 바이다. Neurofibromatosis type 1 (NF1) is a common neurocutaneous syndrome that presents with multiple café-au-lait spots, skinfold freckling, dermatofibromas, neurofibromas, and Lisch nodules. Mutations of the NF1 gene, encoding the protein neurofibromin, have been identified as the cause of this disease. NF1 can also present with precocious puberty and be associated with optic pathway tumors. Hypothalamic hamartoma as the cause of precocious puberty in patients with NF1 has been rarely described in the literature. Here, we report the findings for a patient with NF1 and precocious puberty associated with a hypothalamic hamartoma who had a newly discovered 14-bp deletion mutation in exon 5 of NF1. To our knowledge, this is the first time this combination is reported in the literature.

Mutational Analysis of the NF1 Gene in Two Families with Neurofibromatosis 1 Accompanied by Pheochromocytoma

이현승,김세현,김지훈,배은진,홍선택,박이병,김유진,이시훈 대한내분비학회 2011 Endocrinology and metabolism Vol.26 No.2

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant inherited disorders affecting the nervous system. NF1 is associated with mutations in the NF1 gene, which is located on chromosome sub-band 17q11.2 and contains 57 exons spanning approximately 300 kb of genomic DNA. NF1 is caused by a loss of function mutation of the NF1 gene, a tumor suppressor gene, which encodes for neurofibromin, a GTPase-activating protein (GAP) involved in the negative regulation of Ras activity. The GAP-related domain, which is encoded for by exons 20-27a, is one of the most important functional domains in neurofibromin. The cysteine-serine-rich domain has been recognized as an important functional domain in NF1-related pheochromocytomas. As the result of many genetic analyses of NF1-related pheochromocytomas, pheochromocytoma has generally been recognized as a true component of NF1. We recently experienced two families with NF1 accompanied by pheochromocytoma. The proband of family 1 is a 31-year-old female diagnosed with NF1 and pheochromocytoma. Gene analysis of the proband and her sister showed that the mutation of the NF1 gene (c.7907+1G>A) led to the skipping of exon 53 during NF1 mRNA splicing. The proband of family 2 is a 48-year-old male who was diagnosed with the same condition. Gene analysis demonstrated the mutation of the NF1 gene (c.5206-8C>G) with missplicing of exon 37. These novel germline mutations did not fall into the GAP-related nor the cysteine-serine-rich domains, but into the C-terminal area of the NF1 gene. This suggests that the correlation between the genotype and phenotype of NF1-related pheochromocytoma is somewhat difficult to characterize. Further studies will be necessary to confirm the function of the C-terminal area of the NF1 gene and its contribution to the development of NF1 and pheochromocytoma.