Neuropsychiatric systemic lupus erythematosus in a girl with neurocutaneous melanosis caused by a somatic mutation in NRAS
Neuropsychiatric systemic lupus erythematosus in a girl with neurocutaneous melanosis caused by a somatic mutation in NRAS
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一名患有由 NRAS 体细胞突变引起的神经皮肤黑变病的女孩的神经精神系统性红斑狼疮
DOI：
10.1093/rheumatology/keac130
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发表时间：
2022
期刊：
影响因子：
5.5
通讯作者：
Takahashi Takao
中科院分区：
文献类型：
--
作者：
Inoguchi Tomohiro;Takenouchi Toshiki;Yamazaki Fumito;Kondo Yasushi;Mitamura Hiroto;Kosaki Kenjiro;Takahashi Takao
亲爱的编辑，儿童系统性红斑狼疮占所有病例的10%-20%，单基因背景的发病率更高[1，2]。由RAS信号级联分子的胚系突变引起的单基因疾病称为Rasopathies。系统性红斑狼疮患者并发系统性红斑狼疮已有零星报道[3]。相反，属于RAS信号级联的NRAS中的体细胞激活突变会导致神经性皮肤黑变病(OMIM#249400)。这种罕见的神经皮肤病表现为巨大的先天性黑色素细胞痣并伴有颅内黑色素沉着症[4]。神经精神性系统性红斑狼疮和神经皮肤黑色素沉着症并存的病例尚未见报道。先证者出生时躯干上有一个巨大的黑色素细胞痣，头部和四肢有卫星皮损(图1a)。虽然她的发育和智力正常，但神经影像显示双侧颞叶呈T1高信号，符合颅内黑变病(图1B)。从她的外周血液和黑色素细胞皮损中提取的DNA进行了直接测序。结果发现NRAS基因外显子2(NM_002524)存在杂合性突变。4)：c.182a>；G p.(Gln61Arg)，ChR1(GRCh38)：在皮肤组织样本中：g.114713908T>；C，但不在外周血样本中(图1C)[4]。10岁时出现亚急性头痛、贫血(血红蛋白5.3g/dl)和血小板减少，血小板计数3.4x10~3/μL。眼底镜检查显示双侧乳头水肿(图1D)。脑MRI显示小脑幕硬脑膜强化(图1E)。对脑脊液的分析显示，脑脊液的开放压力升高到29cmH2O，细胞学检查没有恶性肿瘤的证据。患者接受了静脉注射免疫球蛋白的治疗，导致她的头痛和血液异常得到了短暂的改善。当时ANA阳性，滴度为1：1280，呈均匀斑点状，dsDNA抗体滴度为15.8IU/ml(参考范围0~12IU/ml)，抗Smith抗体滴度为26.4U/ml(参考范围0~9.9U/ml)，ACL滴度为17.9U/ml(参考范围0~9.9U/ml)。补体水平正常。血沉为109 mm/h(参考范围3~15 mm/h)，C反应蛋白正常。患者的库姆斯直接试验呈阳性，没有蛋白尿。因此，通过符合ACR/EULAR和SLICC提出的标准，她被诊断为神经精神性SLE[5，6]。她没有颧疹，其他狼疮皮疹，或口腔溃疡。她最初的头痛症状、颅内压升高的硬脑膜强化和双侧乳头水肿可归因于继发于神经精神性系统性红斑狼疮的肥厚性硬脑膜炎。她接受了糖皮质激素、静脉注射环磷酰胺和HCQ的治疗。这种治疗导致贫血、血小板减少和头痛在1周内得到改善，硬脑膜强化在1个月时完全消失(图1F)。在这里，我们记录了一名10岁女孩的神经精神系统性红斑狼疮的发生，该女孩患有先天性巨大黑色素细胞痣和由NRAS体细胞激活突变引起的颅内黑色素沉着症。她的神经精神性系统性红斑狼疮的特征是硬脑膜炎伴颅内压升高，以及由此导致的头痛和与…相关的高血清学滴度。
DEAR EDITOR, SLE in children represents 10–20% of all cases and has a higher incidence of a monogenic background [1, 2]. Monogenic disorders caused by germline mutations in molecules in the RAS signalling cascade are termed RASopathies. The co-occurrence of SLE in patients with RASopathy has been sporadically reported [3]. In contrast, somatic activating mutations in NRAS, which belongs to the RAS signalling cascade, causes neurocutaneous melanosis (OMIM# 249400). This rare neurocutaneous disorder manifests with large congenital melanocytic nevi accompanied by intracranial melanosis [4]. The co-occurrence of neuropsychiatric SLE and neurocutaneous melanosis has not been previously reported. The proposita was born with a large melanocytic nevus on her trunk with satellite lesions on her head and limbs (Fig. 1A). Although her development and intelligence were normal, neuroimaging demonstrated a T1-hyperintensity in the bilateral temporal lobes, compatible with intracranial melanosis (Fig. 1B). Direct sequencing of DNA extracted from her peripheral blood and melanocytic skin lesion was performed. The results showed a previously reported heterozygous mutation in exon 2 of NRAS (NM_002524. 4): c. 182A> G p.(Gln61Arg), chr1 (GRCh38): g. 114713908T> C in the skin tissue sample, but not in the peripheral blood sample (Fig. 1C)[4]. At the age of 10years, she presented with a subacute onset of headaches, anaemia (haemoglobin, 5.3 g/dl), and thrombocytopenia with a platelet count of 3.4 x 103/μl. A fundoscopic examination showed bilateral papilledema (Fig. 1D). Brain MRI demonstrated dural enhancement in the cerebellar tentorium (Fig. 1E). Analyses of the cerebrospinal fluid showed an elevated opening pressure of 29cm H2O, with no evidence of malignancies upon cytological examinations. The patient was treated with iv immunoglobulin, which led to a transient improvement in her headaches and haematologic abnormalities. However, the headaches and haematologic abnormalities recurred within a few days after the completion of the treatment.At that time, a positive serology for ANA was noted, with a positive titre of 1: 1280 and a ‘homogeneous and speckled’pattern; the dsDNA antibody titre was 15.8 IU/ml (reference range, 0–12IU/ml), the anti-Smith antibody titre was 26.4 U/ml (reference range, 0–9.9 U/ml) and the aCL titre was 17.9 U/ml (reference range, 0–9.9 U/ml). The complement levels were normal. The ESR was 109mm/h (reference range, 3–15mm/h), and the CRP level was normal. The patient had a positive direct Coombs test, and did not have proteinuria. Accordingly, she was diagnosed with neuropsychiatric SLE by meeting the criteria proposed by the ACR/EULAR and the SLICC [5, 6]. She did not have malar rash, other lupus rashes, or oral ulcers. Her initial symptoms of headaches, dural enhancement with increased intracranial pressure, and bilateral papilledema were attributable to hypertrophic pachymeningitis secondary to neuropsychiatric SLE. She was treated with glucocorticoids, iv CYC and HCQ. This treatment resulted in an improvement in the anaemia and thrombocytopenia and her headaches within 1week, and complete resolution of the dural enhancement occurred at 1 month (Fig. 1F). Herein, we document the occurrence of neuropsychiatric SLE in a 10-year-old girl with neurocutaneous melanosis with congenital giant melanocytic nevus and intracranial melanosis caused by a somatic activating mutation in NRAS. Her neuropsychiatric SLE was characterized by pachymeningitis with increased intracranial pressure and resultant headaches and high serology titres associated …