Waelchli R, Williams J, Cole T, Dattani M, Hindmarsh P, Kennedy H, Martinez A, Khan S, Semple R K, White A, Sebire N, Healy E, Moore G, Kinsler V A
Department of Paediatric Dermatology, Great Ormond Street Hospital for Children, London, WC1N 3JH, U.K.
Childhood Nutrition Research Centre, UCL Institute of Child Health, London, U.K.
Br J Dermatol. 2015 Dec;173(6):1471-8. doi: 10.1111/bjd.14091. Epub 2015 Nov 17.
Multiple congenital melanocytic naevi (CMN) is a rare mosaic RASopathy, caused by postzygotic activating mutations in NRAS. Growth and hormonal disturbances are described in germline RASopathies, but growth and hormone status have not previously been investigated in individuals with CMN.
To explore premature thelarche, undescended testes, and a clinically abnormal fat distribution with CMN through prospective endocrinological assessment of a cohort of subjects with CMN, and a retrospective review of longitudinal growth of a larger group of patients with CMN from outpatient clinics (which included all subjects in the endocrinological assessment group).
Longitudinal growth in a cohort of 202 patients with single or multiple CMN was compared with the U.K. National Child Measurement Programme 2010. Forty-seven children had hormonal profiling including measurement of circulating luteinizing hormone, follicle-stimulating hormone, thyroid stimulating hormone, adrenocorticotrophic hormone, growth hormone, prolactin, pro-opiomelanocortin, estradiol, testosterone, cortisol, thyroxine, insulin-like growth factor-1 and leptin; 10 had oral glucose tolerance testing 25 had dual-energy X-ray absorptiometry scans for body composition.
Body mass index increased markedly with age (coefficient 0·119, SE 0·016 standard deviation scores per year), at twice the rate of the U.K. population, due to increased adiposity. Three per cent of girls had premature thelarche variant and 6% of boys had persistent undescended testes. Both fat and muscle mass were reduced in areas underlying large naevi, resulting in limb asymmetry and abnormal truncal fat distribution. Anterior pituitary hormone profiling revealed subtle and variable abnormalities. Oral glucose tolerance tests revealed moderate-severe insulin insensitivity in five of 10, and impaired glucose tolerance in one.
Interpersonal variation may reflect the mosaic nature of this disease and patients should be considered individually. Postnatal weight gain is potentially related to the underlying genetic defect; however, environmental reasons cannot be excluded. Naevus-related reduction of fat and muscle mass suggests local hormonal or metabolic effects on development or growth of adjacent tissues, or mosaic involvement of these tissues at the genetic level. Premature thelarche and undescended testes should be looked for, and investigated, as for any child.
多发性先天性黑素细胞痣（CMN）是一种罕见的嵌合型RAS病，由NRAS基因的合子后激活突变引起。种系RAS病中描述了生长和激素紊乱情况，但此前尚未对CMN患者的生长和激素状态进行研究。
通过对一组CMN患者进行前瞻性内分泌评估，以及对来自门诊诊所的一大组CMN患者（包括内分泌评估组的所有受试者）的纵向生长情况进行回顾性分析，探讨CMN患者的性早熟、睾丸未降和临床异常的脂肪分布情况。
将202名单发性或多发性CMN患者的纵向生长情况与2010年英国国家儿童测量计划进行比较。47名儿童进行了激素分析，包括测量循环促黄体生成素、促卵泡生成素、促甲状腺激素、促肾上腺皮质激素、生长激素、催乳素、阿黑皮素原、雌二醇、睾酮、皮质醇、甲状腺素、胰岛素样生长因子-1和瘦素；10名儿童进行了口服葡萄糖耐量试验，25名儿童进行了双能X线吸收法扫描以评估身体成分。
由于肥胖，体重指数随年龄显著增加（系数为0·119，标准误为0·016，每年标准差评分），是英国人群的两倍。3%的女孩有性早熟变异型，6%的男孩有持续性睾丸未降。大痣下方区域的脂肪和肌肉量均减少，导致肢体不对称和躯干脂肪分布异常。垂体前叶激素分析显示存在细微且多变的异常。口服葡萄糖耐量试验显示，10名患者中有5名存在中度至重度胰岛素抵抗，1名存在糖耐量受损。
个体差异可能反映了这种疾病的嵌合性质，应针对患者个体进行考虑。出生后体重增加可能与潜在的遗传缺陷有关；然而，也不能排除环境因素。痣相关的脂肪和肌肉量减少表明局部激素或代谢对相邻组织的发育或生长有影响，或者这些组织在基因水平上存在嵌合现象。对于任何儿童，都应寻找并调查性早熟和睾丸未降的情况。
