一例努南综合征和柯尔氏症病例:偶然还是必然?

Marco Brusasco, Arlind Kalaja, Francesca Satolli, Claudio Feliciani, Maria Beatrice De Felici Del Giudice
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引用次数: 0

摘要

一名 39 岁的白种女性因患 RAF1 突变的努南综合征(NS)而转诊至我院,她的四肢在两个月前出现了瘙痒性皮损。临床表现为上肢和下肢多发脐状丘疹,中央有角化过度的栓塞(图 1,a-b)。患者无糖尿病或慢性肾功能衰竭病史,但患有肥厚型心肌病。血液检查未发现异常。在对皮肤病变进行组织学检查时,发现了一个角化过度的异位毛囊,其表面有毛发碎片、炎症细胞和表皮穿孔。最终确诊为柯尔氏症(KD)。患者接受了窄带紫外线(NB-UVB)光疗,虽然有残留的萎缩性疤痕(图 1,c-d),但症状得到了彻底、持久的缓解。KD 属于穿孔性皮肤病(PD),这是一组异质性皮肤病,其特点是真皮成分经表皮脱落。尽管对穿孔性皮肤病的分类仍有争议,但传统上公认有四种主要形式:反应性穿孔性胶原病、浆膜穿孔性弹性纤维病、穿孔性毛囊炎和 KD (1)。KD 的典型皮肤表现是圆顶状丘疹和结节的糜烂,中央有白色角化栓,主要发生在四肢和臀部。KD 由 Kyrle 于 1916 年描述,常与全身性疾病相关,尤其是慢性肾功能衰竭和糖尿病。其他相关疾病包括慢性肝病、内脏恶性肿瘤和充血性心脏病(1)。尽管尚未达成共识,但控制潜在疾病仍是首要治疗目标。据报道,局部治疗(角质溶解剂、维甲酸和皮质类固醇激素)和全身治疗(皮质类固醇激素、维甲酸、抗生素和光疗)都能控制皮肤表现(2)。根据我们的经验,NB-UVB 是一种有效的一线疗法,可用于 KD 和其他 PD 的弥漫性病变(3)。NS是一种相对常见的RAS病,是一组以Ras-介质活化蛋白激酶(Ras-MAPK)通路缺陷为特征的异质性遗传疾病,估计发病率为1/1000-2500。PTPN11 是最常见的突变基因,占病例的 50%,但目前已发现十多个基因可导致 NS(4)。典型特征包括明显的面部畸形、身材矮小、肺动脉狭窄和其他不同器官的异常。皮肤是常见的受累部位。角质化障碍和毛发异常,如毛囊角化症、毛囊溃疡、波浪状或卷曲的毛发以及头皮毛发稀少,都是常有的描述。其他皮肤症状包括容易瘀伤、皮肤过度松弛、多发性色素沉着和咖啡斑(5)。据我们所知,迄今为止还没有关于 NS 患者出现 KD 的病例报道。KD 的确切发病机制尚不清楚,但有人推测,糖尿病和慢性肾功能衰竭等全身性疾病可导致物质沉积或真皮层改变,从而引发炎症过程,随后经表皮挤出(1)。在我们的病人身上,我们排除了与 KD 常见相关的所有病因。然而,这种表现有可能是患者疾病的直接结果。我们的患者患有弥漫性毛囊角化症,而表皮角化异常和继发性真皮炎症反应是 KD 的可能致病机制之一(1)。另一方面,NS 典型的皮肤过度松弛和脆弱表明存在结缔组织的改变,这可能会引发异常角质化,继而引发经表皮挤压,以及与遗传性结缔组织疾病相关的穿孔性弹力症(1)。此外,我们的患者患有心脏病,这也是与 KD 相关的另一种疾病(5)。尽管这些解释有其吸引力,但目前还没有足够的证据证明 KD 和 NS 之间存在联系,因此有必要收集更多的数据来证实这一假设。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Case of Noonan Syndrome and Kyrle Disease: Casualty or Causality?

A 39-year-old Caucasian woman affected by Noonan Syndrome (NS) mutated in RAF1 was referred to us with itchy lesions on her limbs that had appeared two months earlier. Clinically, there were multiple umbilicated papules with a hyperkeratotic central plug, localized on the upper and lower limbs (Figure 1, a-b). The patient had no personal history of diabetes mellitus or chronic renal failure, but suffered from hypertrophic cardiomyopathy. Blood tests showed no abnormalities. On histological examination of a skin lesion, an ectatic hair follicle with a hyperkeratotic ostium was observed with fragments of hair, inflammatory cells, and epidermal perforation. A final diagnosis of Kyrle disease (KD) was established. The patient underwent narrowband UVB (NB-UVB) phototherapy with residual atrophic scars (Figure 1, c-d), but with a complete and long-lasting resolution of symptoms. KD belongs to perforating dermatoses (PD), a heterogeneous group of skin diseases characterized by the transepidermal elimination of dermal components. Despite the classification of PD still being under debate, four primary forms are traditionally recognized: reactive perforating collagenosis, elastosis perforans serpiginosum, perforating folliculitis, and KD (1). The typical skin manifestation of KD is an eruption of dome-shaped papules and nodules, with a whitish central keratotic plug, mainly localized on the extremities and the buttocks. Described by Kyrle in 1916, KD is frequently associated with systemic diseases, especially chronic renal failure and diabetes mellitus. Other associated conditions include chronic hepatic disease, internal malignancies, and congestive heart disease (1). Despite the absence of a consensus, the control of the underlying disease remains the first therapeutic target. Both topical (keratolytics, retinoids, and corticosteroids) and systemic treatments (corticosteroids, retinoids, antibiotics, and phototherapy) have been reported to control skin manifestations (2). In our experience, NB-UVB is an effective option as first-line therapy in case of diffuse lesions, both in KD and in other PD (3). NS is a relatively common RASopathy, a heterogenous group of genetic diseases characterized by a defect of the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway, with an estimated prevalence of 1/1000-2500. PTPN11 is the most frequent mutated gene, accounting for 50% of cases, but more than ten genes have been identified as causing NS (4). Classical features include a distinctive facial dysmorphism, short stature, pulmonic stenosis, and other anomalies of different organs. The skin is commonly involved. Keratinization disorders and hair abnormalities such as keratosis pilaris, ulerythema ophryogenes, wavy or curly hair, and scarce scalp hair, are often described. Other cutaneous signs include easy bruising, skin hyperlaxity, multiple lentigines, and café-au-lait spots (5). To the best of our knowledge, no cases of KD in patients with NS have been previously reported to date. The exact etiopathogenesis of KD is not clear, but it has been hypothesized that systemic diseases, such as diabetes and chronic renal failure, can cause a deposit of substances or dermis alterations, which triggers the inflammatory process with subsequent transepidermal extrusion (1). In our patient, we ruled out all the causes commonly associated with KD. It is however possible that this manifestation could be a direct result of the patient's illness. Our patient suffered from diffuse keratosis pilaris, and an abnormal epidermal keratinization with a secondary inflammatory dermic response is among the suggested possible pathogenetic mechanisms of KD (1). On the other hand, the hyperlaxity and fragility of the skin typical of NS suggest the presence of altered connective tissue, which could trigger an abnormal keratinization and, subsequently, the transepidermal extrusion, as well as perforating elastosis, which is associated with genetic connective tissue diseases (1). Moreover, our patient suffered from a cardiac disease, another condition associated with KD (5). Although these explanations have their appeal, there is currently insufficient evidence of a link between KD and NS, and it will be necessary to collect additional data to confirm this hypothesis.

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