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Canine noninflammatory alopecia: An approach to its classification and a diagnostic aid
犬非炎性脱毛：分类和诊断方法
Monika M. Welle
翻译：王帆
Abstract
摘要
Noninflammatory alopecia is common in dogs and is a frequent cause to consult a veterinarian. It is also a common reason to take biopsies. Noninflammatory alopecia can be attributed to a decreased formation or cytodifferentiation of the hair follicle or the hair shaft in utero, resulting in congenital alopecia. Congenital alopecia often has a hereditary cause, and examples of such disorders are ectodermal dysplasias associated with gene variants of the ectodysplasin A gene. Noninflammatory alopecia may also be caused by impaired postnatal regeneration of hair follicles or shafts. Such disorders may have a clear breed predilection, and alopecia starts early in life. A hereditary background is suspected in those cases but has not been proven. They are referred to as follicular dysplasia although some of these disorders present histologically like a hair cycle disturbance. Late-onset alopecia is usually acquired and may be associated with endocrinopathies. Other possible causes are impaired vascular perfusion or stress. As the hair follicle has limited possible responses to altered regulation, and histopathology may change during the course of a disease, a detailed clinical history, thorough clinical examination including blood work, appropriate biopsy site selection, and detailed histological findings need to be combined to achieve a final diagnosis. This review aims to provide an overview about the known noninflammatory alopecic disorders in dogs. As the pathogenesis of most disorders is unknown, some statements are based on comparative aspects or reflect the authors’ opinion.
非炎性脱毛在犬中很常见，是咨询兽医的一个常见原因。这也是进行活检的一个常见原因。非炎性脱毛可归因于毛囊或毛干在子宫内的形成或细胞分化减少，从而导致先天性脱毛。先天性脱毛通常有遗传性原因，例如外胚层发育不良是因为外胚层发育不良蛋白A基因变异。非炎性脱毛也可能由出生后毛囊或毛干再生受损引起。这种疾病可能有明显的品种倾向性，并且在早期就开始出现脱毛。这些病例可能有遗传背景，但尚未得到证实。它们被称为毛囊发育不良，尽管其中一些疾病在组织学上表现为毛发周期紊乱。迟发性脱毛通常是获得性的，可能与内分泌疾病有关。其他可能的原因是血管灌注受损或压力。由于毛囊对调节改变的反应有限，且组织病理学可能在病程中发生变化，因此需要结合详细的临床病史、包括血液检查在内的全面临床检查、恰当的活检部位选择和详细的组织学检查结果来做出最终诊断。本文旨在对已知的犬非炎性脱毛疾病进行综述。由于大多数疾病的发病机制尚不明确，部分陈述是基于对比或作者的思考观点。
Keywords
关键词
acquired alopecia, canine, congenital alopecia, hair cycle arrest, noninflammatory alopecia
获得性脱毛、犬类、先天性脱毛、毛发周期停滞、非炎性脱毛
Hypotrichosis or alopecia refers to abnormal thinning of hair or complete hair loss in body regions or on the entire body. Alopecia that is not caused by an internal disease with potentially serious consequences to general health is often regarded as a cosmetic problem. However, if the importance of the hair coat for thermal regulation, physical and immunological protection against external insults, dispersion of sebum and pheromones, sensory perception, social interactions, and camouflage are taken into account, alopecia is in any case affecting the physiological and psychological well-being of the affected individual.Dogs with alopecia are more susceptible to sunburn, temperature extremes, comedone formation, as well as bacterial and fungal infections of the skin.
少毛症或脱毛是指机体局部或全身毛发异常稀疏或完全脱毛。不是由对整体健康有潜在严重后果的内科疾病引起的脱毛通常被认为是一个美观性问题。然而，如果考虑到被毛在温度调节、物理和免疫保护免受外界伤害、皮脂和信息素的分散、感觉感知、社交和伪装方面的重要性，在所有脱毛病例中，都会影响患病动物的生理和心理健康。脱毛的犬更容易被晒伤、温度忽高忽低、形成粉刺，以及皮肤的细菌和真菌感染。
An intact hair coat requires faultless hair follicle (HF) morphogenesis during embryonic life and lifelong recurrent reconstitution of the HF. Both HF morphogenesis and the hair cycle (HC) are tightly regulated and depend on a fully functional stem cell compartment. As outlined in the review on HF structure, morphogenesis, and regeneration in the same issue of this journal, the hair coat, after initial follicular morphogenesis, is preserved by repetitive cycles of periodic stages of HF growth (anagen), regression (catagen), and quiescence (telogen). Hair shedding occurs during the exogen phase and follicles that lack a hair shaft (HS) are in the kenogen stage. The duration of the different HC phases varies between species, breeds, and body locations, and is influenced by age, sex, hormones, and day light. Thus, hair may be shorter or longer on specific body parts, it may have different textures on some body parts, or it may be, depending on the time of the year, thicker or thinner. Most dog breeds have an asynchronous HC with a mixture of anagen (average 40%), telogen (average 17%), and kenogen (average 14%) HFs, but some breeds (eg, poodles) have an anagen-dominated HC with more than 90% of the HFs being in anagen. Due to the breed depend variation in hair fiber thickness and length, HF density, and seasonal changes, the clinical and histological assessment of mild hypotrichosis may be difficult and breed-specific aspects have to be taken into account when the hair coat is evaluated clinically or histologically.
完整的被毛需要毛囊(HF)在胚胎期形态完整以及HF的终身反复重建。HF的形态发生和毛发周期(HC)都受到严格的调控，并依赖于一个功能完整的干细胞区。正如本期杂志中关于毛囊结构、形态发生和再生的综述所概述的那样，在初始毛囊形态发生后，被毛通过毛囊生长期(生长期anagen)、消退期(中间期catagen)和静止期(静止期telogen)的周期性重复循环而保持。毛发脱落发生在脱落期（exogen），而缺乏毛干的毛囊则称为无毛静止期（kenogen）。HC不同阶段的持续时间因物种、品种和机体部位不同而不同，并受年龄、性别、激素和日光的影响。因此，特定部位的毛发可能更短或更长，某些部位的毛发可能有不同的质地，或者，根据一年中的时间，它可能更厚或更薄。大多数犬种的HC是不同期的，包括生长期HF(平均40%)、静止期HF(平均17%)和无毛静止期HF(平均14%)，但有些品种(如贵宾犬)的HC以生长期为主，生长期HF超过90%。由于毛发纤维厚度和长度，HF密度和季节变化程度决定了不同品种，轻度少毛症的临床和组织学评估可能是困难的，在临床或组织学评估被毛时，必须考虑到品种特异性的方面。
Alopecia is a common cause for consulting a veterinarian, and a systemic work-up is mandatory to identify the correct underlying cause. Alopecia can be primary or secondary, and in primary cases, it is either noninflammatory or inflammatory.Noninflammatory alopecia is attributed to a decreased formation or cytodifferentiation of HFs or the HSs in utero or an impaired postnatal regeneration of HFs. The decreased formation of HFs or HSs during embryonic life results in congenital onset alopecia and is most often hereditary. In contrast, lateonset alopecia is usually acquired. Certain dog breeds are born with an intact hair coat but may develop noninflammatory alopecia early in life. In these cases, a hereditary cause is likely. However, a monogenetic trait has not been identified in any of these disorders. Inflammatory primary alopecia is caused by increased destruction of HFs and/or HSs. The cause can be either infectious or immune-mediated. In most cases, inflammation targets primarily the HF; however, the HF can also be affected by inflammatory cells that target other components of the skin (eg, sebaceous glands). Examples of inflammatory alopecia are folliculitis caused by infectious agents (bacteria, dermatophytes, or demodex mites), perifollicular inflammation caused by leishmania, or immune-mediated follicular or perifollicular inflammation (eg, alopecia areata, idiopathic mural folliculitis, perifolliculitis, and sebaceous adenitis). Alopecia as a secondary lesion develops most often subsequent to dermal inflammation and pruritus due to hypersensitivity reactions or ectoparasites.
脱毛是咨询兽医的常见原因，必须进行系统性检查以确定正确的潜在病因。脱毛可以是原发性或继发性的，在原发性病例中，它是非炎性的或炎性的。非炎性脱毛归因于HF或HS在子宫内的形成或细胞分化减少，或出生后HF再生受损。胚胎期HF或HS的形成减少可导致先天性脱毛，且最常为遗传性。相反，迟发性脱毛通常是后天获得的。某些犬种出生时被毛完整，但可能在生命早期发展为非炎性脱毛。在这些病例中，可能有遗传原因。然而，在这些疾病中尚未发现单一遗传特征。原发性炎性脱毛是由HF和/或HS破坏增加引起的。病因可以是感染性的，也可以是免疫介导的。在大多数病例中，炎症主要针对HF;然而，HF也可能受到针对皮肤其他成分(如皮脂腺)的炎症细胞的影响。炎性脱毛的例子包括感染性(细菌、皮肤癣菌或蠕形螨)引起的毛囊炎，利什曼原虫引起的毛囊周炎，或者免疫介导的毛囊或毛囊周炎(如斑秃、特发性毛囊壁性毛囊炎、毛囊周炎和皮脂腺炎)。脱毛作为一种继发性病变，最常发生在过敏反应或体外寄生虫引起的皮肤炎症和瘙痒后出现。
This review aims to provide an overview about primary noninflammatory alopecia in dogs.
本文综述了犬原发性非炎性脱毛的研究进展。
General Considerations and Definitions
概述与定义
The term “dysplasia” is defined as abnormal or disorganized growth or development of cells, tissues, or organs resulting in alterations in size, shape, or organization of body structures. The term “follicular dysplasia” is used for genetically predisposed HF defects, which may be present at birth or develop at young age. With regard to alopecia, it is important to distinguish between (ectodermal) follicular dysplasia and ectodermal dysplasia. While in follicular dysplasia only HFs are affected, in ectodermal dysplasia 2 or more tissues of ectodermal origin are impaired. In human medical literature, ectodermal follicular dysplasia is referred to as nonsyndromic ectodermal dysplasia, whereas ectodermal dysplasia in general is reported as syndromic.
“发育不良”一词是指细胞、组织或器官的异常或无序生长或发育，从而导致机体结构的大小、形状或组织结构的改变。术语“毛囊发育不良”用于遗传倾向性的HF缺陷，可能在出生时出现或在年轻时发生。关于脱毛，重要的是要区分(外胚层)毛囊发育不良和外胚层发育不良。而在毛囊发育不良中，只有HFs受到影响，在外胚层发育不良中，2个或更多的外胚层起源组织受到影响。在人类医学文献中，外胚层毛囊发育不良被称为非综合征型外胚层发育不良，但外胚层发育不良通常被报道为综合征。
Follicular dysplasia can manifest at birth as congenital alopecia. Follicular dysplasias that manifest at birth have been reported in cattle and are known in hairless cat breeds. In dogs, to my knowledge, no congenital follicular dysplasia has been reported, and all congenital alopecic disorders reported in the literature are associated with dental abnormalities and thus are categorized as ectodermal dysplasia. Sole follicular dysplasia in dogs is seen with postnatal onset, and clinical signs appear within the first few years of life. Canine follicular dysplasia that develops after birth is associated with abnormal reconstitution of the inferior portion of the HF or the HS and may present histologically as a cycling defect. In the later cases, the histology is often comparable to acquired HC disturbances, and only the knowledge about the breed affected, the age of onset, and the exclusion of endocrinopathies allows for a definite diagnosis. The fact that hormonal imbalances have been identified in HF dysplasias that develop postnatally suggests a genetic predisposition and explains their histological similarity to acquired HC disorders caused by endocrinopathies. Beside hormones, dysregulation of signaling of molecules derived from ectodermal or mesodermal tissue or a defective stem cell compartment may also affect the cycling capacity of the HF. If the dysplasia results in structural defects of the HS, histological evaluation may fail to see these defects and analysis of the HSs by trichograms or electron microscopy may be required. Follicular dysplasia may also be associated with an impaired function of tissue derived from the neuroectoderm such as in color dilution alopecia.
毛囊发育不良可在出生时表现为先天性脱毛。出生时表现出的毛囊发育不良在牛中已有报道，也见于无毛猫品种。据我所知，在犬类中，没有先天性毛囊发育不良的报道，文献中报道的所有先天性脱毛性疾病都同时有牙齿异常，因此被归类为外胚层发育不良。犬的唯一毛囊发育不良见于出生后发病，临床症状出现在出生后几年内。出生后发生的犬毛囊发育不良与HF或HS下部的异常重建有关，并可能在组织学上表现为毛囊周期缺陷。在后者病例中，组织学通常与获得性HC紊乱相似，只有了解患病品种、发病年龄和排除内分泌疾病才能做出明确诊断。事实上，在出生后发生的HF发育不良中，已确定有激素失调，这一事实提示了遗传易感性，并解释了其与内分泌疾病引起的获得性HC疾病的组织学有相似性。除激素外，来自外胚层或中胚层组织的分子信号失调或有缺陷的干细胞区也可能影响HF的循环能力。如果发育不良导致HS的结构缺陷，组织学评估可能看不到这些缺陷，可能需要通过毛发检查或HS电子显微镜分析。毛囊发育不良也可能与神经外胚层组织功能受损有关，如色素稀释性脱毛。
The term “ectodermal dysplasia” in general refers to clinically and genetically heterogeneous inherited conditions in which the development of 2 or more tissues of ectodermal origin is impaired. Thus, affected animals may present with congenital hereditary alopecia/hypotrichosis and defects in other body locations, including brachygnathism, dental, thymic, or genital abnormalities.
术语“外胚层发育不良”一般是指2个或更多外胚层起源组织发育受损的临床和遗传异质性遗传病。因此，患病动物可能表现为先天性遗传性脱毛/毛少和其他机体部位的缺陷，包括短颌、牙齿、胸腺或生殖器异常。
Ectodermal dysplasia, which is associated with congenital alopecia, is mostly caused by variants of the ectodysplasin A (EDA) gene. EDA is a member of the tumor necrosis factor (TNF) family and is involved in ectodermal/mesodermal interaction. This interaction is essential for the formation of several structures that arise from the ectoderm, including the skin, sweat glands, nails, and teeth. During HF morphogenesis, EDA signaling is important for early placode formation. Binding of EDA-A1 to its receptor (EDAR) results in the recruitment of the intracellular EDAR-associated death domain (EDARADD) adapter protein and the activation of the NF-κB signaling pathway, while EDA-A2 binds to the EDA2R, also known as X-linked ectodermal dysplasia receptor (XEDAR). EDARADD can contribute to hypohidrotic ectodermal dysplasia (HED) in mice, human beings, and bovine. The clinical phenotype depends on the gene variant. Some variants lead to a complete loss of the protein function and a severe clinical picture, whereas other variants are associated with residual EDA activity and milder phenotypes.
与先天性脱毛相关的外胚层发育不良多由外胚层发育不良蛋白A (EDA)基因变异引起。EDA是肿瘤坏死因子(TNF)家族成员之一，参与外胚层/中胚层的相互作用。这种相互作用对于由外胚层产生的几种结构的形成是必不可少的，包括皮肤、汗腺、指甲和牙齿。在HF的形态发生过程中，EDA信号对早期平台的形成很重要。EDA-A1与其受体(EDAR)结合导致细胞内EDAR相关死亡结构域(EDARADD)接头蛋白的募集和NF-κB信号通路的激活，而EDA-A2与EDA2R结合，也被称为x连锁外胚层发育不良受体(XEDAR)。EDARADD可导致小鼠、人类和牛的少汗性外胚层发育不良(HED)。临床表型取决于基因变异。一些变异导致蛋白质功能完全丧失和严重的临床表现，而其他变异与残留的EDA活性和较轻的表型相关。
Hair Cycle Disturbance/Arrest
毛发周期紊乱/停止
As outlined in detail in the review on HF structure, morphogenesis, and regeneration in this journal issue, the maintenance of the HC and thus the reconstitution of the inferior portion of the HF and the HS are highly conserved processes and are tightly regulated. It involves follicular stem cells as well as numerous molecules derived from epithelial, mesenchymal, and neuroectodermal cells as well as the extracellular matrix of the follicular and dermal environment and is influenced by systemic factors such as hormones, age, genetics, and environmental factors, such as the time of the year.
在本刊关于HF结构、形态发生和再生的综述中，详细阐述了HC的维持以及HF和HS下部的重建是高度保守的过程，受到严格的调控。它涉及到毛囊干细胞以及来自上皮细胞、间充质细胞和神经外胚层细胞的许多分子，以及毛囊和真皮环境的细胞外基质，并受到激素、年龄、遗传等全身因素和环境因素(如季节)的影响。
If 1 or several extrinsic or intrinsic factors of this complex regulatory network are deregulated, the delicately balanced crosstalk of the various signals that influence the HC is disturbed and results in deregulation of the HC. It is important, although not known in the dog, to consider that the different primary and secondary HF types may be regulated differently, and thus, a HC disturbance may primarily affect primary or secondary HFs. The distinct regulation of primary and secondary HF morphogenesis and cycling has been shown in mice and Cashmere goat. Depending on the factors that are deregulated and in which stage the different HFs are in at the onset of the deregulation, different HC stages or HF types may be affected. As a consequence, either anagen induction, anagen promotion or cytodifferentiation, catagen induction, catagen promotion, telogen induction or telogen promotion or several of these stages are impaired and the HC disturbance may affect all or only some HF types. As each HC phase has an impact on the consecutive phase, an ongoing HC disturbance will result histologically in a similar clinical phenotype. For example, failure of anagen induction results in a higher number of telogen follicles, which will eventually lose their HSs (kenogen follicles). If lack of anagen induction remains kenogen follicles will become atrophic over time. In a study histologically investigating some of the HC arrest disorders (endocrinopathies, alopecia X, alopecia of unknown origin), we could show that in all of these diseases 3-fold to 4-fold increases of kenogen follicles were seen histologically, whereas the number of anagen follicles was decreased dramatically. The kenogen follicles underwent subsequent atrophy. The abovementioned increased amount of kenogen follicles in alopecia is also observed on the human scalp. It is important to understand that only an increased number of kenogen and atrophic follicles result in the clinical picture of alopecia (Fig. 1a, b). Telogen follicles still have a club hair, and thus, a higher number of telogen follicles do not result in alopecia. Of course during the disease course, it may happen that the number of telogen follicles is transiently increased. It also has to be noted that up to 20% of kenogen HFs may be normal in many dog breeds. They serve as reserve follicles to grow a thicker hair coat, if needed. In contrast, in anagen-dominated dog breeds, and on the human scalp, kenogen HFs are only a small percentage of the HFs present, and in anagen-dominated breeds, some anagen follicles may be present in biopsies from dogs with a HC disorders. Besides the decreased amount of anagen follicles and the increased number of kenogen and atrophic follicles additional histological findings in HC arrest disorders may be (1) increased infundibular keratin and dilation of the infundibula (Fig. 1b), (2) excessive trichilemmal cornification (Fig. 1a), (3) distorted (dysplastic) follicles (see Fig. 7a), (4) transiently increased numbers of telogen follicles (Fig. 1a), (5) transiently increased numbers of catagen follicles, (6) epidermal atrophy (Fig. 1b), (7) epidermal hyperplasia (if secondary infections are present), (8) epidermal hyperkeratosis (Fig. 1a), (9) dermal atrophy, and (10) epidermal hyperpigmentation (Fig. 1b).
如果这个复杂的调控网络中的1个或几个外在的或内在的因素被解除控制，影响HC的各种信号之间微妙的平衡串扰就会被扰乱，导致HC失调。重要的是要考虑不同的原发性和继发性HF类型可能受到不同的调节，因此，HC的干扰可能主要影响原发性或继发性HFs，尽管在犬中尚未了解这一点。在小鼠和绒山羊中，原发性和继发性HF的形态发生和循环具有独特的调节作用。不同的HC阶段或HF类型可能会受到影响，这取决于导致失调的因素以及不同的HF在失调开始时所处的阶段。其结果是生长期诱导、生长期促进或细胞分化、中间期诱导、中间期促进、静止期诱导或静止期促进或其中几个阶段受损，HC的紊乱可能影响全部或仅部分HF类型。由于HC的每个期相都会对相邻期相产生影响，因此持续的HC紊乱会导致组织学上相似的临床表型。例如，生长期诱导失败会导致更多的静止期毛囊，最终会HS消失 (无毛静止期毛囊)。如果缺乏生长期诱导，无毛静止期毛囊将随着时间的推移而萎缩。在一项组织学研究中，我们调查了一些HC停滞性疾病(内分泌疾病，X型脱毛，不明原因的脱毛)，我们可以表明，在所有这些疾病的组织学上，无毛静止期毛囊的数量增加了3到4倍，而生长期毛囊的数量显著减少。无毛静止期毛囊随后出现萎缩。在人的头皮上也观察到脱毛中前述的无毛静止期毛囊数量的增加。重要的是要了解只有无毛静止期和萎缩的毛囊数量增加才会导致脱毛的临床表现(图1a, b)。静止期毛囊仍然有棍棒状毛发，因此，较高数量的静止期毛囊不会导致脱毛。当然在病程中，也可能出现静止毛囊数量一过性增加的情况。还必须注意的是，高达20%的无毛静止期HF可能是正常的许多犬品种。如果需要，它们作为储备毛囊来长出更厚的毛发。相比之下，在生长期占优势的犬种中，在人类头皮上，无毛静止期HF只占HF的一小部分，在生长期占优势的犬种中，一些生长期毛囊可能存在于HC失调的犬的活检组织中。除了生长期毛囊数量的减少和无毛静止期和萎缩毛囊数量的增加，HC停滞性疾病的其他组织学发现可能是(1)漏斗部角质增加和漏斗部扩张(图1b)，(2)毛膜过度角化(图1a)，(3)扭曲(发育不良)毛囊(图7a)，(4)静止期毛囊数量短暂增加(图1a)，(5)中间期毛囊数量短暂增加，(6)表皮萎缩(图1b)，(7)表皮增生(如果有继发性感染)，(8)表皮角化过度(图1a)，(9)真皮萎缩，(10)表皮色素沉着(图1b)。
 Figure 1. Canine skin showing typical features of a hair cycle disturbance. Hematoxylin and eosin. Figure 1a. Numerous telogen hair follicles in which the hair shaft is surrounded by abundant trichilemmal keratin (black arrows) are seen in this image. The hair shafts are also visible in the infundibula, which present with large amounts of infundibular keratin (white arrows surrounded with a black line). As the telogen follicles still harbor a hair shaft, they do not contribute to the degree of alopecia. In this dog, the lack of anagen follicles and the presence of numerous atrophic follicles (black arrows surrounded with a white line) indicate the alopecia seen in this dog. Note, the epidermal hyperkeratosis. Figure 1b. In this biopsy, a follicular compound composed of telogen hair follicles (black arrows) is present but the vast majority of the compounds consist of kenogen follicles, which present in the case with abundant trichilemmal keratin (star). There is also infundibular hyperkeratosis (white arrows surrounded with a black line) and a hyperpigmented, thin epidermis.
图1所示。具有毛发周期紊乱的典型特征的犬皮肤。苏木精-伊红。图1a：图中可见大量静止期毛囊，其中毛干被丰富的外毛根角蛋白(黑色箭头)包围。在漏斗部也可见毛干，有大量的漏斗部角蛋白(白色箭头周围有一条黑线)。由于静止期毛囊仍然有毛干，不会导致脱毛。在这只犬上，生长期毛囊的缺乏和大量萎缩的毛囊(黑色箭头周围有一条白线)表明这只犬的脱毛。注意，表皮角化过度。
图1 b：在该活检中，有一种由静止期毛囊(黑色箭头)组成的毛囊化合物，但绝大多数化合物由无毛静止期毛囊组成，在该病例中，无毛静止期毛囊具有丰富的外毛根毛囊角蛋白(星型)。还有漏斗部角化过度(白色箭头周围有一条黑线)和色素沉着的薄表皮。
The increased percentage of kenogen follicles may be due to different reasons:
无毛静止期毛囊比例的增加的鉴别诊断:
1.Signals that induce a new anagen phase at the end of the telogen phase are missing/reduced. The club hair will be shed eventually during exogen, and the empty follicles remain (hairless telogen/kenogen) and become atrophic over time.
1.在静止期结束时诱导新生长期的信号缺失/减少。在毛发脱落期，成团毛发最终会脱落，而空毛囊仍然存在(无毛静止期)，并随着时间的推移变得萎缩。
2.Exogen has occurred prematurely, and the empty telogen follicle is not yet competent to enter a new anagen phase.
2.毛发脱落期过早发生，空的静止期毛囊还不能进入新的生长期。
3.Signals which are maintaining the anagen phase (anagen promotion) are missing; the HFs enter catagen prematurely and thus enter the subsequent telogen phase earlier. At the same time, the signals which are necessary for anagen initiation are not more effective. This results in a higher number of telogen follicles, which eventually lose the HS and remain in kenogen until adequate signals initiate a new anagen phase.
3.维持生长期(促进生长期)的信号缺失;HF过早地进入下一个静止期，从而更早地进入随后的静止期。与此同时，生长素启动所必需的信号并没有更有效。这导致更多的静止期毛囊，最终失去HS并保持在静止期，直到足够的信号启动进入新的生长期。
The lack of signals to initiate the next HC phase may also be the reason for a transiently increased percentage of catagen or telogen follicles.
缺乏启动下一个HC期的信号也可能是中间期或静止期毛囊比例短暂增加的原因。
The impact of hormones, associated with canine alopecia on the different HC phases, is shown in Figure 2. This figure shows that the same hormone has an effect on various HC phases and underlines why histology may look alike in all HC arrest disorders and the histologic features are dependent on the disease duration and the HC phase at the time of disease onset.
与犬脱毛相关的激素对不同HC期的影响如图2所示。该图显示相同的激素对不同的HC阶段有影响，并强调了为什么所有HC停滞疾病的组织学看起来都很相似，组织学特征取决于疾病持续时间和疾病发作时的HC阶段。
Figure 2. The impact of glucocorticoids, estrogens, thyroid hormones, and stress-related molecules on the hair cycle. The same hormone or molecule may have an effect on various hair cycle phases, which explains that endrocinopathies may histologically look alike and also that other factors such as stress might result in a hair cycle disturbance. Note that thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T3/4) have an stimulating effect on the hair cycle, whereas estrogens and glucocorticoids have an inhibitory effect.
图2。糖皮质激素、雌激素、甲状腺激素和应激相关分子对毛发周期的影响。相同的激素或分子可能对不同的毛发周期阶段有影响，这解释了内分泌疾病可能在组织学上看起来相似，也解释了其他因素(如：应激)可能导致毛发周期紊乱。需要注意的是，促甲状腺激素(TSH)、三碘甲状腺原氨酸(T3)和甲状腺素(T3/4)对毛发周期有刺激作用，而雌激素和糖皮质激素有抑制作用。
Alopecia With Congenital Onset
先天性脱毛
Congenital alopecia refers to the widespread to complete absence of hair at birth. It is seen regularly by breeders and in veterinary clinics but only a limited number of cases have been reported in the literature, and even a smaller number have been worked up genetically. Novel techniques, such as whole genome sequencing, facilitate the discovery of the causative gene variants, and the number of cases with a known underlying gene variant is increasing.
先天性脱毛是指出生时毛发普遍或完全缺失。饲养员和兽医诊所经常看到这种情况，但在文献中只报告了有限数量的病例，甚至更少的数量是由基因引起的。全基因组测序等新技术有助于发现致病基因变异体，而已知潜在基因变异体的病例数量正在增加。
Congenital alopecia is not always inherited, but may also be caused by a metabolic imbalance or an in utero infection. However, noninherited cases, such as maternal dietary iodine deficiency or intrauterine virus infections, have been reported in farm animals only. Congenital alopecias in dogs follow monogenetic inheritance patterns and are inherited through autosomal recessive, autosomal dominant, or X-linked modes. De novo mutations have been seen as well. Depending on the gene affected, HF morphogenesis can be disturbed during induction, organogenesis, or cytodifferentiation.
先天性脱毛并不总是遗传的，但也可能是由代谢失衡或子宫内感染引起的。然而，非遗传性病例(如母亲膳食碘缺乏或子宫内病毒感染)仅在农场动物中有报道。犬的先天性脱毛遵循单一基因遗传模式，常染色体隐性、常染色体显性或x连锁遗传模式。也观察到新生突变。根据受影响的基因，HF形态发生可能在诱导、器官发生或细胞分化期间受到干扰。
Accordingly, histology will reveal complete absence of HFs (aplasia caused by impaired HF induction), incomplete HF formation (dysplasia caused by impaired organogenesis), or inner root sheath and/or HS defects (dysplasia caused by impaired cytodifferentiation).If cytodifferentiation of the HS is impaired, HFs may look histologically normal or only the inner root sheath of the inferior portion may present with histological changes such as vacuoles or altered trichohyalin granules. The latter has not been reported in dogs but has in certain cat breeds and cattle. If only HS defects are present, the histological evaluation might fail to make the diagnosis, but trichograms or electron microscopy of HSs may be helpful to identify structural HS defects, which result in hair breakage.
因此，组织学将显示HF完全缺失(由HF诱导受损引起的发育不全)，HF不完全形成(由器官发育受损引起的发育不全)，或内根鞘和/或HS缺陷(由细胞分化受损引起的发育不全)。如果HS的细胞分化受损，HF在组织学上可能看起来正常，或仅下方的内根鞘出现空泡或改变的毛透明蛋白颗粒等组织学改变。后者尚未在犬中报告，但在某些猫品种和牛中有报道。如果仅存在HS缺陷，组织学评估可能无法做出诊断，但HS毛发镜检或电镜有助于识别结构性HS缺陷，从而导致毛发断裂。
Follicular Aplasia
毛囊发育不全
Aplasia of HFs is seen when early placode formation during organogenesis does not occur. The mechanisms that regulate placode formation are complex and insufficiently understood. They have only been studied in detail in rodents.As outlined above, the EDA/EDAR signaling pathway plays an important role in placode formation.
当器官发生过程中没有发生早期的基板形成时，可观察到HF的发育不全。调控基板形成的机制是复杂的，而且还没有得到充分的了解。它们只在啮齿类动物中被详细研究过。如上所述，EDA/EDAR信号通路在基板形成中起重要作用。
Canine ectodermal dysplasia resulting in follicular aplasia has been reported as congenital ectodermal defect, congenital ectodermal dysplasia, and X-linked ectodermal dysplasia. Dogs with ectodermal dysplasia may lack, like other species with the same disease, other structures of ectodermal origin such as eccrine sweat glands, sebaceous glands, lacrimal glands, or nasolabial glands (Fig. 3a).
犬外胚层发育不良导致毛囊发育不全的报道有先天性外胚层缺陷、先天性外胚层发育不良和x连锁外胚层发育不良。患有外胚层发育不良的犬可能像患有相同疾病的其他物种一样，缺乏外胚层起源的其他结构，如分泌汗腺、皮脂腺、泪腺或鼻唇腺(图3a)。
The clinical presentations of canine cases of various breeds have been nicely summarized in reviews and several case reports.The affected animals are completely alopecic or have a reduced number of hairs in various anatomic locations (especially the head, pinnae, neck, back, and tail) (Fig. 3b). Eyelashes and vibrissae may be lacking. The remaining hair has an abnormal texture, and is either coarse or fine, breaks easily, and can be epilated without effort. In some cases, the alopecia and hypotrichosis are most severe in newborn animals, and some fine hairs grow over time.
已有详细的综述和几个病例报告描述了不同品种犬病例的临床表现。患病动物完全脱毛或在各个解剖部位(特别是头部、耳廓、颈部、背部和尾部)毛发数量减少(图3b)。可能缺少睫毛和触须。剩下的毛发质地异常，或粗或细，容易断裂，可以毫不费力地脱毛。在某些病例中，脱毛和毛少在新生动物中最严重，并且随着时间的推移会长出一些细毛。
Several variants in the EDA gene encoding for EDA have been identified causing X-linked HED, the most common form of ectodermal dysplasia in dogs. In a poodle, however, which presented with clinical signs of X-linked HED, no variants in the EDA gene were identified, suggesting that other genes may also cause this disease in dogs.
编码EDA的EDA基因的几个变体已被确定导致x连锁HED，这是犬中最常见的外胚层发育不良形式。然而，在一只表现出x连锁HED临床症状的贵宾犬中，没有发现EDA基因的变异，这表明其他基因也可能导致犬患上这种疾病。
Aplasia of HFs without dental dysplasia have, to the best of our knowledge, not been reported in the literature in dogs, although they most likely exist. There are reports from swine in which the number of HFs is significantly reduced but the apocrine sweat glands and the teeth are not affected.
据我们所知，没有牙齿发育不良的HF发育不全在犬的文献中没有报道，但它们很可能存在。有来自猪的报告，HF的数量显著减少，但大汗腺和牙齿不受影响。
Congenital Alopecia Caused by Impaired Hair Follicle Organogenesis
由毛囊器官形成受损引起的先天性脱毛
Congenital alopecia/hypotrichosis also occurs when the causative gene variants affect HF organogenesis. In these cases, HF placodes were formed, but the morphogenesis of HFs is altered during the different stages of organogenesis. Histologic lesions in these cases vary depending on the underlying gene variant. In any case, HFs are not fully developed, are too short, and are malformed. The infundibulum and the dermal papilla (DP) may or may not be present. If HSs are produced, they are very thin and break easily. There are several dog breeds where a spontaneous mutation has been propagated on purpose and the phenotype is now recognized as breed standard (eg, Chinese crested dog, Mexican hairless dog, and Peruvian Inca Orchid) (Fig. 3c–f). Hairlessness in these 3 breeds is inherited as a monogenic autosomal semidominant trait. Hairless dogs are always heterozygous. Whereas the Mexican hairless dog is truly hairless, some HFs develop in Chinese crested dogs. There are 3 phenotypes in the Chinese crested dogs: the true hairless, the semicoated, and the powderpuff (haired phenotype). The HF density in the hairless phenotype is much lower than in the 2 haired phenotypes and if HFs are present they are simple. As these dog breeds also have dental abnormalities, the phenotype is considered as ectodermal dysplasia. A frameshift mutation the forkhead box I3 (FOXI3) gene has been identified as the cause of the hairless phenotype in the Chinese crested dog, the Mexican hairless dog, and the Peruvian Inca Orchid dog. The hairless phenotype in these dog breeds can be explained by the biological function of FOXI3. In mice, it has been shown that the expression of Foxi3 is regulated by ectodysplasin in HF placodes and that mutations in Foxi3 result in the downregulation of several stem cell signature genes. It has also been shown that FOXI3 in mice is essential for molar crown patterning, which most likely explains the dental phenotype in these dog breeds.
当致病基因变异影响HF器官形成时，也会发生先天性脱毛/少毛。在这些病例中，HF基板形成，但在器官发生的不同阶段，HF的形态形成发生改变。这些病例的组织学病变因潜在的基因变异。在所有病例中，HF都没有完全发育，太短，并且是畸形的。漏斗部和毛乳头(DP)可能存在也可能不存在。如果有HS，则很细，很容易断。有几个犬品种的自发突变已经被有意地繁殖，并且表型现在被认为是品种标准(例如，中国冠毛犬，墨西哥无毛犬和秘鲁印加兰犬)(图3c-f)。这3个无毛品种是一种单基因常染色体半显性遗传性状。无毛犬总是杂合子。而墨西哥无毛犬是真正的无毛，中国冠毛犬有一些HF。中国冠毛犬有3种表型:真无毛、半毛型和粉扑型(有毛表型)。无毛表型的HF密度远低于2种有毛表型，如果存在HF，则它们是简单HF。由于这些犬种的牙齿也有异常，因此被认为是外胚层发育不良。叉头框I3 (FOXI3)基因移码突变已被确定为导致中国冠毛犬、墨西哥无毛犬和秘鲁印加兰犬无毛表型的原因。FOXI3的生物学功能可以解释这些犬种的无毛表型。在小鼠中，研究表明HF基板中的Foxi3表达受外胚层发育不良蛋白的调节，并且Foxi3突变可导致数个干细胞特征基因的下调。研究还表明，在小鼠中，FOXI3对臼齿冠的形成至关重要，这很可能解释了这些犬种的牙齿表型。
In dogs, no reports are available in the literature that describe failure of HF organogenesis in dogs other than the abovedescribed breeds. However, there are reports of failure of HF organogenesis in other domestic animal species.
在犬中，除上述犬种外，文献中没有关于HF器官形成失败的报道。然而，在其他家畜物种中也有HF器官形成失败的报道。
 Figure 3. Clinical and histological images from dogs with congenital follicular dysplasia. Figure 3a. Skin from a mixed-breed dog with follicular aplasia. Note that glands are also lacking. Hematoxylin and eosin. Figure 3b. Mongrel presenting with inherited noninflammatory alopecia caused by follicular aplasia. The degree of alopecia varies on different body parts. Picture courtesy of Gila Zur. Figure 3c. Chinese crested dog presenting according to the breed standard as a true hairless dog. Most parts of the body are hairless, but hair is present on the distal legs, the top of the head, the pinnae, parts of the neck, and the tail. Picture courtesy of Tosso Leeb. Figure 3d Skin from a true hairless Chinese crested dog. Hair follicles and glands are mostly absent, but 1 dysplastic hair follicle is still present (arrow). Hematoxylin and eosin. Figure 3e. Higher magnification of Figure 3d. The dysplastic follicle is composed of an epithelial part (white arrow) underneath which mesenchymal cells are aggregated (black arrow). Note, the pigment aggregates surrounding the base of the hair follicle. Hematoxylin and eosin. Figure 3f. Skin from a Mexican hairless dog. The infundibula have been formed and are filled with abundant keratin, resulting in the formation of comedones (right side of the image). Epithelial cells underneath the infundibula are rare (white arrow), but if present some mesenchymal cells may be located underneath these epithelial cells (black arrow). Hematoxylin and eosin.
图3。先天性毛囊发育不良犬的临床和组织学图像。
图3a：一只患有毛囊发育不全的杂交犬的皮肤。注意也缺乏腺体。苏木精-伊红染色。图3b：由于毛囊发育不全，出现遗传性非炎性脱毛表现的杂交犬。不同部位的脱毛程度不同。图片由Gila Zur提供。图3c：中国冠毛犬按品种标准为真无毛犬。机体的大部分部位是无毛的，但腿远端、头顶、耳廓、颈部和尾部都有毛发。图由tosoleeb提供。图3d：真正的无毛中国冠毛犬的皮肤。毛囊和腺体大多缺失，但仍有1个发育不良的毛囊(箭头)。苏木精-伊红染色。图3e：放大倍数更高的图3d。发育不良的毛囊由上皮部分(白色箭头)组成，上皮下聚集着间充质细胞(黑色箭头)。注意，色素聚集在毛囊底部周围。苏木精-伊红染色。图3f：一只墨西哥无毛犬的皮肤。漏斗已经形成，并充满了丰富的角蛋白，导致粉刺的形成(图右侧)。漏斗下方的上皮细胞很少(白色箭头)，但如果上皮细胞下方有一些间质细胞(黑色箭头)。苏木精-伊红染色。
Dysplasia Associated With Insufficient Hair Shaft Quality Due to Impaired Cytodifferentiation
由于细胞分化受损导致毛干质量不佳相关的发育不良
Despite the fact that coat abnormalities are common in veterinary medicine, only 7 inherited HS defects have been reported so far in domestic animals. Some of these defects result in alopecia present already at birth, whereas others most likely develop during cytodifferentiation of the cycling anagen HF. In dogs, trichorrhexis nodosa, trichoptilosis, medullary trichomalacia, spiculosis, and bald thigh syndrome in sight hounds have been reported. In trichorrhexis nodosa, nodes are formed along the HS and the hair is abnormally fragile following trivial injury. This disorder can be acquired or congenital and has been described in golden retrievers. Congenital trichoptilosis has been reported in related male golden retrievers. Medullary trichomalacia has been reported in German shepherd dogs, but it is unknown if this disorder is acquired or congenital. In medullary trichomalacia, the medulla of the HS is vacuolated resulting in hyperfragility of the HS. Bald thigh syndrome is seen in greyhounds and related sighthound breeds (Fig. 4a). Because of the clear breed predisposition, a genetic component is most likely involved. In the literature, this syndrome has also been reported as pattern baldness and as follicular dysplasia; however, in a recent study, an impaired cytodifferentiation resulting in HS fractures has been identified as an underlying cause. On the molecular level, the phenotype is associated with downregulation of genes and the corresponding proteins in the HS (eg, keratin 1 and desmocollin), which are important for the proper assembly of the HS (Fig. 4b, c). Recently, a canine case with bulbous swellings of the HSs, which resembled lanceolate hair phenotype seen in mice and 2 cats, has been observed. Genetic analysis determined a desmoglein 4 variant similar to mice and cats with the same phenotype( Sarah Kiener and Tosso Leeb, personal communication).
尽管被毛异常在兽医学中很常见，但迄今为止，在家养动物中仅报道了7种遗传性HS缺陷。其中一些缺陷导致的脱毛在出生时就已经存在，而另一些则很可能在HF周期生长期的细胞分化过程中发生。在犬中，已报道了结节性脆毛症、毛裂、毛髓软化症、针状体毛发增多症和视觉型猎犬的腿秃综合征。在结节性脆毛症中，结节沿HS形成，毛发在轻微损伤后异常脆弱。这种疾病可以是获得性的或先天性的，在金毛猎犬中有描述。在相关的雄性金毛寻回犬中有先天性毛裂的报道。德国牧羊犬有过毛髓软化症的报道，但目前尚不清楚这种疾病是后天的还是先天性的。在毛髓软化症中，HS的髓质空泡化，导致HS的高脆性。腿秃综合征见于灵缇犬和相关的视觉型猎犬品种(图4a)。因为明确的品种倾向性，最有可能为遗传相关性。在文献中，这种综合征也被报道为模式脱毛和毛囊发育不良。然而，在最近的一项研究中，导致HS破裂的细胞分化受损被确定为潜在病因。在分子水平上，表型与HS中基因和相应蛋白(如角蛋白1和桥粒胶蛋白)的下调相关，这些蛋白对HS的正确组装很重要(图4b, c)。最近，观察到一例犬的HS毛球肿胀，类似于在小鼠和2只猫中观察到的披针形毛发表型。基因分析确定了一种与具有相同表型的小鼠和猫相似的桥粒芯糖蛋白4变异体。
 Figure 4. Greyhound with bald thigh syndrome. Figure 4a. The caudal and medial aspect of the thigh and the proximal leg down to the stifle is alopecic. Picture courtesy of Silvia Rüfenacht. Figure 4b. Hair follicles from a greyhound with bald thigh syndrome. Hair shafts are fractured and trichilemmal keratin is assembled underneath the hair shaft. Figure 4c. Abnormally assembled trichilemmal keratin is seen in the distal lumen of the isthmus. The presented histological findings are rarely seen, and trichograms may be the better way to diagnose bald thigh syndrome. Hematoxylin and eosin.
图4。患腿秃综合征的灵缇犬。图4a。大腿的尾侧和内侧以及小腿的近端到膝关节是秃毛。图片由Silvia提供Rüfenacht。图4b。患腿秃综合征的灵缇犬的毛囊毛干断裂，毛膜角蛋白在毛干下方组装。图4c。在峡部远端管腔内可见异常聚集的外毛根鞘角蛋白。腿秃综合征的组织学表现罕见，毛发镜检可能是诊断腿秃综合征的较好方法。苏木精-伊红染色。
Inherited Alopecia With Early Postnatal Clinical Manifestation
遗传性脱毛伴出生后早期出现临床表现
Hairlessness in the American Terrier (Hairless Rat Terrier)
美国㹴无毛(无毛鼠㹴)
Hairlessness is the desired phenotype of the American hairless terrier and is inherited as an autosomal recessive trait. Puppies are born with a sparse, fuzzy coat over their entire body and then gradually lose their coat from the nose backward until they are entirely bald. This typically occurs by 6 weeks of age. Eyebrows and whiskers are retained. Teeth may be missing but most dogs have normal dentition. The dogs are otherwise healthy. Histological features have not been described. The condition is associated with a deletion in the serum/glucocorticoid regulated kinase family member 3 gene (SGK3). SGK3 has been shown to be important in postnatal HF development in mice.
无毛是美国无毛㹴的受欢迎的表型，并作为一种常染色体隐性性状遗传。幼犬出生时全身毛发稀疏，然后逐渐从鼻子后面脱落，直到完全秃掉。这通常发生在6周龄。眉毛和胡须被保留。牙齿可能缺失，但大多数犬的牙列正常。这些犬在其他方面都很健康。组织学特征尚未描述。这种疾病与血清/糖皮质激素调节激酶家族成员3基因(SGK3)的缺失有关。SGK3已被证明在小鼠出生后HF的发生中起重要作用。
Juvenile Alopecia in the Scottish Deerhound
苏格兰猎鹿犬的幼年脱毛症
In contrast to the American hairless terrier, hairlessness in the Scottish deerhounds is undesired. It is caused by a frameshift insertion in the SGK3 gene and is inherited as a recessive trait. Affected puppies are born with sparse hair and lose it within the first 2 months of life. The hair does not regrow. Histology has not been described, and dogs are otherwise healthy.
与美国无毛㹴相反，苏格兰猎鹿犬的无毛是不受欢迎的。它是由SGK3基因中的移码插入引起的，并作为隐性性状遗传。患病幼犬出生时毛发稀少，并在出生后2个月内脱落。毛发不会再生。组织学没有描述，犬在其他方面都很健康。
Noninflammatory Alopecia With a Clear Breed Predisposition, Postnatal Onset, and a Most Likely Hereditary Cause
非炎性脱毛与明确的品种易感性，出生后发病，和最可能的遗传原因
There are several noninflammatory alopecic conditions with a clear breed predisposition and development of the alopecia during the first years of life, which indicates an impaired postnatal reconstitution of the HF. Due to the clear breed disposition, an underlying hereditary cause is likely, although no causative genes have been identified in the disorders that have been genetically evaluated. Thus, it may be speculated that a polygenic trait and other nongenetic factors, such as diet and an altered hormone metabolism, are involved in the pathogenesis.Histological features in most of those conditions are insufficiently described. If dogs were biopsied, only a small number of affected dogs have been investigated and different pathologists were involved.
有几种非炎性脱毛疾病具有明显的品种易感性，并且在生命最初几年内发生脱毛，这表明HF出生后重建受损。由于明确的品种倾向性，所以可能有潜在的遗传性，但在已进行遗传评估的疾病中没有发现致病基因。因此，可以推测，多基因性状和其他非遗传因素，如饮食和激素代谢的改变，参与了发病机制。大多数这些疾病的组织学特征尚不充分描述。如果对犬进行了活检，那么只对少数患病的犬进行了调查，不同的病理学家参与了调查。
Known diseases associated with postnatal follicular dysplasia are described.
描述与出生后毛囊发育不良相关的已知疾病。
Hypotrichosis and Alopecia in the Irish Water Spaniel
爱尔兰水猎犬的少毛症和脱毛
Hypotrichosis and alopecia in the Irish water spaniel is characterized by nonpruritic, noninflammatory, regionalized hair loss affecting the ventral and latero-dorsal neck, the flanks, the dorsum, the rump, the caudal part of the thighs, and the distal tail. The coat color changes from reddish brown to grayish brown. Pedigree analysis suggests a dominant mode of inheritance. A similar clinical presentation is also seen in the American water spaniel, although it has not been described in the literature. Hormone testing suggests an abnormality of steroidogenesis, and the hair coat regrew in some dogs after dietary changes. Histologically, the HFs’infundibula are dilated and filled with abundant keratin in the alopecic areas. The proximal HFs are atrophic. Melanin aggregates are present in the HSs, the follicular outer root sheath, and around the base of the follicles. These changes are also seen in the haired areas. As no control dogs were examined in this histologic study, it cannot be determined whether the pigment aggregates are normal for this breed.
爱尔兰水猎犬的少毛症和脱毛的特征是无瘙痒、无炎症、区域性脱毛，影响腹侧和侧背颈部、体侧、背部、臀部、大腿尾部和尾部远端。被毛颜色由红棕色变为灰棕色。家系分析提示显性遗传方式。类似的临床表现也见于美国水猎犬，但它没有在文献中描述。激素检测提示类固醇生成异常，一些犬在饮食改变后毛发重新生长。组织学上，脱毛区HF漏斗部扩张并充满丰富的角蛋白。近端HF萎缩。黑色素聚集物存在于HS、毛囊外根鞘和毛囊基底周围。这些变化也可见于有毛区域。由于在这个组织学研究中没有对照犬，所以不能确定这个品种的色素聚集是否正常。
Follicular Dysplasia of the Portuguese and Spanish Water Dog
葡萄牙和西班牙水犬毛囊发育不良
This type of follicular dysplasia has only been described in the Portuguese water dog, but is seen also in the Spanish water dog, which is a related breed. The clinical and histological findings are similar in both breeds and resemble those of Irish and American water spaniels (Fig. 5a–d). The coat color may change from black to reddish brown. Hair loss occurs at a median age of 2 years. Both males and females are affected. Histologically, the HF infundibula are severely dilated and plugged with keratin. HFs may have an irregular outer contour and are either in telogen or in anagen. Anagen follicles may be small. Hairs may be absent from HFs or may appear fragmented and thin. Hair shaft dysplasia starts in the lower part of the inferior portion of the HF (Fig. 5b–d). There may be scattered clumps of melanin within follicular keratin and within follicular epithelium. Vacuolar changes in the inner and outer root sheath and the matrix cells have been reported.
这种类型的毛囊发育不良只在葡萄牙水犬中被描述过，但也在西班牙水犬中被看到，这是一个相关的品种。这两个品种的临床和组织学结果相似，类似于爱尔兰和美国的水猎犬(图5a-d)。毛色可能从黑色变为红棕色。脱毛发生的中位年龄为2岁。雄性和雌性都患病。组织学上，HF漏斗部严重扩张并被角蛋白堵塞。HF可能具有不规则的外轮廓，处于休眠期或生长期。生长期毛囊可能很小。HF可能没有毛发，或者可能出现碎片状和稀薄。毛干发育不良始于HF下段的下方(图5b-d)。在毛囊角蛋白和毛囊上皮内可能有散在的黑色素团块。内、外根鞘和基质细胞的空泡性改变已有报道。
 Figure 5. Follicular dysplasia in Spanish and Portuguese water dogs. Figure 5a. A Spanish water dog presents with regionalized hair loss on the dorsum, the rump, and parts of the lateral thorax. Picture courtesy of Marcos Fernández Monzón. Figure 5b. Skin from a Portuguese water dog. Anagen hair follicles are present, but hair shaft and inner root sheath formation is impaired in the suprabulbar region (black arrow). Hematoxylin and eosin. Figure 5c. Skin from a Portuguese water dog. Adjacent to an anagen hair follicle with a normal hair shaft, a dysplastic follicle characterized by the presence of irregularly arranged keratin, which may be derived from a fragmented hair shaft (black arrow), is seen. Hematoxylin and eosin. Figure 5d. Skin from a Portuguese water dog. Vacuolar changes in the inner root sheath and the matrix cells of the bulbar and suprabulbar region of the hair follicle. Hematoxylin and eosin.
图5。西班牙和葡萄牙水犬的毛囊发育不良图5a：西班牙水犬表现为背部、臀部和侧胸部分的区域性脱毛。图片由Marcos提供Fernández Monzón。图5b：葡萄牙水猎犬的皮肤。生长期毛囊存在，但球上区域的毛干和内根鞘形成受损(黑色箭头)。苏木精-伊红染色。图5c：葡萄牙水猎犬的皮肤。与毛干正常的生长期毛囊相邻的是发育不良的毛囊，其特征是存在不规则排列的角蛋白，角蛋白可能来自于碎片状的毛干(黑色箭头)。苏木精-伊红染色。图5d：葡萄牙水猎犬的皮肤。毛囊球部和球上区内根鞘和基质细胞的空泡变化。苏木精-伊红染色。
Follicular Dysplasia of the Curly Coated Retriever
卷毛寻回犬的毛囊发育不良
Follicular dysplasia of the curly coated retriever has been described as symmetrical, nonpruritic alopecia and/or frizzy coat changes, usually affecting the caudal thighs, axillae, dorsum, and the neck (Fig. 6a). The age of onset varies from 4 months to 6 years (median 13 months). Alopecia may be waxing and waning. Histology is characterized by a reduced number of anagen follicles and increased numbers of kenogen and atrophic follicles. Infundibula are dilated and filled with abundant keratin. Melanin aggregates are present in the HSs and the outer root sheath; however, this may be normal in brown or black dogs (Fig. 6b, c).
卷毛寻回犬的毛囊发育不良被描述为对称性、非瘙痒性脱毛和/或卷曲的毛发变化，通常累及大腿尾端、腋窝、背部和颈部(图6a)。发病年龄4月龄-6岁，中位年龄13个月。脱毛可能有多有少。组织学特征为生长期毛囊数量减少，无毛静止期毛囊和萎缩毛囊数量增加。漏斗部扩张，充满丰富的角蛋白。黑素聚集物存在于HS和外根鞘中;然而，这在棕色或黑色犬中可能是正常的(图6b, c)。
 Figure 6. Follicular dysplasia with postnatal onset. Figure 6a. Follicular dysplasia in a curly coated retriever. The dog presents with noninflammatory alopecia on the neck and the cranial part of the dorsum. Picture courtesy of Katarina Varjonen. Figure 6b. Skin from a curly coated retriever with follicular dysplasia. The number of hair follicles per follicular compound is reduced. The hair shaft is fragmented and presents with variably sized melanin aggregates (black arrow). Hematoxylin and eosin. Figure 6c. Cross-section through 2 infundibula of a skin biopsy from a curly coated retriever with follicular dysplasia. In the left infundibulum, variably sized melanin aggregates are seen in the otherwise normal appearing hair shaft (black arrow). In the right infundibulum, melanin aggregates (black arrow) are seen, but a hair shaft is not present. Hematoxylin and eosin
图6。出生后发病的毛囊发育不良。图6a：卷曲毛猎犬的毛囊发育不良。犬颈部和背部头部出现非炎性脱毛。图片由Katarina Varjonen提供。图6b：毛囊发育不良的卷曲毛猎犬的皮肤。每个复合毛囊的毛囊数量减少。毛干呈碎片状，并有大小不等的黑色素聚集物(黑色箭头)。苏木精-伊红染色。图6c：一只毛囊发育不良的卷曲毛猎犬皮肤活检的2个漏斗部截面。在左侧漏斗部，在其他外观正常的毛干(黑色箭头)中可以看到大小不一的黑色素聚集物。在右侧漏斗部，可以看到黑色素聚集物(黑色箭头)，但没有毛干。苏木精-伊红染色。
Alopecia of the Chesapeake Bay Retriever
切萨皮克湾寻回犬的脱毛
Alopecia of the Chesapeake Bay retriever is characterized by hair loss affecting the axillae, the latero-ventral thorax, the flanks, the ventrum, the dorsum, the rump, and/or the caudal part of the thighs. Hormonal investigations showed increased adrenal and sex steroid concentration in some cases. Histopathology is characterized by severe infundibular hyperkeratosis, follicular atrophy, and occasional melanin clumping with malformed, often thin HSs.
切萨皮克湾寻回犬的脱毛特征是腋窝、侧腹、体侧、腹、背、臀部和/或大腿尾部的毛发脱落。激素检查显示部分病例肾上腺和性激素浓度增高。组织病理学特征为严重的漏斗部过度角化，毛囊萎缩，偶见黑色素团块伴畸形，通常HS细。
Alopecia in the Pont Audemer Spaniel
庞特奥德默猎犬脱毛
The Pont Audemer spaniel is derived from the Irish water spaniel. Alopecia in the Pont Audemer spaniel is limited to the brown-haired areas of the trunk and ears, and develops within the first 2 years of life. Histological findings include severely dilated HF infundibula with hyperkeratosis. No information is available about the HC stages in affected dogs. However, in 1 study, vacuolar degeneration and apoptosis of keratinocytes of the inner and outer root sheath, suggesting that anagen follicles are present, have been reported. Melanin aggregates in the HSs and outer root sheath have also been reported. However, this may be associated with the coat color of the affected areas.
庞特奥德默猎犬源自爱尔兰水猎犬。庞特奥德默猎犬的脱毛局限于躯干和耳部的棕色毛发区域，并在出生后2年内发展。组织学表现为HF漏斗部严重扩张伴角化过度。没有关于患病犬的HC阶段的信息。然而，在一项研究中，内、外根鞘的角质形成细胞出现空泡变性和凋亡，提示存在生长期毛囊。HS和外根鞘内的黑色素聚集物也有报道。然而，这可能与患病区域的毛色有关。
Recurrent Flank Alopecia
复发性体侧脱毛
Recurrent flank alopecia is characterized by recurrent episodes of well-demarcated alopecia that affects several canine breeds, but boxers, Rhodesian ridgebacks, Airedale terriers, French bulldogs, English bulldogs, and schnauzers are predisposed. In these dog breeds, recurrent flank alopecia is relatively common. It has been described also as seasonal flank alopecia, seasonal growth hormone deficiency, canine idiopathic cyclic flank alopecia, cyclic follicular dysplasia, and follicular dysplasia.
复发性体侧脱毛的特点是反复发作的明确界限的脱毛，影响几个犬种，但拳师犬、罗得西亚脊背犬、爱尔兰㹴、法国斗牛犬、英国斗牛犬和雪纳瑞是易感的。在这些犬种中，复发性体侧脱毛是相对常见的。它也被描述为季节性体侧脱毛，季节性生长激素缺乏症，犬特发性周期性体侧脱毛，周期性毛囊发育不良和毛囊发育不良。
The existence of a strong breed predilections implies a hereditary component; however, the photoperiod and seasonal climactic variations influence the onset of alopecia and hair regrowth. The response to melatonin in many cases underlines this association. Nevertheless, there is evidence that systemic intrinsic factors play a role in the pathogenesis since lesional skin grafts of dogs with recurrent flank alopecia on the back of athymic mice resulted in hair regrowth faster than in the donor dogs.
强烈的品种倾向性的存在意味着遗传成分。然而，光周期和季节气候变化影响脱毛和毛发再生的发生。在许多病例中，对褪黑素的反应强调了这种联系。然而，有证据表明系统内在因素在发病机制中起作用，因为在无胸腺小鼠背部进行皮肤移植复发性体侧脱毛犬的病变导致毛发再生速度快于供体犬。
Clinically, the lesions are distinctive and are characterized by recurrent episodes of sharply demarcated alopecic areas bilaterally in the flank region. The dorsal midline and the thorax may be involved as well. The alopecic skin is hyperpigmented. Hair may regrow partially or complete before it is lost again. Regrown hair may have an altered texture and can be darker. Histologically, the HF infundibula are severely dilated, elongated, and plugged with orthokeratotic follicular keratin that extends into the openings of all follicles assembled in 1 follicular compound. The lower follicular segments of the compounds are short, atrophic, and may have a distorted shape. The term “Witches foot” or “Warlocks foot” is used to describe the dilated infundibulum overlying this group of toe-like, shortened, and irregular primary and secondary follicles (Fig. 7a).
临床上，这种病变具有特征性，其特征是反复发作的双侧体侧区边界清晰的脱毛区域。背侧中线和胸部也可能患病。脱毛皮肤色素沉着。毛发在再次脱落之前可能会部分或完整地重新生长。重新生长的毛发可能会有一个改变的纹理，可以是更深的。组织学上，HF漏斗严重扩张、延长，并被角化型毛囊角蛋白堵塞，角化性毛囊角蛋白延伸至1个毛囊化合物中组装的所有毛囊的开口。该复合毛囊下段短、萎缩，可能有变形的形状。术语“女巫脚”或“魔术师脚”用于描述这组脚趾状、缩短且不规则的初级和次级毛囊上的漏斗部扩张(图7a)。
 Figure 7. Follicular dysplasia with postnatal onset. Figure 7a. Skin from a Rhodesian ridgeback with recurrent flank alopecia. The hair follicle infundibula are severely dilated, elongated, and plugged with orthokeratotic follicular keratin that extends into the openings of all follicles assembled in the follicular compound (white arrows surrounded by black line). The lower follicular segments of the compounds are short, atrophic, and may present a distorted shape (black arrows surrounded by white line). Therefore, the term “Witches foot” is used to describe this histological presentation. The epidermis is hyperpigmented. Hematoxylin and eosin. Figure 7b. Atypical recurrent alopecia in a Cesky Fousek. Well-demarcated alopecia is seen on the lateral thorax. In contrast to typical recurrent flank alopecia, the alopecic skin is not hyperpigmented. Picture courtesy of Silvie Neradilová. Figure 7c. Alopecia in the Lagotto Romagolo. The dog presents with bilateral hair loss on the trunk extending to the dorsum. Picture courtesy of Petra Roosje. Figure 7d. Skin from a Lagotto Romagolo with alopecia. The infundibula are severely dilated and filled with abundant keratin resulting in comedone formation (white arrow surrounded by black line). The hair follicles are in kenogen (star) or atrophic (black arrow surrounded with a white line). Hematoxylin and eosin.
图7。出生后发病的毛囊发育不良。图7a：具有复发性体侧脱毛的罗得西亚脊背部的皮肤。毛囊漏斗部严重扩张、拉长，并被角化型毛囊角蛋白堵塞，角蛋白延伸至毛囊复合物(白色箭头被黑线包围)中所有毛囊的开口。该复合毛囊下段短、萎缩，并可能呈现扭曲的形状(黑箭头被白线包围)。因此，术语“女巫脚”被用来描述这种组织学表现。表皮色素沉着。苏木精-伊红染色。图7b：一只捷克犬的非典型复发性体侧脱毛，可见边界清楚的脱毛。与典型的复发性图册脱毛相比，脱毛皮肤没有色素沉着。图片由Silvie提供Neradilová。图7c：拉戈托罗马阁挪露犬的脱毛。该犬表现为躯干向背部延伸的双侧毛发脱落。图片由Petra Roosje提供。图7d。拉戈托罗马阁挪露犬脱毛皮肤。漏斗部严重扩张，充满丰富的角蛋白，导致粉刺形成(白色箭头被黑线包围)。毛囊呈圆形(星形)或萎缩状(黑箭头周围白线)。苏木精-伊红染色。
Atypical Recurrent Flank Alopecia
非典型复发性体侧脱毛
Atypical recurrent alopecia is seen in several hunting dog breeds such as the German short hair pointer and the Cesky Fousek (Fig. 7b). Recurrent alopecia affecting the face only has been described in the Cane Corso and in several Dogues de Bordeaux. Similar to typical recurrent flank alopecia, the existence of a strong breed predilections implies a hereditary component. Atypical recurrent flank alopecia is more severe than typical recurrent flank alopecia and may become permanent with time. In contrast to the typical recurrent flank alopecia, the skin in the alopecic areas is not hyperpigmented. Histologic findings in cases of atypical recurrent flank alopecia are comparable to those observed in typical recurrent flank alopecia.
非典型的复发性脱毛见于几种猎犬，如德国短毛犬和捷克犬(图7b)。仅影响面部的复发性脱毛在意大利卡斯罗犬和几只波尔多猎犬中有描述。与典型的复发性体侧脱毛相似，强烈的品种倾向性的存在意味着遗传成分。非典型复发性体侧脱毛比典型复发性体侧脱毛严重，并可能随着时间的推移而成为永久性。与典型的复发性体侧脱毛相比，脱毛区域的皮肤没有色素沉着。非典型复发性体侧脱毛的组织学表现与典型复发性体侧脱毛的组织学表现相似。
Alopecia in the Lagotto Romagolo
拉戈托罗马阁挪露犬脱毛
Alopecia in the Lagotto Romagolo is characterized by bilateral hair loss on the trunk and usually starts in autumn/winter (Fig. 7c). This disease has been seen for a few years and started in the Swedish Lagotto population. It has been reported also as follicular dysplasia.
拉戈托罗马阁挪露犬脱毛的特征是躯干两侧脱毛，通常开始于秋/冬(图7c)。这种疾病已经发现了几年，并开始在瑞典拉古发病。也有报道称毛囊发育不良。
Seasonal cycling is observed in about half of the affected dogs. Alopecia onset or worsening of the condition is associated with the estrus, but hormonal profiles are normal. Histology is characterized by severely dilated infundibula filled with abundant keratin and often fragmented HSs. Follicles are in telogen, kenogen, or atrophic (Fig. 7d).
在大约一半的患病犬身上观察到季节性循环。脱毛的发作或恶化与发情期有关，但激素水平正常。组织学特征为漏斗部严重扩张，充满丰富的角蛋白和经常碎片化的HS。毛囊处于静止期、萎缩期或萎缩期(图7d)。
Pomeranians With Alopecia X
博美犬X型脱毛
Alopecia X has been described in the past as adult-onset growth hormone deficiency (hyposomatotropism), growth hormoneresponsive alopecia, castration-responsive alopecia, biopsyresponsive alopecia, and congenital adrenal hyperplasia-like syndrome. By breeders, it is known as “black skin disease” or “coat funk.” It has been reported in several dog breeds that have a plush or wooly coat with a dense undercoat. Reported breeds are Pomeranians, Keeshonds, Schipperke dogs, chow chows, Samoyeds, Siberian Huskies, and Alaskan malamutes. In addition, alopecia X has been reported in toy and miniature poodles, although these breeds have a completely different coat type. The strong breed predisposition, pedigree analysis of affected dogs, and the onset of the disease at a relatively young age suggest a hereditary influence in the disease pathogenesis. As the vast majority of studies on alopecia X have been done with Pomeranians, it is the author’s opinion that the term alopecia X should be reserved for the specific hair loss disorder in Pomeranians or at a maximum for dogs belonging to the European Spitz breed according to the Federation Cynologique Internationale (FCI https://www.fci.be/en/nomenclature/5-Spitz-and-primitive-types.html#s4). These include the German spitz in all size varieties (keeshound, giant spitz, medium-sized spitz, miniature spitz, and Pomeranian) and the Italian spitz, which is also known as the Italian volpino. For these dogs, it is known that they are closely related, which makes it more likely that the hereditary cause for the alopecia might be shared across these breeds. All other breeds reported to have alopecia X are genetically further apart, and thus, different genes may cause the alopecia. Therefore, this author would propose to call their alopecic disorder alopecia X-like.
在过去，X脱毛被描述为成年发病的生长激素缺乏症(生长激素缺乏症)、生长激素反应性脱毛、去势反应性脱毛、活检反应性脱毛和先天性肾上腺增生样综合征。被繁育者称为“黑皮病”或“被毛放克症”。据报道，在几个品种的犬有一个毛绒或羊毛大衣与密集的底毛。报道的品种有博美犬、荷兰毛狮犬、比利时犬、松狮犬、萨摩耶犬、西伯利亚哈士奇和阿拉斯加雪橇犬。此外，在玩具和迷你贵宾犬中也有X脱毛的报道，但这些品种有着完全不同的被毛类型。强大的品种倾向性，系谱分析的患病犬，疾病发病在相对年轻的年龄提示在疾病发病的遗传影响。由于绝大多数关于X型脱毛的研究都是在博美犬中进行的，因此作者认为X型脱毛这个术语应该保留在博美犬中特定的脱毛疾病，或者根据国际犬种联盟，最多用于属于欧洲丝毛犬品种的犬.其中包括各种尺寸的德国丝毛犬(荷兰毛狮犬, 大型丝毛犬、 中型丝毛犬、 迷你丝毛犬和博美犬)和意大利丝毛犬，也被称为意大利斡派瑙犬。对于这些犬来说，已知它们是近亲，这使得脱毛的遗传原因更有可能在这些品种之间共享。据报道，所有其他有X型脱毛的品种在基因上相距更远，因此，不同的基因可能导致脱毛。因此，笔者建议将其脱毛疾病称为“x样脱毛”。
Alopecia X affects young adult Pomeranians and may present in dogs younger than 1 year of age. However, some dogs do not develop alopecia until they are 4 to 5 years. Alopecia is seen more often, but not exclusively, in male dogs. Hair loss is noninflammatory, progressive, and bilateral symmetrical and spares the head, tail, and distal extremities (Fig. 8a). The skin is often hyperpigmented. 17-hydroxyprogesterone (17-OHP) is increased in dogs with alopecia X and was thought to be the result of an abnormal activity of the 21-hydroxylase enzyme. Simultaneously, baseline cortisol concentrations correlated with progesterone concentrations in Pomeranians. Treatment results for Pomeranians with alopecia X suggest that alterations in the steroid hormone metabolism are causative for the HC arrest. This is also supported by a study that performed whole transcriptome profiling of skin biopsies from Pomeranians with alopecia X, which provided evidence of abnormal cutaneous steroidogenesis characterized by the dysregulation of genes encoding enzymes in the steroid hormone metabolism. However, relevant gene variants were not identified in affected dogs with either whole genome sequencing or selected sequencing of genes involved in steroid hormone metabolism or HF development (21-hydrolase gene, cathepsin L2 gene, patched homolog 2 gene). In a recent study, it was suggested that an increased number of mitochondrial gene mutations are associated with the HC arrest in Pomeranian dogs.
X脱毛影响年轻的成年博美犬，可能出现在小于1岁的犬。然而，有些犬直到4到5岁才会出现脱毛。脱毛在雄性犬中更常见，但不完全是。脱毛为非炎性、渐进性、双侧对称，不累及头、尾和四肢远端(图8a)。皮肤常色素沉着。17-羟孕酮(17-OHP)在X型脱毛犬中增加，并被认为是21-羟化酶活性异常的结果。同时，博美犬的基线皮质醇浓度与孕酮浓度相关。对博美X型脱毛患犬的治疗结果表明，类固醇激素代谢的改变是导致HC停滞的原因。这也得到了对博美X型脱毛患犬皮肤活检标本进行全转录组分析的研究的支持，该研究提供了以类固醇激素代谢中编码酶的基因失调为特征的皮肤类固醇生成异常的证据。然而，无论是全基因组测序还是与类固醇激素代谢或HF发生相关的基因(21-水解酶基因，组织蛋白酶L2基因，补丁同源基因2)的选定测序，均未在患病犬中发现相关的基因变异。最近的一项研究表明，线粒体基因突变数量的增加与博美犬的HC停滞有关。
Histologically, alopecia X is characterized by a reduced number of anagen follicles and, compared with other HC disorders, a relatively high number of telogen follicles, as well as kenogen and atrophic follicles (Fig. 8b). These histologic findings resemble the findings in dogs with hyperestrogenism (Fig. 8d).
组织学上，X脱毛的特征是生长期毛囊数量减少，与其他HC疾病相比，静止期毛囊数量相对较多，以及无毛静止期和萎缩性毛囊(图8b)。这些组织学结果与雌性激素过多犬的结果相似(图8d)。
 Figure 8. Figure 8a. Alopecia X in a Pomeranian. The dog presents with bilateral symmetrical alopecia that spares the head, the distal extremities, and the tail. Picture courtesy of Petra Roosje. Figure 8b. Typical findings in alopecia X are a severely reduced number of anagen follicles, a relatively high number of telogen follicles (black arrow), and numerous kenogen follicles (star). Trichilemmal keratin in the telogen and kenogen follicles is abundant resulting in flame follicles. Infundibula are dilated and filled with large amounts of keratin (white arrow surrounded with a black line). Hematoxylin and eosin. Figure 8c. Hyperestrogenism in a male dog with a Sertoli cell tumor. The perineal-genital region, the caudal abdomen, and the medial thighs are alopecic. Note the linear preputial erythema typical for hyperestrogenism. Picture courtesy of Monika Linek. Figure 8d. Skin from a mixed-breed dog with hyperestrogenism. Like in alopecia X, hair follicles are in telogen, kenogen, or atrophic. Trichilemmal keratin around the hair shafts of the telogen follicles and in the kenogen follicles is abundant. Infundibula are dilated, and anagen follicles are missing. Hematoxylin and eosin.
图8。图8a：博美犬的X脱毛。该犬表现为双侧对称性脱毛，不包括头部、远端四肢和尾部。图片由Petra Roosje提供。图8b:X型脱毛的典型表现是生长期毛囊数量严重减少，静止期毛囊数量相对较多(黑色箭头)，无毛静止期毛囊数量较多(星号)。在休止毛囊和无毛静止期毛囊中有丰富的毛膜角蛋白，从而形成火焰毛囊。漏斗扩张并充满大量角蛋白(白色箭头被黑线包围)。苏木精-伊红染色。图8c：一只患支持细胞瘤的雄性犬的高雌激素症会阴-生殖器区域、尾腹和大腿内侧脱毛。注意典型的高雌激素症的线状包皮红斑。图片来自Monika Linek。图8d：患有高雌激素症的杂交犬的皮肤。与X型脱毛一样，毛囊处于静止期、无毛静止期或萎缩。在静止期毛囊的毛干周围和无毛静止期毛囊中有丰富的毛膜角蛋白。漏斗扩张，生长期毛囊缺失。苏木精-伊红染色。
Alopecia X-Like Disorders in Breeds Not Related to the European Spitz Breeds (Schipperke Dogs, Siberian Huskies, Alaskan Malamutes, Samoyeds, Chow Chows, Miniature, and Toy Poodles)
与欧洲丝毛犬种无关的X样脱毛(比利时犬、西伯利亚哈士奇、阿拉斯加雪橇犬、萨摩耶犬、松狮犬、迷你犬和玩具贵宾犬)
As outlined in the paragraph about alopecia X, the author prefers to use the term alopecia X-like disorder for the alopecic conditions of unknown cause in the other double-coated breeds and the miniature poodle. However, the clinical presentation and the histological findings reported for Schipperke dogs are similar to those reported for Pomeranians with alopecia X.The histological findings in the other dog breeds affected with an HC disorder of unknown cause have, to the best of the author’s knowledge, not been described in detail and thus cannot be compared with alopecia X.
正如在关于X脱毛段落中所概述的那样，作者更喜欢使用术语X样脱毛疾病来描述其他双层毛品种和迷你贵宾犬中未知原因的脱毛疾病。然而，比利时犬的临床表现和组织学结果与博美犬的X型脱毛相似。据作者所知，其他犬种的未知原因HC疾病的组织学结果没有被详细描述，因此无法与X型脱毛进行比较。
Color Dilution Alopecia
色素稀释性脱毛
Color dilution alopecia can occur in all breeds with dilute coat colors, including mongrels, but is seen more commonly in blue Doberman pinschers, silver Labradors, Weimaraners, Yorkshire terriers, and Irish setters. The disease is also known as blue Doberman syndrome, fawn Irish setter syndrome, and blue dog disease. In dogs, coat color dilution, leading to the specific pigmentation phenotypes, blue, gray, fawn, or red, is caused by a defective transfer of melanosomes to the matrix cells in the HF bulb. Up to now, 3 variants in the melanophilin gene (MLPH) have been identified as causes of the dilute phenotype in dogs. The defect in melanosome transfer results in large aggregates of melanosomes, which appear histologically as large pigment clumps in the HS, the follicular lumen, and the outer root sheath. Despite the fact that MLPH gene variants cause coat color dilution in many dog breeds, not all dogs with a dilute coat color develop color dilution alopecia. Thus, yet unidentified factors appear to be required for the development of alopecia. These are most likely hereditary factors associated with 1 or several stages of HS pigmentation, including melanosome formation, melanin production, and transfer of melanosomes to the matrical cells of the hair bulb.
色素稀释性脱毛可以发生在所有浅色毛品种犬，包括杂种犬，但更常见的是蓝色杜宾犬、银色拉布拉多犬、威玛猎犬、约克夏㹴和爱尔兰雪达犬。这种疾病也被称为蓝色杜宾综合征、浅黄色爱尔兰雪达犬综合征和蓝犬症。在犬中，毛色稀释，导致特定的色素沉着表型，蓝色、灰色、浅黄色或红色，是由黑素小体转移到HF毛球基质细胞的缺陷引起的。到目前为止，已经确定了3种嗜黑素基因(MLPH)的变异是导致犬的稀释表型的原因。黑素小体转移缺陷导致大的黑素小体聚集，在组织学上表现为大的色素团块，在HS、毛囊腔和外根鞘。尽管MLPH基因变异导致许多犬种的毛色稀释，但并不是所有毛色稀释的犬都会出现色素稀释性脱毛。因此，目前尚未确定的因素似乎是导致脱毛的必要因素。这些很可能是与HS色素沉着的1个或几个阶段相关的遗传因素，包括黑素小体形成、黑色素生成和黑素小体转移到毛球的基质细胞。
Clinically, the alopecia primarily affects the trunk, and histologically, large melanin aggregates are present within the HS and the outer root sheath (Fig. 9a, b). It has been suggested that the large melanosome aggregates damage the HS cuticle and fracture of the HS. As large melanosome aggregates are also present in normally haired dogs with a dilute hair coat (eg, Weimaraners or Doberman pinschers without alopecia), it is difficult to make a definite diagnosis based on histology alone and clinical information is needed. A ruptured HS cuticle, fractured HSs, and abundant free pigment may be histological keys to decide whether it is color dilution alopecia or not. If the HS cuticle in most HSs is intact, it is likely that the color dilution is not the cause for the alopecia.
临床上，脱毛主要影响躯干，组织学上，大的黑素聚集体存在于HS和外根鞘内(图9a, b)。有研究提示，大的黑素小体聚集体破坏HS角质层和HS破裂。由于大的黑素小体聚集物也存在于毛发稀释的正常毛发犬(如没有脱毛的魏玛犬或杜宾犬)中，因此仅根据组织学很难做出明确诊断，需要临床信息。HS角质层破裂、HS断裂、游离色素丰富可能是判断是否是稀释性脱毛的组织学关键。如果大部分HS的角质层是完整的，那么色素稀释很可能不是导致脱毛的原因。
 Figure 9. Figure 9a. Silver Labrador with color dilution alopecia. The alopecia affects the trunk and the abdomen. Picture courtesy of Silvia Rüfenacht. Figure 9b. Skin from a dog with color dilution alopecia. The melanin aggregates in the epidermis indicate that this skin biopsy is from a color dilute dog. Abundant free pigment aggregates are present in the infundibula. Hair shafts are not seen. Large, irregularly sized melanin aggregates are present in the outer root sheath and the bulb. Hematoxylin and eosin. Figure 9c. Skin from an alopecic area from a dog with black hair follicular dysplasia. The histological features resemble those of a dog with color dilution alopecia. However, note that no melanin aggregates are present in the epidermis. Hematoxylin and eosin. Figure 9d. Black hair follicular dysplasia in a Jack Russell terrier. The white-haired areas are still haired, whereas the formerly black-haired areas are alopecic. Picture courtesy of Monika Linek.
图9。图9a：银色拉布拉多犬患色素稀释性脱毛。躯干和腹部脱毛。图片由Silvia提供Rüfenacht。图9b：色素稀释性脱毛犬的皮肤。表皮中的黑色素聚集表明这张皮肤活检来自一只浅色犬。漏斗中存在丰富的游离色素聚集体。毛干看不到。大的、大小不规则的黑色素聚集物存在于外根鞘和毛球中。苏木精-伊红染色。图9c：来自一只具有黑色毛囊发育不良的犬的脱毛区域的皮肤。组织学特征与色素稀释性脱毛犬相似。然而，请注意表皮中没有黑色素聚集物。苏木精-伊红染色。图9d：杰克罗素㹴的黑色毛囊发育不良。白毛区域仍然有毛发，而以前的黑发区域已经脱毛。图片来自Monika Linek。
Black Hair Follicular Dysplasia
黑色毛囊发育不良
Black hair follicular dysplasia is seen in bi- or tricolored dogs and has been reported in bearded collies, Jack Russell terriers, large Münsterländer dogs, salukis, and a New Zealand huntaway dog. Black hair follicular dysplasia is inherited as an autosomal recessive trait and is most likely related to color dilution alopecia. Within the first year of life, the black hair coat gets dull and brittle and the hairs break easily, finally resulting in complete alopecia of the black-haired areas of the head, pinnae, neck, and back (Fig. 9d). Like in color dilution alopecia, large melanin aggregates are present within the HS,the follicular lumen, and the outer root sheath; thus, abnormal processing and transport of melanin may play a role in the pathogenesis. Follicles are distorted and contain fragmented HSs (Fig. 9c). Scanning electron microscopy has shown that the HS cuticle is absent over large areas of the hair fiber. The white-haired areas are histologically normal.
黑色毛囊发育不良见于双色或三色犬，并已在长须牧羊犬、杰克罗素㹴、大明斯特兰德犬、萨卢基犬和新西兰猎犬。黑色毛囊发育不良是一种常染色体隐性遗传性状，最可能与色素稀释性脱毛有关。出生后1年内，黑毛被膜变钝变脆，易断毛，最终导致头部、耳廓、颈部和背部的黑毛区域完全脱毛(图9d)。与色素稀释性脱毛一样，大的黑色素聚集物存在于HS、毛囊腔和外根鞘内;因此，黑素的异常加工和转运可能在发病机制中起一定作用。毛囊变形，含有碎裂的HS(图9c)。扫描电子显微镜显示，HS角质层在毛发纤维的大部分区域是缺失的。白发区域组织学正常。
Follicular Dysplasia in Weimaraners
威玛犬毛囊发育不良
Follicular dysplasia in Weimaraners, also a color dilute dog breed, affects young adults and presents with progressive alopecia of the trunk associated with recurrent folliculitis/furunculosis. The head and limbs are not affected. The HS abnormalities, the histopathological lesions, and scanning electron microscopy findings are similar, but less pronounced, to findings in color dilution alopecia. However, this form of alopecia occurs rarely in Weimaraners, and only few cases have been reported.
威玛犬毛囊发育不良，也是一种色素稀释的犬种，影响年轻犬，表现为进行性干性脱毛，并伴有复发性毛囊炎/疖病。头部和四肢不受影响。HS异常、组织病理学病变和扫描电镜检查结果与色素稀释性脱毛相似，但不太明显。然而，这种形式的脱毛在魏玛犬中很少发生，只有少数病例被报道。
Alopecia in the Frisian Waterdog (Wetterhoun)
弗里斯兰水犬的脱毛（荷兰水猎犬）
Alopecia in the Frisian waterdog has not yet been reported in the literature, but has been investigated within the frame of a doctoral thesis from the Vetsuisse Faculty of Bern. Clinically, dogs present with nonpruritic, noninflammatory bilateral truncal hair loss affecting only the pigmented coat, similar to the Pont Audemer spaniel. Less curly, thinner, and dull HSs are present in border areas. Histologic findings in alopecic skin consist of dilated keratin-filled infundibula, an increased number of kenogen HFs, a decreased number of anagen HFs, and decreased diameters of HFs and HSs. Small numbers of apoptotic keratinocytes were infrequently seen in the isthmus region. Small pigment aggregates in the HSs and the infundibular lumen were also present. Trichography indicates less curly hair and more HSs without medulla in border areas (Anja Ebner and Petra Roosje, personal communication).
弗里斯兰水犬的脱毛尚未在文献中报道，但已经在伯尔尼的Vetsuisse学院的博士论文的框架内进行了研究。在临床上，犬表现为非瘙痒性、非炎性双侧躯干毛发脱落，仅影响色素被毛，这与西班牙蓬托德梅尔猎犬相似。在边缘区域有较少的卷曲，较薄和无光泽的HS。脱毛皮肤的组织学表现为角蛋白充盈的漏斗部扩张，无毛静止期HF数量增加，生长期HF数量减少，HF和HS直径减小。在峡部很少见到少量凋亡的角质形成细胞。HS和漏斗腔内也存在小的色素聚集物。毛层摄影术显示在边境地区较少的卷发和更多的无髓质HS。
Alopecia in Labrador Retrievers
拉布拉多寻回犬脱毛
An alopecic condition with early onset is seen in Labrador retrievers in the United States (Candace Souza, personal communication). The dogs have no underlying endocrinopathy and no coat color dilution. This condition has not been described in the literature, and histological findings are unknown.
在美国的拉布拉多寻回犬中可以看到一种早发性脱毛疾病。这些犬没有潜在的内分泌疾病，也没有毛色稀释。这种情况尚未在文献中描述，组织学结果尚不清楚。
Alopecia Associated With Miniaturization of the Hair Follicles (Canine Pattern Alopecia)
与毛囊小型化相关的脱毛(犬模式脱毛)
Canine pattern alopecia (pattern baldness) affects predisposed breeds with short smooth hair coats, such as dachshunds, Boston terriers, and Chihuahuas. Breed predilections suggest a genetic basis. Canine pattern alopecia develops within the 1 year of life, and the dogs develop a bilaterally symmetric thin coat on the pinnae; the skin caudal to the pinnae; the caudal thighs; the perineal skin; or the ventral neck, chest, and abdomen (Fig. 10a). HF miniaturization is a proposed key feature of the syndrome, but histology and trichograms, analyzing the HSs quality, have not been performed in most cases (Fig. 10b). Thus, it cannot be excluded that some cases are rather associated with follicular dysplasia resulting in structurally impaired HSs, and the term pattern alopecia has been applied wrongly. This has been shown recently for sighthounds.
犬模式脱毛(模式脱毛)影响具有短而光滑毛的品种，如腊肠犬、波士顿㹴和吉娃娃。品种偏好表明有遗传基础。犬模式脱毛在1岁内发生，并且在耳廓上形成两侧对称的细小被毛;耳廓尾侧的皮肤;大腿尾端;会阴皮肤;或颈部、胸部和腹部腹侧(图10a)。HF小型化被认为是该综合征的一个关键特征，但大多数病例没有进行组织学和毛发镜检和HS质量分析(图10b)。因此，不能排除一些病例与毛囊发育不良有关，导致HS结构受损，而模式脱毛这一术语被错误地应用。这在最近的视觉型猎犬身上得到了证明。
Follicular miniaturization is also seen in human female and male pattern hair loss. In humans, it has been proposed that follicular miniaturization is caused by a shortened anagen phase. As initiation of the next anagen phase is not more effective, the telogen phase is prolonged. The telogen follicles eventually lose their HS, which leads to an increase in kenogen follicles, which over time may get more and more atrophic, possibly ending in follicular deletion.
毛囊小型化也见于人类女性和男性脱毛。在人类中，已经提出毛囊小型化是由于生长期缩短引起的。由于下一个生长期的开始不是更有效，静止期延长。静止期毛囊最终会失去HS，导致无毛静止期毛囊增加，随着时间的推移，毛囊可能会越来越萎缩，最终可能导致毛囊缺失。
 Figure 10. Figure 10a. Canine pattern alopecia (pattern baldness) in a dachshund. There is a bilateral symmetric thin hair coat on the pinnae. Picture courtesy of Monika Linek. Figure 10b. The hair follicles are miniaturized and mostly in telogen. The infundibula are filled with thin hair shafts. Hematoxylin and eosin. Figure 10c. Ischemic dermatopathy in a collie. The multifocal alopecia is seen in the periocular area, on the cheek extending from the lips, and caudal to the nasal planum. Erythema and small crusts are seen on the lip and the cheek. Picture courtesy of Monika Linek. Figure 10d. Skin from a dog with ischemic dermatopathy. Hair follicles are severely atrophic and only short epithelial strands are left. The connective tissue surrounding the hair follicle is prominent and homogenized. The dermal collagen is pale. Inflammatory cells are distributed in a random (“confetti-like”) pattern throughout the dermis. The epidermis is slightly hyperplastic and multifocal; there is pigmentary incontinence. Hematoxylin and eosin.
图10。图10a：腊肠犬模式脱毛(模式脱毛)。耳廓上有双侧对称的细小被毛。图片来自Monika Linek。图10b：毛囊缩小，大部分处于静止期。漏斗部充满了细细的毛干。苏木精-伊红染色。图10c：柯利牧羊犬缺血性皮肤病多灶性脱毛见于眼周区域，从嘴唇延伸至面颊部，尾部至鼻平面。红斑和小结痂见于唇和面颊。图片来自Monika Linek。图10d：缺血性皮肤病犬的皮肤。毛囊严重萎缩，仅留下短的上皮链。毛囊周围结缔组织突出且均质化。真皮胶原蛋白呈苍白色。炎症细胞以随机的(“纸屑样”)模式分布于整个真皮。表皮轻度增生，呈多灶性;有色素性失禁。苏木精-伊红染色。
Follicular Lipidosis in Rottweiler Dogs
罗威纳犬的毛囊性脂质沉积症
Follicular lipidosis is rare and has been only reported in 4 Rottweiler dogs. The affected dogs presented with partial alopecia on the mahogany or tan points of the face and feet within the first year of age. In neighboring areas, hairs turned mouse gray. In biopsies of affected skin, ballooning of the matrical cells due to lipid deposition was seen. Mainly hair bulbs of primary anagen HFs were affected. Rare vacuoles were also seen in HSs. Some HSs presented with an irregular contour and changes in the cuticle.
毛囊性脂质沉积症是罕见的，仅在4只罗威纳犬中报道。患犬小于一岁，表现为面部足部红褐色或褐色点状部分脱毛。在邻近区域，毛发变成了老鼠灰色。在患病皮肤的活组织检查中，由于脂质沉积，可见基层细胞肿胀。主要影响生长期主毛HF的毛球。HS罕见空泡化。部分HS外形不规则，毛小皮发生改变。
Pituitary Dwarfism in German Shepherd Dogs, Saarloos and Czechoslovakian Wolfdogs, and Tibetian Terriers
德国牧羊犬、萨鲁犬、捷克斯洛伐克狼犬和藏獒的垂体性侏儒症
Pituitary dwarfism in German Shepherd dogs, Saarloos and Czechoslovakian wolfdogs, and Tibetian terriers is an autosomal recessively inherited disease, which is associated with mutations in the LIM homeobox3 gene in all 4 dog breeds. This gene variant leads to a defect in the organogenesis of the adenohypophysis, resulting in a combined deficiency of growth hormone, thyroid stimulating hormone (TSH), and prolactin, whereas the production of adrenocorticotropic hormone is normal. Besides growth retardation, affected dogs lack primary hairs and have prominent secondary hairs resulting in a puppy coat. Over time, bilateral symmetrical alopecia progresses and the skin becomes hyperpigmented.
德国牧羊犬、萨洛斯犬、捷克斯洛伐克狼犬和藏獒的垂体性侏儒症是一种常染色体隐性遗传病，与所有4个犬种的LIM同源盒3基因突变有关。该基因变异导致腺垂体的器官发生缺陷，导致生长激素、促甲状腺激素(TSH)和催乳素的联合缺乏，而促肾上腺皮质激素的产生正常。除了生长迟缓，患犬缺乏主毛，次毛明显，导致外观呈现幼犬被毛。随着时间的推移，进一步发展为双侧对称性脱毛，皮肤色素沉着。
Acquired Alopecia Associated With an Impaired Hair Cycle
获得性脱毛与毛发周期受损有关
Hair Cycle Disorders of Endocrine Origin
内分泌性毛发周期紊乱
Endocrinopathies (eg, hyperadrenocorticism, hyperestrogenism, and hypothyroidism) are due to imbalances in hormones and manifest as nonpruritic, bilateral symmetric alopecia or hypotrichosis resulting from a deregulation of the HC. The remaining hair coat is dull and dry, can be easily epilated, and fails to regrow after clipping. Whereas the cause for the endocrinopathy is known, in most cases the specific action of the deregulated hormones on the canine HF has not yet been studied. A recent review summarized the effect of various hormones on the HF. As outlined above (Fig. 2), different hormones have a similar impact on the different HC phases. Thus, although the different endocrinopathies may have the tendency to present with specific histological features at some stage of the disease, histologic findings are similar and a definite diagnosis has to be based on the appropriate combination of clinical history, clinical features, clinical pathology testing, specific endocrine testing, and sometimes imaging.
内分泌疾病(如肾上腺皮质功能亢进、雌激素增多症和甲状腺功能减退)是由激素失衡引起的，表现为HC失调导致的非瘙痒性、双侧对称性脱毛或少毛。残存的被毛暗淡干燥，易脱毛，剃毛后无法再生。然而，已知病因是内分泌疾病，在大多数病例中，激素失调对犬HF的具体作用还没有被研究。最近的一篇综述总结了各种激素对HF的影响。如上所述(图2)，不同的激素对HC的不同阶段有相似的影响。因此，虽然不同的内分泌疾病在疾病的某些阶段可能有特定的组织学表现，但组织学表现是相似的，必须根据适当的临床病史、临床特征、临床病理学检查、特定的内分泌检查，有时还需要影像学检查来确定诊断。
In general, it can be said that, in addition to the lack/reduction in anagen HFs, typical histological features of associated with different endocrinopathies are:
总的来说，除了生长期HF的缺乏/减少外，与不同内分泌疾病相关的典型组织学特征有:
• Alopecia X and hyperestrogenism—mainly telogen and kenogen follicles (Fig.8b, d).
•X型脱毛和雌激素增多症——主要是静止期和无毛静止期毛囊(图8b、d)。
• Hyperadrenocorticism—abundant kenogen follicles and severe follicular atrophy as well as dermal atrophy and a thin epidermis. Comedone formation is typical (Fig. 11a).
•肾上腺皮质机能亢进-大量的无毛静止期毛囊和严重的毛囊萎缩以及真皮萎缩和表皮薄。粉刺形成是典型表现(图11a)。
• Hypothyroidism—anagen or telogen, normal sized primary follicles, and kenogen or atrophic secondary follicles. In addition, epidermal hyperplasia may develop if concurrent infections are present. Dermal mucinosis may be seen, but is rare (Fig. 11b).
•甲状腺功能减退-生长期或静止期，正常大小的初级毛囊，以及无毛静止期或萎缩的次级毛囊。此外，如果并发感染，也可能发生表皮增生。可能出现真皮层粘液增多症，但很罕见(图11b)。
However, as stated above, these “typical” features may change during the disease course. For example, a dog with hyperestrogenism may present with severe follicular atrophy.
然而，如上所述，这些“典型”特征可能在病程中发生变化。例如，一只雌性激素增多症的犬可能会出现严重的毛囊萎缩。
 Figure 11. Hair cycle disorders of endocrine origin Figure 11a. Skin from a dog with hyperadrenocorticism. Hair follicles are severely atrophic (black arrow surrounded by a white line), in kenogen (star), and rarely in telogen (black arrow). Comedone formation (white arrow surrounded by a black line) is typical, and anagen follicles are missing. Hematoxylin and eosin. Figure 11b. Skin from a dog with hypothyroidism. The primary hair follicles are of normal size and in anagen (asterisk), whereas the secondary hair follicles are in kenogen or atrophic (black arrow surrounded with white line). Infundibula are dilated and filled with a large amount of keratin. Hematoxylin and eosin. Figure 11c. Alopecia associated with hyperadrenocorticism in a poodle. The alopecia affects the neck and the entire trunk, but spares the head and extremities. Picture courtesy of Iwan Burgener. Figure 11d. Alopecia associated with hypothyroidism in a dog. Alopecia involves the legs proximal to the hocks, the rump, the dorsum, the ventrum, and parts of the head. Picture courtesy of Luc Beco.
图11。内分泌疾病导致的毛发周期障碍；图11a：肾上腺皮质亢进的犬的皮肤。毛囊严重萎缩(被白线包围的黑色箭头)，出现无毛静止期(星形)，罕见静止期(黑色箭头)。典型的粉刺形成(被黑线包围的白色箭头)，生长期毛囊缺失。苏木精-伊红。图11 b。患有甲状腺功能减退症的犬的皮肤。初级毛囊大小正常，处于生长期(星号)，而次级毛囊处于无毛静止期或萎缩期(被白线包围的黑箭头)。漏斗部扩张，充满大量角蛋白。苏木精-伊红。图11 c。一只贵宾犬的肾上腺皮质机能亢进相关的脱毛。颈部和整个躯干脱毛，但不影响头部和四肢。图片由Iwan Burgener提供。图11 d。与甲状腺功能减退症相关的犬脱毛。脱毛涉及到腿跗关节近端、臀部、背、腹和头部部分。图片由Luc Beco提供。
Hypothyroidism. Hypothyroidism is a commonly seen endocrinopathy in mainly older dogs of medium to large breeds. Clinical signs are associated with the deficiency of triiodothyronine (T3) and thyroxine (T4).In dogs, like in human beings, the HF is considered to be an important target for thyroid hormones. Deficiency of thyroid hormones is most often caused by idiopathic thyroid atrophy or lymphocytic thyroiditis. Clinical lesions of hypothyroidism start with a dull, dry, easily epilated hair coat that fails to regrow after clipping. Subsequently, alopecia develops in areas of hair coat friction, including the tail, elbows, hips, around the neck, and on the dorsal surface of the nose. Symmetric truncal alopecia is not as common as once thought (Fig. 11d).
甲状腺功能减退。甲减是一种常见的内分泌疾病，主要见于中大型犬的老年犬。临床症状与三碘甲状腺氨酸(T3)和甲状腺素(T4)缺乏相关。和人类一样，犬HF被认为是甲状腺激素的一个重要靶点。甲状腺激素缺乏最常由特发性甲状腺萎缩或淋巴细胞性甲状腺炎引起。甲状腺功能减退的临床病变开始变的暗淡、干燥、被毛易脱，剃毛后不长。随后，脱毛发生在毛发摩擦的部位，包括尾巴、肘部、臀部、颈部周围和鼻背表面。对称性躯干脱毛并不像以前认为的那样常见(图11d)。
Thyroid hormones affect the HF in various ways. From other species, the following data are available in the literature:
甲状腺激素以多种方式影响HF。从其他物种来看，文献中有以下数据:
•Thyroid hormones promote the anagen HC phase:
•甲状腺激素促进HC生长期;
°Thyroid hormones (T3, T4) downregulate apoptosis of human matrix keratinocytes, and T4 upregulates their proliferation.
°甲状腺激素(T3、T4)下调人基质角质形成细胞凋亡，T4上调基质角质形成细胞增殖。
°T4 prolongs the duration of anagen of human HFs in vitro.
°体外实验中，T4能延长人HF生长期。
°In mice and rats, topically applied T3 enhances both skin and hair growth.
°在小鼠和大鼠中，外用T3可以促进皮肤和毛发的生长。
°In female human scalp HF organ culture, TSH failed to have a significant effect on human HS elongation, anagen duration, or matrical cell proliferation. Thus, it was concluded that despite the presence of functional TSH receptors in human scalp HFs, the elevated levels of TSH seen in hypothyroid patients may result from thyroid hormone effects.
°在女性人头皮HF器官培养中，TSH对人头皮HS延长、生长持续时间或基质细胞增殖没有显著影响。因此，我们得出结论，虽然人类头皮HF中存在功能性TSH受体，但甲状腺功能低下患者中TSH水平升高可能是甲状腺激素作用的结果。
Hyperadrenocorticism (Cushing’s disease/syndrome). Hyperadrenocorticism is a common cause of alopecia in dogs and the result of a prolonged exposure to inappropriately high plasma concentrations of (free) cortisol. Naturally occurring disease is usually caused by bilateral adrenal cortical hyperplasia secondary to a functional pituitary neoplasm, and less often by a functional adrenal cortical neoplasm. Iatrogenic hyperadrenocorticism is also common in dogs and is due to administration of exogenous glucocorticoids or treatment with trilostane. Rarely, accidental topical contact with glucocorticoids used on the skin of human beings may cause lesions, particularly in small dogs. The alopecia in hyperadrenocorticism spares the head and extremities and is accompanied by comedone formation and thin skin resulting in the risk of increased bruising, poor wound healing, and increased susceptibility to infections (Fig. 11c). Calcification of the dermis (calcinosis cutis) on the dorsal head, neck, and back, and sometimes also in inguinal and abdominal areas and extremities, can occur in dogs. It is seen most often with iatrogenic hyperadrenocorticism.
肾上腺皮质亢进(库欣病/综合征)。肾上腺皮质亢进是犬脱毛的常见原因，是长期暴露于不适当的高血浆浓度(游离)皮质醇的结果。自然发生的疾病通常由继发于功能性垂体瘤的双侧肾上腺皮质增生引起，而较少由功能性肾上腺皮质肿瘤引起。医源性肾上腺皮质功能亢进在犬中也很常见，是由于外源性糖皮质激素的使用或使用曲洛斯坦的治疗。在极少数情况下，偶然外用接触使用在人类皮肤用药糖皮质激素可能导致病变，尤其是在小型犬。肾上腺皮质功能亢进的脱毛不影响头部和四肢，并伴有粉刺形成和皮肤薄，导致瘀伤增加、伤口愈合不良和易感染增加(图11c)。犬上可发生真皮钙化(皮肤钙质沉着症)发生在头背部、颈部和背部，有时也发生在腹股沟、腹部和四肢。最常见于医源性肾上腺皮质功能亢进。
Glucocorticoids affect the HF in various ways. From other species, the following data are available in the literature:
糖皮质激素以多种方式影响HF。从其他物种来看，文献中有以下数据:
• Impaired anagen induction |
Steroids result in the reduction in DP cells in mice. The DP plays a crucial role in the activation of follicular stem cells and when the number of DP cells is too low the HF fails to enter anagen.
•生长期诱导受损
类固醇导致小鼠DP细胞减少。DP在毛囊干细胞的激活中起着至关重要的作用，当DP细胞数量过低时，HF无法进入生长期。
• Shortened anagen and premature catagen induction
In mice, glucocorticoids reduce the mitotic activity of hair matrix cells and stimulate their differentiation. This finding could be in line with a shortened anagen cycle phase resulting in premature catagen induction.
•生长期缩短和过早诱导入中间期
在小鼠中，糖皮质激素降低毛基质细胞的有丝分裂活性并刺激其分化。这一发现可能与生长期周期阶段缩短，导致过早诱导入中间期。
Dexamethasone treatment reduces the number of human DP cells in vitro and downregulates the expression of the KI-67 protein, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF).It is known that the DP is essential for the growth and the differentiation of follicular keratinocytes.
体外实验中，地塞米松治疗能减少人DP细胞数量，下调KI-67蛋白、血管内皮生长因子(VEGF)和肝细胞生长因子(HGF)的表达。众所周知，DP对毛囊角质形成细胞的生长和分化至关重要。
Elevated levels of plasma glucocorticoids in chronic stress also inhibit the proliferation of DP cells and suppress the expression of VEGF.
慢性应激时血浆糖皮质激素水平升高也会抑制DP细胞的增殖并抑制VEGF的表达。
Dexamethasone increases the expression of dickkopf-1 (DKK1), a known catagen inducer, in DP cells and a neutralizing DKK1 antibody attenuates the Dexamethasone-induced inhibition of HS elongation and delays Dexamethasone-induced catagen in mice.
地塞米松增加了DP细胞中dickkopf-1 (DKK1)的表达，DKK1是一种已知的中间期诱导因子，且中和性DKK1抗体减弱了地塞米松诱导的小鼠HS延长抑制，并延缓了地塞米松诱导中间期。
Dexamethasone induces the activity of the androgen receptor in human and murine DP cells, which might result in a shortened anagen phase.
地塞米松诱导人、鼠DP细胞雄激素受体活性，可能导致生长期缩短。
Hyperestrogenism. Hyperestrogenism can develop in male and female dogs. In females, higher estrogen levels originate from ovarian cysts, and rarely ovarian neoplasm. In males, elevated serum estrogen concentrations are mostly derived from functional sertoli cell tumors or less commonly testicular interstitial cell tumors. Estrogen administration for the treatment of estrogen-responsive urinary incontinence, vaginitis, or prostate hypertrophy and hyperplasia has also caused hyperestrogenism in dogs.Rarely, accidental topical or oral contact with estrogens used on the skin of human beings may cause lesions due to skin contact or licking, particularly in small dogs. The bilateral symmetrical alopecia often begins in the perineal–genital region before it progresses to the abdomen, caudal and medial thighs, chest, flanks, and neck (Fig. 8c). Hyperpigmentation may be seen. In addition to endocrine alopecia, female dogs have enlarged vulvas and abnormalities of the estrus cycle. Male dogs can develop gynecomastia, a pendulous prepuce, a linear preputial erythema (Fig. 8c), or an enlarged prostate because of squamous metaplasia of prostatic ducts.
雌激素过多症。雄性和雌性犬均可发生雌激素过多症。在雌性中，较高的雌激素水平来自卵巢囊肿，罕见来自卵巢肿瘤。在男性中，血清雌激素浓度升高主要来源于功能性支持细胞瘤或少见的睾丸间质细胞瘤。雌激素用于治疗雌激素反应性尿失禁、阴道炎或前列腺肥大和增生也会导致犬的雌激素过多。在极少数情况下，意外局部或口腔接触人类皮肤上使用的雌激素可能会因皮肤接触或舔舐而引起病变，尤其是对小型犬。双侧对称性脱毛通常从会阴-生殖器区域开始，然后发展到腹部、大腿尾部和内侧、胸部、体侧和颈部(图8c)。可能可见色素沉着。除了内分泌脱毛，母犬还有外阴增大和发情周期异常。雄性犬可能会出现雄性乳房发育、包皮下垂、包皮线状红斑(图8c)或前列腺导管鳞状化生导致的前列腺增大。
Estrogens affect the HF in various ways. From other species, the following data are available in the literature
雌激素以多种方式影响HF。从其他物种，文献中可获得以下数据
• Impaired anagen onset:
•生长期受损
In mice, it has been shown that estrogen induces apoptosis of precortex cells and causes premature catagen induction by the upregulation of transforming growth factor β2 (TGF-β2). Immediately after the HF enters premature catagen, the expression of bone morphogenic protein 4 (BMP4) is increased. It is speculated that the upregulation of BMP4 prevents the transition of HFs from telogen to anagen, thus resulting in an increased number of telogen follicles.
在小鼠实验中，研究表明雌激素诱导皮层前细胞凋亡，以及通过上调转化生长因子β2 (TGF-β2)诱导过早进入中间期。HF过早进入中间期后，骨形态发生蛋白4 (BMP4)表达升高。推测BMP4的上调阻止了HF从静止期向生长期的转变，从而导致静止期毛囊数量的增加。
• Premature catagen induction
•诱导过早进入中间期
Estrogens alter gene expression of several HC-relevant genes and signaling pathway members, such as the mitogen-activated protein kinase pathway and the TGF/BMP family, and are thus involved in the initiation and promotion of catagen by the induction of apoptosis.
雌激素改变了几个HC相关基因和信号通路成员的基因表达，如丝裂原活化蛋白激酶途径和TGF/BMP家族，从而通过诱导细胞凋亡中间期的启动和促进。
In isolated human HFs, it has been shown that estrogen inhibited matrix keratinocyte proliferation and enhanced their entry into apoptosis.
在分离的人HF中，雌激素抑制基质角质形成细胞增殖并促进其细胞凋亡。
Miscellaneous Noninflammatory Acquired Alopecic Disorders
其他非炎性获得性脱毛
Post-Clipping Alopecia
剃毛后脱毛
Post-clipping alopecia is characterized by a lack of hair regrowth after clipping. The underlying cause is unclear, but it seems to occur more often in dogs with a long telogen HC phase (eg, Siberian huskies and other breeds with a thick undercoat). Thus, it may well be that many cases of post-clipping alopecia are due to the fact that hair regrowth after clipping takes longer because the dogs have been clipped in an early telogen stage and hair will regrow only when the long telogen phase in these dogs is finished and the HFs reach the next late anagen stage. In addition, vascular perfusion changes in response to cutaneous temperature changes after clipping and underlying preclinical endocrinopathies have been discussed as possible causes.
剃毛后脱毛的特征是剃毛后毛发缺乏再生。潜在的原因尚不清楚，但似乎更经常发生在有较长的HC期的犬(例如，西伯利亚哈士奇和其他厚底毛品种)。因此，许多剃毛后脱毛的病例很可能是由于剃毛后的需要更长的时间毛发再生，因为犬在静止期早期被剃毛，只有当这些犬的长静止期结束和HF到达下一个生长期晚期时，毛发才会再生。此外，剃毛后皮肤温度变化引起的血管灌注改变和潜在的临床前内分泌疾病也被讨论为可能的病因。
Alopecia Associated With Excessive Hair Loss—Telogen Effluvium
与过度脱毛相关的脱毛-静止期脱毛
Telogen effluvium is rare in dogs and is the result of excessive premature shedding of the HSs (exogen). Thereafter, synchronized initiation of new anagen occurs. Thus, the major histological finding is that all HFs are in telogen or more often already in anagen. Dogs are nevertheless bald since the HSs have not yet reached the skin surface. The underlying cause for the synchronization of the HC in dogs is not known. In humans, various causes of telogen effluvium have been identified, such as stress, illness, medications with all-trans retinoic acid and salicylic acid, excessive ultraviolet light, nutritional deficiencies, lymphocytotoxic (autoimmune) activity, and long-term use of estrogen-containing contraceptives. It is likely that similar causes induce excessive shedding in animals.
静止期脱毛在犬中是罕见的，是HS(脱毛期)过度过早脱落的结果。此后，新生长期同步开始。因此，主要的组织学发现是所有的HF都处于静止期，或者更多的时候已经处于生长期。然而，犬是没毛的，因为HS还没有到达皮肤表面。犬的HC同步化的潜在原因尚不清楚。在人类中，已经确定了导致静止期脱毛的各种原因，如压力、疾病、含有全反式维甲酸和水杨酸的药物、紫外线照射过量、营养缺乏、淋巴细胞毒性(自体免疫)活性和长期使用含雌激素的避孕药。在动物上很可能有相似的原因导致过度脱毛。
Anagen Effluvium/Defluxion
生长期脱毛/脱落
Anagen effluvium is due to interruption of the mitotic activity of the rapidly proliferating anagen hair bulb matrix cells. It is most often related to chemotherapy and is best documented in humans. It is rarely seen in dogs and mostly affects breeds with an anagen-dominated HC, but other breeds may be affected as well. In dogs, chemotherapy-associated anagen effluvium has been most commonly associated with doxorubicin and 5-fluorouracil therapy. However, other chemotherapeutic agents result in alopecia as well. The abrupt cessation of mitotic activity of the matrix cells leads to a narrowing of the proximal portion of the HF and the production of fragile HSs. When these fragile HSs reach the skin surface, they break and anagen effluvium occurs. In 1 study, the onset of alopecia after the beginning of the drug administration ranged from 7 to 120 days, and the time to resolution ranged from 42 to 150 days. Diagnosis is based on clinical history, physical examination, and microscopic examination of pulled hairs (trichograms). In the early course of the disease, the pulled hairs have irregularly narrowed or pointed ends. In the late course, only telogen hairs, which are not mitotically active, can be pulled since all anagen hairs have been lost.
生长期脱毛是由于生长期毛球基质细胞快速增殖的有丝分裂活动中断所致。最常与化疗有关，并在人类中有详细记录。这种情况在犬中罕见，主要影响以生长期HC为主的品种，但其他品种也可能患病。在犬中，与化疗相关的生长期脱毛最常与多柔比星和5-氟尿嘧啶治疗相关。然而，其他化疗药物也会导致脱毛。基质细胞有丝分裂活动的突然停止导致HF近端部分变窄和脆性HS的产生。当这些脆弱的HS到达皮肤表面时，它们就会破裂，就会发生生长期脱毛。在1项研究中，在开始用药后出现脱毛的时间为7-120天，至脱毛消退的时间为42-150天。诊断是基于临床病史、体格检查和拔毛镜检(毛发镜检)。在病程早期，被拔的毛发有不规则的变窄或尖端。在病程晚期，由于所有生长期的毛发都已脱落，被拔的毛发全是不具有有丝分裂活性的静止期。
Alopecia Associated With Ischemic Dermatopathy
与缺血性皮肤病相关的脱毛
Ischemic dermatopathy is caused by impaired vascular perfusion and is associated with an underlying vasculopathy or vasculitis. In a recent study, miniature poodles, Chihuahuas, Maltese, Yorkshire terriers, and Jack Russell terriers were significantly over-represented, and about 50% of the cases were associated with a vaccine. Clinically, focal or multifocal alopecia is the most common lesion. Lesions are found mostly on the pinnae, vaccination sites, periocular regions or in the face, and on the tail (Fig. 10c). Besides alopecia crusts, scale, erythema, erosions or ulcers, and hyperpigmentation are seen commonly. Pruritus may be present. Systemic signs have been seen in about a third of the dogs. Histologically, primary and secondary HFs are severely atrophic and may be absent. HFs are described as “fading” follicles. They are devoid of HSs, and only a thin, short epithelial strand remains in the HF. Prominence and homogenization of the connective tissue surrounding the HF is a frequent finding (Fig. 10d). Vascular lesions are seen in the capillaries and small arterioles and are characterized by loss of vascular distinction or endothelial cells. Inflammation of the vessel walls is seen rarely in dogs. The dermal collagen is pale and is described to have a smudged appearance. Lymphocytes and plasma cells are distributed randomly (“confetti-like”) throughout the dermis and eventually the panniculus. Dermal edema and/or mucin deposition is seen frequently. Vacuolation of epidermal basal keratinocytes and rare apoptotic cells, described as cell poor interface dermatitis, may be seen. The detailed pathogenic mechanisms of how ischemia affects the HFs are unknown. In 1 study, it has been shown that under hypoxic culture conditions the capacity of follicular stem cells to form clonal colonies is impaired.
缺血性皮肤病由血管灌注受损引起，并与潜在的血管病变或血管炎相关。在最近的一项研究中，小型贵宾犬、吉娃娃犬、马尔济斯犬、约克夏犬和杰克罗素梗犬发病率明显偏高，约50%的病例与疫苗有关。临床上，局灶性或多灶性脱毛是最常见的病变。病变主要见于耳廓、疫苗接种部位、眼周区域或面部和尾部(图10c)。除脱毛外，结痂、皮屑、发红、糜烂或溃疡和色素沉着也很常见。可能存在瘙痒。大约三分之一的犬出现了全身症状。组织学上，初级和次级HF均严重萎缩，可能缺失。HF被描述为“褪色”的毛囊。它们缺乏HS, HF中只剩下一条细而短的上皮带。常见HF周围结缔组织突出且均质化(图10d)。血管病变见于毛细血管和小动脉，以血管分化或内皮细胞丧失为特征。血管壁的炎症在犬中很少见。真皮胶原蛋白呈苍白状，有污迹（smudged）外观。淋巴细胞和浆细胞在真皮层和脂膜中随机分布(“彩纸样”“confetti-like”)。常可见皮肤水肿和/或黏蛋白沉积。可见表皮基底角质形成细胞空泡化和罕见细胞凋亡，称为少细胞性界面性皮炎。缺血如何影响HF的详细致病机制尚不清楚。1项研究表明，在低氧培养条件下，毛囊干细胞形成克隆集落的能力受损。
Traction Alopecia
牵拉性脱毛
Traction alopecia is the results of chronic partial ischemia that is not associated with an underlying vascular pathology. It occurs when rubber bands are applied tightly to retain the hair and is the result of a repetitive or continuous impaired blood supply to HFs and adjacent skin. The impaired blood supply is due to shearing and compression of the smaller diameter blood vessels due to prolonged forces of traction. It most often presents as focal alopecia on the top of the head or on the ears in longhaired dogs. Once developed, the alopecia is long term and generally permanent. Histologically, depending on alopecia duration, HFs are either in kenogen or are atrophic, and may be partially or completely lost and replaced by dermal fibrosis. Adnexal glands are also usually atrophic and may be absent.
牵拉性脱毛是慢性局部缺血的结果，与潜在的血管病变无关。当用橡皮筋紧紧地绑住毛发时，就会发生这种情况，这是HF和邻近皮肤的血液供应反复或持续受损的结果。血液供应受损是由于长时间的牵引力导致血管不连续和血管直径变小所致。最常表现为长毛犬头顶或耳上的局灶性脱毛。一旦发展，脱毛是长期的，一般是永久性的。组织学上，根据脱毛的持续时间，HF要么是在无毛静止期，要么是萎缩，可能部分或完全缺失，并被真皮纤维化所取代。附件腺也通常萎缩，可能缺失。
“Postinflammatory Alopecia” and Hair Cycle Arrest of Unknown Cause
“炎症后脱毛”和不明原因的毛发周期停滞
In addition to the disorders described, noninflammatory alopecia, associated histologically with an impaired HC, may be seen in cases for which the causes and/or the diagnoses remains unclear. As outlined in the review on HF structure, morphogenesis, and regeneration in the same issue of this journal, the HC is a tightly regulated and highly conserved process that involves numerous signals derived from epithelial, neuroendocrine, and mesenchymal cells. These signals converge on HF stem cells, transient amplifying cells, and also during cytodifferentiation. Many of these signals have not yet been identified in rodents or dogs. Nevertheless, these finely balanced activators and inhibitors have an impact on the normal function or dysfunction of the HC. A detailed review on the impact of inflammation on the HC and epidermal regeneration is provided in a recent review.
除了上述疾病外，组织学上与HC受损相关的非炎性脱毛也可见于病因和/或诊断尚不明确的病例。正如本期杂志中关于HF结构、形态发生和再生的综述所概述的那样，HC是一个受到严格调控且高度守恒的过程，涉及来自上皮细胞、神经内分泌细胞和间充质细胞的众多信号。这些信号集中在HF干细胞、瞬时扩增细胞和细胞分化过程中。其中许多信号尚未在啮齿动物或犬上发现。然而，这些精细平衡的激活剂和抑制剂对HC的正常功能或功能障碍均有影响。最近的一篇综述详细综述了炎症对HC和表皮再生的影响。
Examples of possible mechanisms resulting in an impaired HC are as follows:
导致HC受损的可能机制示例如下:
• In mice, sonic stress results in the recruitment of substance P and nerve growth factor, which results in perifollicular inflammation, HF keratinocyte apoptosis, premature HF regression (catagen induction), and inhibition of HF keratinocyte proliferation.
• In systemic stress conditions, plasma glucocorticoids are elevated through activation of the hypothalamo-pituitary-adrenal axis. The effects of steroids have been discussed earlier.
• Chronic restraint stress increases the number of substance P immunoreactive nerve fibers and activates mast cells.
• Chronic restraint stress inhibits hair growth by prolonging the telogen stage and delaying the subsequent anagen and catagen stage.
• Stress is associated with premature catagen development in mice.
• In humans, examination stress results in shift the immune response to a TH1 response and transiently hampers hair growth. However, the changes stay within a physiological range.
• Mast cell degranulation triggers catagen induction.
• Skin-resident macrophages undergo apoptosis prior to SC activation at anagen onset. This process is linked to distinct gene expression, including Wnt transcription. Experimental induction of macrophage apoptosis during early telogen results in stem cell activation in vivo. A macrophage-specific pharmacological inhibition of wingless / integrated (WNT) production delays HF growth.
• A subset of dermal macrophages secretes oncostatin M, maintains HF stem cell growth, and inhibits hair growth.
• Data from mice suggest that interleukin (IL)-6 family members inhibit hair growth in a dose-dependent manner. As increased levels of IL-6 are present in dermal inflammation, IL-6 may play a partial role hair growth inhibition seen in inflammatory disease.
•在小鼠中，声波应激导致P物质和神经生长因子的募集，从而导致毛囊周炎症、HF角质形成细胞凋亡、HF过早消退(诱导中间期)和抑制HF角质形成细胞增殖。
•在全身性应激情况下，血浆糖皮质激素通过下丘脑-垂体-肾上腺轴的激活而升高。类固醇的作用已经在前面讨论过了。
•慢性约束应激增加P物质免疫反应性神经纤维的数量并激活肥大细胞。
•慢性约束压力通过延长静止期和延迟随后的生长期和中间期来抑制毛发生长。
•应激与小鼠过早进入中间期有关。
•在人类中，考试压力会导致免疫反应转变为TH1反应，并暂时阻碍头发生长。然而，这些变化保持在生理范围内。
•肥大细胞脱颗粒触发诱导中间期。
•皮肤巨噬细胞在生长初期SC激活之前发生细胞凋亡。这一过程与不同的基因表达有关，包括Wnt转录。在体内实验诱导静止期早期巨噬细胞凋亡，导致干细胞活化。巨噬细胞特异性药物抑制无翅/整合(WNT)的产生可延缓HF的生长。
•真皮巨噬细胞的一个亚群分泌抑癌素M，维持HF干细胞生长，抑制毛发生长。
•来自小鼠的数据表明，白细胞介素(IL)-6家族成员以剂量依赖的方式抑制毛发生长。由于皮肤炎症中存在IL-6水平升高，IL-6可能在炎性疾病中发挥抑制毛发生长的部分作用。
These data at least suggest that also in dogs, stress or inflammatory mediators released by mast cells, or other cells of the innate immune system, may result in HC arrest disorders.
这些数据至少表明，在犬上，应激或肥大细胞或先天免疫系统的其他细胞释放的炎症介质可能导致HC紊乱疾病。
Summary
总结
Noninflammatory alopecia in dogs may be present at birth, develop early at life with a presumed hereditary cause, or is clearly acquired. The underlying gene variants or the detailed underlying pathogenesis is unknown for most cases. Since the HF has only limited possibilities to respond to an impaired regulation and since histopathology may change during the course of a disease, histologic findings can be similar in different diseases. Thus, histology may suggest an underlying cause, but is not reliable. A detailed clinical history, a thorough clinical examination including blood work, the appropriate selection of the biopsy site, and the detailed histological findings need to be combined to achieve a final diagnosis.
犬的非炎性脱毛可能在出生时就有，可能在生命早期就有推测的遗传性原因，或者明显是后天获得的。大多数病例的潜在基因变异或详细的发病机制尚不清楚。由于HF对调节受损做出反应的可能性有限，并且由于组织病理学可能在疾病过程中发生变化，因此不同疾病的组织学发现可能相似。因此，组织学可能提示潜在病因，但并不可靠。需要详细的临床病史、包括血液检查在内的全面临床检查、适当选择活检部位以及详细的组织学检查结果相结合，才能做出最终诊断。
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发表于 2023-12-18 11:39:20
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