FOLLICULAR DYSPLASIAS AND OTHER ALOPECIAS

Transcription

1 FOLLICULAR DYSPLASIAS AND OTHER ALOPECIAS 4th Latin American Congress of Veterinary Dermatology, Mérida, México de junio, 2018 Manon Paradis, DMV, MScV, Dipl. ACVD, Department of clinical sciences, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada. INTRODUCTION Follicular dysplasias encompasse a group of genetic, non-inflammatory dermatological disorders resulting in hair loss and altered coat quality. They include many ill-defined alopecic disorders that are either coat colour-linked (e.g., colour dilution alopecia, black hair follicular dysplasia) or non-coat colour-linked (e.g., canine recurrent flank alopecia, alopecia X and the various breed associated follicular dysplasias). The goal of this presentation is to describe and discuss the clinical features, diagnosis and treatment of the different type of canine follicular dysplasias. For the ease of presentation, hair follicle dysplasias will be divided into those where hair follicle dysplasia is so severe that no hair shaft formation is seen at all, and those where hair shafts are formed by dysplastic hair follicles. The latter will be further sub-divided into colour-linked and non coloured-linked follicular dysplasia. 1

2 HAIR FOLLICLE DYSPLASIA WITHOUT HAIR SHAFT FORMATION Hair follicle dysplasias without hair shaft formation are essentially all congenital disorders (i.e. present at birth). CONGENITAL HYPOTRICHOSIS Congenital hypotrichosis is the term used to describe dogs born with abnormal haircoat. Cases have been reported in several breeds and in mongrels. Some of those cases have not been sufficiently evaluated to determine whether other ectodermal defects were present. Ectodermal dysplasia describes a group of disorders characterized by abnormality in embryonic development and gives rise to mature structures that are deficient in number, size, character, or function such as skin and appendages (hair, nails and sweat glands) and teeth. Some ectodermal dysplasia cases are inherited as a X-linked recessive trait (i.e. seen predominantly in males). Clinical features Dogs with ectodermal dysplasia are born with a symmetrical alopecia typically affecting the frontotemporal, sacral, abdominal and proximal limb regions. In addition to the alopecia, they have oligodontia (with peg-shaped teeth), and glandular (epitrichial and atrichial sweat, sebaceous, lacrimal, tracheal, and bronchial) aplasia. Histopathological examination of skin biopsies reveals absence of hair follicles, arrector pili muscles, sebaceous and sweat (epitrichial and atrichial) glands. As opposed to human patients, these dogs do not suffer from hyperthermia because skin atrichial (eccrine) sweat glands are only located in footpads and have little thermoregulatory significance. HAIRLESS BREEDS The hairless breeds resulted from intentional breeding of dogs with a spontaneous genetic mutation. It is now known that the Chinese crested dog, the Mexican hairless dog (aka Xoloitzcuintli), and the hairless Peruvian dog all share the same mutation. The hairlessness is inherited as a monogenic autosomal semidominant trait linked to chromosome 17. Heterozygous dogs are hairless, and homozygous mutants die during embryogenesis. The Mexican hairless dog date back more than 3000 years, whereas the Chinese crested dog, which is now the most popular hairless breed, is a much more recent breed (late 1800 s). The haired (homozygous normal or wild-type ) Chinese crested dog littermates have long fur and are known as powderpuffs. Hairless littermates are devoid of hair except for the crown of the head, lower parts of the extremities and the tail. The haired ( wild-type ) Peruvian and Mexican hairless dogs have short haircoats. The phenotype of hairless dogs is now classified as canine ectodermal dysplasia because these dogs have missing or abnormally shaped teeth in addition to a sparse or absent hair coat. Skin biopsy reveals rudimentary primary follicles with distended follicular infundibula. Mesenchymal condensation beneath cystic follicular infundibula suggests remnants of potential dermal papilla. The sweat glands are not affected. Adult hairless dogs often exhibit numerous comedones, most prominent on the dorsum, ventral neck, distal extremities, and prepuce with secondary bacterial folliculitis. Also, for obvious reasons, they are prone to actinic damage. The American hairless terrier, which is a mutant of the American rat terrier, is not so well characterized but do appear to fall into the ectodermal defect category. It appears to have an autosomal recessive mode of inheritance. 2

3 HAIR FOLLICLE DYSPLASIA WITH HAIR SHAFT FORMATION Hair follicle dysplasias with hair shaft formation are essentially all acquired alopecias. These dogs are born with a normal hair coat, however, an acquired alopecia develops from as early as 3 months of age (e.g., black hair follicular dysplasia) to as late as over 10 years (e.g., some dogs with recurrent flank alopecia or Alopecia X). This group of follicular dysplasias can be further divided histologically into categories in which there are abnormalities in the process of melanization of the pilosebaceous units (e.g., colour dilution alopecia) and those where the hair cycle is abnormal (e.g., canine recurrent flank alopecia, alopecia X). COLOUR DILUTION ALOPECIA (CDA) Colour dilution alopecia (formerly colour mutant alopecia), is an uncommon inherited disorder which causes tardive alopecia in some dogs with diluted (e.g., blue or fawn) hair coats. Etiopathogenesis CDA is a neuroectodermal dysplasia inherited as an autosomal recessive trait. It appears to be a disorder of melanosome transfer within the melanocyte but the etiopathogenesis is still not fully understood. Mutations in or near the melanophilin (MLPH) gene are causing dilute coat colour in dogs (at least in Doberman, beagle and large Munsterlander). In dogs, coat colour dilution is unfortunately often accompanied by alopecia. More than 20 breeds segregate for dilute coat colour. However, alopecia does not develop in all dogs with blue of fawn coats, and the frequency varies within affected breeds. The dilute mutation is required but not sufficient to develop alopecia. The risk to develop CDA appears to be breed specific and depends on other factors not yet determined. For example, most (if not all) Blue Dobermans will develop some degree of alopecia, while most Weimaraners won t. Dilute hairs have larger pigment granules than the non-dilute red or black hairs. The initial hair loss is due to hair shaft fracture at the point of melanin clumping (aggregated melanosomes), and secondary bacterial folliculitis further contributes to the hair loss. However, these are not usually sufficient to explain the extent of alopecia. It is possible that the melanin accumulation in bulbar melanocytes and large pigment clumps, which can separate the bulbar matrix cells, cause significant damage to the hair bulb or that the abnormal transfer of melanosomes in CDA results in a lack of stimulation of the hair bulb keratinocytes which may lead to resting, non-cycling follicles. Alternatively, an independent secondary disease process could be the cause of follicular inactivity. Clinical features CDA has been most widely recognised and reported in blue Doberman pinschers, but it also has been seen in several other breeds with dilute coat colours such as Dachshund, whippet, Italian Greyhound, Chow Chow, Yorkshire terrier, Chihuahua, and more recently in silver Labradors. First clinical signs are usually noticed between 3 and 12 months of age, although some dogs with very mild coat colour dilution (e.g., steel blue) may present alopecia later in life. Affected dogs show a progressive alopecia, scaling and comedones affecting only the dilute areas of the hair coat. Affected dogs are prone to secondary bacterial folliculitis, which may cause pruritus and aggravate the hair loss. Lesions are usually slowly progressive with age. Breed predisposition and presence of alopecia restricted to the diluted areas are evocative of this disorder. Trichoscopic examination of plucked hairs shows numerous large, unevenly distributed, melanin clumping 3

4 of irregular shape and sizes along the hair shafts. The bulging pigment clumps may cause distortion and fracture of the hair. It is important to note, however, that the presence of melanin clumping indicates the action of dilution genes and does not necessarily mean the animal has, or will develop, CDA. Histological examination of skin biopsies from affected areas shows dilated, keratin filled hair follicles, and abnormal melanin aggregates in the epidermal and follicular basal cells, hair bulbs, hair shafts, and follicular lumen, and numerous peribulbar melanophages. With time, all follicular activity ceases and the follicles become dilated and cystic. Differential diagnosis CDA is a non-inflammatory disorder which can mimic endocrine skin diseases. Endocrinopathies such as hypothyroidism as well as demodicosis should be considered as differential diagnosis, and all underlying causes of superficial folliculitis should also be considered when the latter is present. Treatment CDA is an incurable, genetically determined dermatosis. Affected dogs are healthy otherwise, with the exception of secondary pyoderma. Keratomodulating and antiseptic shampoos and moisturisers may help to reduce the incidence of pyoderma and scaling. Pyoderma should be treated with systemic antibiotics as needed. Palliative therapy may be carried out with melatonin, retinoids or essential fatty acids to improve hair and skin conditions, although there is not studies documenting there efficacy. Melatonin, used as a non-specific hair cycling inducer, has been reported anecdotally to be effective in promoting hair regrowth in 12 dogs (which included a few blue Doberman) with CDA (Vetderm Listserv survey). There is no information, however, on duration of the beneficial effect. BLACK HAIR FOLLICULAR DYSPLASIA Black hair follicular dysplasia (BHFD) is a rare disorder of early onset in which dogs loose hairs in the black areas of their hair coat. Etipathogenesis BHFD is a familial disorder with an early onset, which is believed to be autosomal recessive. Recent studies have suggested that it has the same molecular defect as in CDA, supporting the premise that CDA and BHFD merely represent various forms of severity. Clinical features BHFD has been recognized in a variety of breeds such as Bearded collie, Saluki, Border collie, King Charles spaniel, Jack Russel terrier, Gordon setter as well as mixed-breed dogs. Affected dogs are born normal but hair coat changes, noticed exclusively in the black-haired areas, are seen as early as 4 weeks of age. Initially, there is loss of lustre of the black hairs, followed by progressive hair loss until all black hairs are lost (as early as 9 months of age). Excessive scaling occurs in the affected areas. The hair loss is permanent. Differential diagnosis The early onset, colour-linked alopecia makes the diagnosis straightforward in most cases. Demodicosis and dermatophytosis should be part of the differential diagnosis in some clinical presentations. In addition, other types of follicular dysplasias, such as CDA and follicular dysplasia of the adult black and red Doberman Pinschers could be included in the differential diagnosis, at least based on histopathological findings. 4

5 Skin biopsies in the affected black areas reveal clumped melanin in follicular basal cells and hair matrix cells. Large melanin aggregates are seen within the hair shafts. The follicles are dilated and filled with keratin, hair shaft fragments, and large clumps of free melanin. Numerous peribulbar melanophages are seen in the dermis. These pigmentary changes are similar but usually less pronounced than they are in CDA. BHFD has been reported in large Munsterlander puppies, although it would seem more appropriate to name it CDA since affected dogs are born with a grey and white coat (rather than black and white). Treatment No effective treatment has been reported for this genodermatosis. A therapeutic approach similar to that of CDA could be attempted. BLACK- AND RED-COATED DOBERMAN PINSCHERS FOLLICULAR DYSPLASIA A follicular dysplasia of red or black Doberman Pinschers (FDRBDP) have been reported by Miller in Alopecia occurs between 1 and 4 years of age and begins in the flank region and progresses slowly to involve the caudal dorsum and entire flank region. The hypotrichosis is apparently permanent. These dogs share many histopathological features of CDA and BHFD. However, they do not have a dilute coat colour nor have pigmentary clumping in the epidermal melanocytes which is a feature of CDA. Because Doberman pinschers are predisposed to CRFA, CDA, FDRBDP and hypothyroidism, and because these four disorders can share clinical resemblance, skin biopsies and a thyroid function evaluation should be performed in any Doberman with an undefined endocrine-type alopecia. HAIR FOLLICLE DYSPLASIA IN WEIMARANERS There is a distinct form of alopecia in Weimaraners that has been named Follicular dysplasia of the Weimaraner. A genetic defect is assumed but the underlying pathogenesis has not been elucidated yet. Clinicopathological findings are almost identical to CDA, except that the degree of severity is milder, suggesting that it could be another variant of a neuroectodermal dysplasia of the follicular pigmentary unit. Alopecia occurs in young adults of both gender, usually between 1 and 3 years of age. Alopecia involves the back, lateral and ventral thorax, flanks and abdomen, but spares the head and limbs. In the affected region, hair shafts break and follicles are prone to recurrent bacterial infection. Plucked hair shafts from affected areas contain large aggregates of melanin. In contrast to normal Weimaraners, the aggregates are larger and more numerous, and accompanied by large circular cuticular defects. Histopathological examination of skin biopsies from affected areas bears many similarities to CDA, but findings are less severe. Hair bulbs and hair shafts show melanocytes with large aggregates of melanosomes. Many hair follicles are distorted by large amounts of infundibular keratin. CANINE FOLLICULAR LIPIDOSIS This is a rare and presumably hereditary disease of hair follicles that develops within the first months after birth for which the underlying pathogenesis is unknown. Clinical features 5

6 This disease has only been described in young Rottweilers. Anecdotal cases have also been seen in other breeds (Julie Yager, personal communication). It is characterized by early onset alopecia, affecting mahogany-coloured areas on the feet and face. Follicular lipidosis is characterized on histopathological examination by intracytoplasmic lipid-filled vacuoles within cells of the hair follicle matrix. Similar vacuoles may be seen in the hair shaft. Alopecia is most likely a result of increased hair shaft fragility. ALOPECIA X Alopecia X is the name most veterinary dermatologists are now using to refer to the following disease(s): pseudo-cushing, adult onset growth hormone (hyposomatotropism) deficiency, growth hormone responsive alopecia, castration-responsive alopecia, adrenal sex hormone imbalance, congenital adrenal hyperplasia like-syndrome, Lysodren responsive dermatosis, post-clipping alopecia (of plush-coated breeds), follicular dysplasia of Husky and other Nordic breeds (Woolly syndrome, coat funk in malamute), follicular growth dysfunction of the plush-coated breeds, black skin disease of Pomeranians, and more recently hair cycle arrest. The diversity in proposed names is based, at least in part, upon the differences in endocrine evaluation results and/or clinical responses to various therapeutic modalities. Etiopathogenesis Alopecia X is a disorder on which so much has been said and written but for which little is really known or understood. The aetiology remains obscure although a genetic predisposition to an unidentified hormonal imbalance is plausible, but a defect residing at the hair follicle level is also possible. If the problem is a primary disorder of the hair growth cycle, various stimuli (including different hormones) could draw hair follicles into anagen phase. In the 80 s, the hypothetical pathogenesis of alopecia X was an adult onset growth-hormone deficiency. This theory was however discarded since many dogs with this condition had normal growth hormone levels. In the 90 s, the theoretical pathomechanism was an imbalance of adrenal steroid intermediates and sex hormones, possibly due to a deficiency in 21-hydroxylase enzyme. However, it was later shown that not all dogs with alopecia X have abnormalities in adrenal steroid or sex hormone concentrations and that there was no association of hair regrowth with changes in hormone concentrations. In addition, a decrease in hormone concentrations was not necessarily observed in neutered dogs showing favourable response following melatonin administration. Moreover, the canine 21-hydroxylase gene was later cloned and sequenced in Pomeranians with alopecia X, and no mutations in the gene were detected. It has also been suggested that the alopecia may be due to a mild but prolonged increase in basal cortisolemia, instead of adrenal sex hormone imbalance. This hypothesis was based on work done in miniature poodles and Pomeranians with alopecia X which had increased urinary cortisol/creatinine ratios but normal post-acth stimulation cortisol levels. However, this theory seems unlikely because no other clinical signs of hypercortisolemia (pu/pd, polyphagia, pendulous abdomen, etc.) are seen in dogs with alopecia X. It is possible that miniature Poodles (anagen based hair growth cycle) have a different etiopahogenesis than the plush-coated breeds (telogen based hair growth cycle). Paradoxically, however, it was found in a retrospective evaluation of adrenal hormone panels that adrenal sex hormone levels in miniature Poodles most resemble Pomeranians, and both breeds often show hair regrowth following the same therapy (e.g., trilostane). New theories on the etiopathegenesis of alopecia X are focusing on genetics and hair follicle receptors. 6

7 Extrinsic (e.g., hormones) as well as intrinsic (e.g., cytokines, growth factors, receptors) factors are involved in the hair follicle cycle. Anagen initiation involves complex interactions between factors (estrogen receptors among others). The role of oestrogen receptors was investigated in a cohort of Pomeranians (excluding intact females) with alopecia X. Hair regrowth following melatonin administration (which may block oestrogen receptors) was not associated with a change in oestrogen receptor-α staining. It is possible that hair follicles of dogs with alopecia X require stimulation from other molecules (e.g., noggin, insulin growth factors, etc.) in conjunction with blocking of the oestrogen receptors. There is growing evidence that androgens might be involved in this syndrome. Indeed, significant hair growth has been observed in a number of dogs with alopecia X following castration, as well as with the use of various antiandrogen drugs such as osaterone acetate, deslorelin, finasteride and dutasteride. Alopecia X, which occurs most commonly in breeds bred for hirsutism (double coat and dense under coat), may indeed be caused by a primary follicular defect, similar to male pattern baldness, with a sexhormone related signal for expression. Indeed, men with pattern baldness do not always have elevated sex hormone concentrations; instead their hair follicles respond abnormally to a normal hormonal signal (e.g. receptor problems). Clinical features Alopecia X is seen in many breeds, but especially in Nordic breeds with plush coat (e.g., Pomeranian, Chow Chow, Keeshond, Samoyed, Malamute and Husky), and miniature poodle. The age at onset of alopecia is quite variable occurring usually between 1 to 10 years of age. Dogs of both sexes can be affected regardless of neutering status. Alopecia can start before or after neutering. Permanent hair regrowth is often observed following castration of affected intact male dogs. The symmetrical, non-inflammatory alopecia observed in alopecia X mimics that of endocrine alopecia. Initially, there is loss of primary hairs (with retention of secondary hairs) in frictional areas (around the neck, caudo-medial thighs and tail). Gradually, all hair is lost in those regions and eventually the truncal primary hairs are also lost, giving the remaining coat a puppy-like appearance. With time (several months to years), the secondary hairs become sparse, and hyperpigmentation of the exposed skin and/or colour change in the remaining hair coat may be seen. The head and legs are usually spared. A tendency to regrow hair at the biopsy site following skin biopsy or traumatic stimuli (e.g. skin scraping, sunburn, pyoderma) is a common finding (however not constant or pathognomonic) in this syndrome. Differential diagnosis This includes hypothyroidism, spontaneous and iatrogenic hyperadrenocorticism, hyperoestrogenism due to functional gonadal neoplasms o human estrogen cream, telogen defluxion, other follicular dysplasias, and, in some cases, sebaceous adenitis. The diagnosis is based on history, physical examination findings and by exclusion of disorders listed in differential diagnosis. Histopathological examination of skin biopsies reveals changes consistent with endocrinopathies. Decreased amount and size of dermal elastin fibers were reported (chronic cases) in initial reports of adult onset growth hormone deficiencies. Later, the presence of "flame follicles" (excessive tricholemmal keratinisation) gained popularity over the elastin fibers. It is not known whether the flame follicle is simply a nonspecific expression of follicular growth arrest in the plush-coated breeds, or whether haircoat abnormalities featuring flame follicles are united by a common etiopathogenesis. However, even if flame follicles are neither pathognomonic nor observed in every cases of alopecia X, histopathological evaluation should at least confirm atrophic/endocrine changes and rule out other 7

8 disorders such as sebaceous adenitis or colour-linked follicular dysplasia. Results of routine laboratory tests (CBC, chemistry profile, urinalysis) are typically normal, as those for thyroid and adrenal function tests. Reproductive hormone panel (measured before and following ACTH stimulation) has been recommended in the past. However, a retrospective study has demonstrated its uselessness in ruling in or ruling out alopecia X. Treatment In an intact male, the first recommendation is castration. More than 50% of the dogs will regrow a normal hair coat which is generally permanent. Although less frequently documented in intact female dogs, this syndrome may also respond to ovariohysterectomy. In neutered animals, numerous forms of therapy have been associated with hair regrowth but unfortunately the result is not predictable and may be a short-term effect. Oral melatonin is currently the most popular first line of treatment. It is cheap and safe, and partial to complete hair regrowth occurs in approximately 30 to 40% of the cases when administered at the rate of 3-6 mg/dog q8 to 12h for 3 to 4 months. The exact mechanism by which melatonin induce hair growth in alopecia X is not known. The hair growth might be due to either modulation of sex hormone levels, interference with cortisol production, action at the hair follicle level by blocking oestrogen receptors (oestrogen can inhibit anagen initiation) or a less likely actual melatonin deficiency. Mitotane (Lysodren, O,p'-DDD) has been reported to be efficacious in dogs with alopecia X. Although the induction dose recommended is lower than for hyperadrenocorticism (e.g., mg/kg, q24h for 5 days, then q7-14 days as maintenance), the side effects such as hypoadrenocorticism associated with this drug should be carefully considered before using it in affected animals, and close monitoring is essential. Trilostane (Vetoryl ), a competitive inhibitor of β-hydroxysteroid dehydrogenase, which interferes with adrenal steroidogenesis, has been used with success in many Pomeranians, miniature Poodles, and malamutes with alopecia X. The main disadvantages of this treatment modality is its cost and the possibility (albeit uncommon) of adrenal necrosis. Medroxyprogesterone acetate was investigated in a recent study because it is known that synthetic progestins can induce growth hormone secretion in the mammary gland of dogs. Following four monthly subcutaneous injections, partial hair regrowth was observed only in a few dogs. Although no side effects were observed in this study, prolong administration of medroxyprogesterone acetate may induce mammary nodules, cystic endometrial hyperplasia, and diabetes mellitus. A growing body of evidence suggests that androgens are involved in alopecia X. In addition to the hair regrowth observed in a large number of intact male dogs suffering alopecia X following castration, success has also been obtained with various anti-androgen drugs such as osaterone acetate, deslorelin, finasteride and dutasteride. Osaterone acetate (Ypozane ) is a steroid with potent anti-androgen and partial progestagen effect, licensed for the treatment of canine benign prostatic hyperplasia. Success rate of up to 75% has been obtained with this drug when administered daily orally for one week every 3 months (Vetderm Listserv survey). Recently, Desloreline (Superolin ), a long acting GnRH agonist commercialized as implants for reversible chemical castration in dog, was shown effective in the majority of intact male dogs, but was generally ineffective in spayed females affected with alopecia X. 8

9 5-α-reductase inhibitors such as finasteride and dutasteride block the action of the 5-α-reductase enzyme that converts testosterone to dihydrotestosterone. Finasteride (a type II 5-α-reductase inhibitor) significantly decreases serum and tissue dihydrotestosterone concentrations in humans and in dogs. In men with androgenic alopecia, the balding scalp with its miniaturized follicles contains increased amounts of dihydrotestosterone compared with the nonbalding scalp. Oral administration of finasteride (Propecia 1 mg/tablet) daily decreases scalp and serum dihydrotestosterone concentrations, and promote hair growth although continued daily use of finasteride is needed in man for sustained benefit. Finasteride (Proscar, 5 mg/tablet) has been used in the treatment of benign prostatic hyperplasia in man and in dogs and appears to be safe. Dutasteride (Avodart, 0.5 mg/capsule), a dual (type I and II) 5-α-reductase inhibitor, is also approved for the treatment of benign prostatic hyperplasia in man. Although not labelled for androgenic alopecia in men, it is very effectively promotes hair regrowth. Both of these drugs we effective in a few dogs with alopecia X treated by the author. Current studies are investigating the presence of type I and type II 5-α-reductase enzyme in the dog skin. Other treatment modalities such as exogenous oestrogen, methyltestosterone, growth hormone, leuprolide acetate, L-deprenyl, and medroxyprogesterone acetate have been recommended or investigated. However, these therapies are no longer recommended due to adverse effects, cost, availability and/or poor effectiveness. More recently, microneedling has been described as a potential treatment for alopecia X. Prognosis Alopecia X is essentially an aesthetic problem. With the exception of a few dogs where a superficial pyoderma will be seen, these dogs are otherwise healthy. If melatonin is not helpful, the pros and cons of the various therapeutic options need to be discussed with the owner. It is important to state that benign neglect is considered a valid management alternative. Due to cost, availability and/or side effects related to various treatments, owners will often choose not to have their dogs treated. Rather than promoting more aggressive treatments (e.g. mitotane, trilostane), one s efforts could be toward client education and promotion of acceptance of the alopecia (i.e. sweater therapy ). CANINE RECURRENT FLANK ALOPECIA Canine recurrent flank alopecia (CRFA) is characterized by episodes of truncal alopecia that often reoccur on a yearly basis. Pathogenesis The high incidence in some breeds and the familial character of CRFA suggest a genetic influence although the specific cause remains obscure. The seasonal nature and recurrence suggests that photoperiod may be involved. There is a higher incidence of CRFA at higher latitude (around or north of the 45 parallel). In Australia and New Zealand, the onset of CRFA appears to be the reverse of what we see in the northern hemisphere (but also during their short photoperiod season) supporting a link of light exposure to this disorder. Exposure to abnormally long photoperiods (i.e. several extra-hours of artificial light) associated with indoor housing (common in dogs from colder climate) would result in a decrease of endogenous melatonin secretion. Recently, Vandenabeele has shown systemic rather than local factors with effect on specific hair follicles. This was demonstrated by skin transplants of CRFA affected dogs on athymic nude mice that showed normal hair growth in the transplanted skin (whereas the donor site still showed alopecia). Studies on fibroblast growth factor-18 (FGF-18) did not support the hypothesis that an increase in this growth factor precedes initiation of anagen phase in dogs (as it has been noted in people recovering from alopecia areata). 9

10 Clinical signs CRFA is characterized by a fairly abrupt onset of non-scarring alopecia, usually bilaterally symmetric, with well-demarcated borders and often markedly hyperpigmented alopecic skin. The alopecia is usually confined to the thoracolumbar region but occasionally this is seen in association with alopecia on the dorsum of the nose, base of the ears, base of tail and perineum. Spontaneous regrowth of a normal pelage occurs in 3 to 8 months (range: 1 to 14 months) although some individuals grow hair of a different colour in previously-affected areas (e.g., melanotrichia in Boxers and aurotrichia in miniature Schnauzers). In a few dogs, hair regrowth may become less complete after several yearly episodes; it may even progress to a permanent flank alopecia and marked hyperpigmentation. Approximately 20% of CRFA cases may have only one isolated episode of flank alopecia during their life; however, most dogs will develop recurrent alopecic episodes for years. Some dogs have an occasional year when the alopecia does not recur. The degree of alopecia is variable, with some dogs developing a virtually identical hair loss (size and duration) year after year, and other dogs developing larger areas and/or longer episodes of hair loss as years go by. Lesions may be more seasonal in northern climates than in equatorial regions. Rarely, alopecia at the bridge of the nose, the base of the ears, the base of the tail and/or the perineum, which also manifest a spontaneous regrowth and recurrence, have been observed in conjunction with thoracolumbar alopecia in some breeds such as Airedales, golden retrievers, griffon Korthals, Dobermans, wire-haired pointers, and giant Schnauzers. Another atypical presentation was recently reported by Vandenabeele in a cane Corso dog showing recurrent alopecia restricted to the face and ears. The mean age at the onset of the first episode is approximately 4 years (range: 8 months to 11 years). The majority of dogs have an onset of alopecia between November and March in the Northern hemisphere. Dogs of either sex and of all reproductive status can be affected. Several breeds are at higher risk of developing CRFA with Boxers account for approximately half of all cases. It appears to be rare to absent in the plush-coat Nordic breeds, German Shepherd Dog, and Cocker Spaniel. Rachid reported CRFA in nine boxers with concomitant non-pruritic, multifocal annular crusted lesions confined to the alopecic areas. Histopathologically, the inflammatory lesions were characterized as interface dermatitis. The alopecia and the interface dermatitis ran parallel courses of spontaneous remission and recurrence, or persistence, respectively. The relationship between the two histological reaction patterns is not known. For most cases of CRFA, the diagnosis is based on signalment, history and clinical signs. Histopathological findings (such as "witch s feet and hypermelanosis of the sebaceous gland) are supportive of but not pathognomonic of CRFA. In a dog presented at his first episode, other causes of alopecia such as endocrinopathies (e.g., hypothyroidism, HAC) or other follicular dysplasias need to be ruled out. Hypothyroidism remains an important differential diagnosis for CRFA (due to its frequency, and breed and age overlap). Moreover, hypothyroidism and CRFA have been diagnosed concurrently in a few dogs. Treatment The unpredictable course of CRFA and the spontaneous regrowth of hair render the evaluation of any therapeutic agent difficult, whether used to prevent CRFA or to shorten an existing episode of alopecia. Oral melatonin can be administered before or shortly after the onset of alopecia. Dogs affected with CRFA appear healthy otherwise, and benign neglect is also a valuable therapeutic approach. 10

11 BREED SPECIFIC FOLLICULAR DYSPLASIAS Non colour-linked follicular dysplasias have been described in Irish water spaniel, Portuguese water dog, Chesapeake Bay retriever, Curly coated retriever, and Pont Audemer spaniel. Etiopathogenesis It is unknown whether these breed specific follicular dysplasias share the same genetic defect or if they are distinct entities. It is at least plausible that the Chesapeake Bay retriever and the Irish water spaniel follicular dysplasias are the same since the Irish water spaniel is one of the several breeds used to create the Chesapeake Bay retriever. Portuguese water dog follicular dysplasia is characterized by a symmetrical truncal alopecia which occurs in males or females, black or brown coated, and predominantly in dogs with curly rather than wavy hair coat. In general, the hair loss, which has a familial tendency, first occurs in young adults and involved the flanks or saddle region. Several episodes of alopecia and spontaneous hair regrowth occur in most dogs, but the new hairs do not have the texture and quality of normal hairs. Eventually the alopecia becomes permanent. It has been suggested that the alopecia is due to a follicular dysplasia with abnormal melanization of the pilosebaceous units. Irish water spaniel follicular dysplasia is characterized by an hypotrichosis or alopecia affecting the latero-caudal neck, flanks, dorsum, rump or caudal aspect of the thighs, in addition to the short coat on the ventral neck and the tail, which are special characteristics of the breed. Clinically, affected dogs seem to show different patterns of hair loss that are evocative of canine pattern alopecia, follicular dysplasia of the Portuguese water dog, as well as CRFA. A follicular dysplasia has been reported in Husky, however, I personally consider this clinicpathological presentation no different from alopecia X. Breed predisposition and clinical signs are suggestive of this condition. Histopathology revealed features similar to CRFA and follicular dysplasia associated with abnormal melanization, although the clinical findings described in these breeds may vary. Histology of skin specimens shows various degrees of follicular hyperkeratosis, numerous follicles in ketogen (hairless telogen follicle), melanin clumping and dysplastic hair follicles. In the Portuguese water dog follicular dysplasia, unique histopathologic findings have been described. They include prominent apoptosis of kerartinocytes in the inner root sheath, and dissolution or the hair matrix of anagen follicles. Treatment These genetically based dermatoses are incurable. Affected dogs are healthy otherwise with the exception of secondary pyoderma. In some cases, melatonin and essential fatty acid supplementation may improve the coat quality and reduced the severity of the alopecia. Canine pattern alopecia (CPA) is a relatively common disorder which may present with several different syndromes. The two main forms of CPA are the ventral type, the most common syndrome, and the pinnal type. CANINE PATTERN ALOPECIA CPA has been recognized in several short-coated breeds. The etiology is unknown, but the strong breed and familial predisposition suggest that genetic predisposition is involved. CPA may be an overshoot reaction to artificial selection pressure favouring the fine, delicate coat sought by breeders. Over the last decades, smooth hair dachshund breeders have been able to significantly decrease the incidence of CPA, ventral type by selective breeding but with the result of dogs generally having a coarser hair coat. 11

12 Clinical signs CPA affects dogs of either sex and of any reproductive status. A progressive alopecia that remains restricted to the described areas usually starts before one year of age. CPA, ventral type: progressive alopecia developing along the ventral neck, chest and abdomen, the caudomedial aspect of thighs, perineum and the postauricular regions (base of the ear pinnae) CPA, pinnal type: progressive alopecia of the convex aspect of the ear pinnae, starting around 6 months of age. Alopecia and melanoderma of Yorkshire terrier: alopecia and hyperpigmentation of the convex aspect of the ear pinnae and the bridge of the nose. This is most likely the same disorder as CPA, pinnal type reported on a different appellation. The diagnosis is based on the history, the dermatological examination and exclusion of other diagnoses. Histopathological findings are characterized by miniaturisation of hair follicles. Treatment This disease is just an esthetic problem and no effective treatment has been reported with the exception of anecdotal success with melatonin. CONCLUSION At this point in time, our understanding of follicular dysplasias is rather limited. Genome-wide association studies (GWAS) might shed some light on these disorders in a near future. GWAS have recently established the 3 major genes that together account for most coat phenotype in dogs. Fibroblast growth factor 5 (FGF5) is associated with long hair, keratin 17 (KRT17) is associated with the degree of curl, and a variant in the R-spondin 2 gene (RSPO2) is associated with wiry coat and presence of furnishings, which include moustaches, eyebrows and increased hair on legs. Let s hope that this technology will eventually help us understand the array of varied and seemingly complex follicular dysplasia phenotypes, and that genetic tests will be available in the foreseeable future. 12