Pili Torti: A Feature of Numerous Congenital and Acquired Conditions

Pili torti is a rare condition characterized by the presence of the hair shaft, which is flattened at irregular intervals and twisted 180° along its long axis. It is a form of hair shaft disorder with increased fragility. The condition is classified into inherited and acquired. Inherited forms may be either isolated or associated with numerous genetic diseases or syndromes (e.g., Menkes disease, Björnstad syndrome, Netherton syndrome, and Bazex-Dupré-Christol syndrome). Moreover, pili torti may be a feature of various ectodermal dysplasias (such as Rapp-Hodgkin syndrome and Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome). Acquired pili torti was described in numerous forms of alopecia (e.g., lichen planopilaris, discoid lupus erythematosus, dissecting cellulitis, folliculitis decalvans, alopecia areata) as well as neoplastic and systemic diseases (such as cutaneous T-cell lymphoma, scalp metastasis of breast cancer, anorexia nervosa, malnutrition, cataracts, and chronic graft-vs.-host disease). The condition may also be induced by several drugs (epidermal growth factor receptor inhibitors, oral retinoids, sodium valproate, and carbamide perhydrate). The diagnosis of pili torti is based on trichoscopic or microscopic examination. As pili torti is a marker of numerous congenital and acquired disorders, in every case, the search for the signs of underlying conditions is recommended.


Introduction
Pili torti, also known as "twisted hair", was first described by Galewsky, and, independently, by Ronchese in 1932 [1,2]. It is characterized by the presence of the hair shaft, flattened at irregular intervals and twisted 180 • along its long axis, with each twist being 0.4 to 0.9 mm wide and occurring in groups of 3 to 10 ( Figure 1) [3].
Pili torti is a form of hair shaft disorder with increased fragility [4]. It is classified into inherited or acquired. A wide range of changes associated with pili torti suggest specific pathophysiological mechanisms [5]. In inherited forms, the twisting of the hair is caused by an unequal development of the outer root sheath cells. Cell vacuolation and the irregular thickness of the outer root sheath at the suprabulbar level induce an uneven molding of the inner root sheath and hair shaft [6]. In acquired forms, a perifollicular inflammation followed by fibrosis generates rotational forces and deforms the hair follicle [7]. The cross-sectional area of pili torti hair is significantly smaller than a normal hair sample (2210 ± 1090 vs. 3370 ± 821 (µm 2 ); p < 0.001) and the tensile strength of pili torti is 2.1 times lower than that of normal hair [8]. No abnormalities in the hair cortex keratin within pili torti axis are observed [5].
Clinically, patients with pili torti have fragile, brittle, dry, and coarse hair. Patchy alopecia may develop. The scalp hair, especially in the occipital and temporal areas, is most commonly affected [9]. However, the eyebrows, eyelashes, axillary, and pubic hair may also be involved [9]. Usually, not all hair is affected by pili torti, and only a part of hair length may be changed [10]. Isolated pili torti may be occasionally found in the normal scalp. However, it may be associated with numerous local and systemic conditions [11,12].
In this review, we analyse current data about the possible causes of pili tori and discuss the underlying conditions. Available data on the management of pili torti are presented.

Inherited Pili Torti
Inherited pili torti may be categorized as: classic early onset (Ronchese type), late onset (Beare type), and pili torti associated with genetic diseases or syndromes [2].

Early Onset (Ronchese) Type
The classic (Ronchese) form is an autosomal dominant or recessive condition, beginning in the early childhood [2,13]. The disease onset is between the third month and third year of life. Girls with blond hair are most commonly affected. In early onset pili torti, clusters of twists of hair are usually detected. The condition often improves with age, especially after puberty [2,13].

Late Onset (Beare) Type
Late onset type is an autosomal dominant disorder, typically occurring after puberty. It is more commonly observed in individuals with dark hair. Contrary to the early onset type, the twists of hair are usually single in the late onset type [2,13].

Pili Torti in Genetic Diseases or Syndromes
The list of genetic diseases and syndromes associated with pili torti is presented in Table 1. The most common conditions are described below.

Menkes Disease
Menkes disease, also known as kinky hair disease, is a rare neurodegenerative disease with X-linked recessive inheritance [45]. It is caused by different mutations in the ATPase Copper Transporting Alpha (ATP7A) gene, that result in the failure of copper absorption in the intestines followed by copper deficiency [46].
Pili torti is the most characteristic hair shaft defect in Menkes disease. The twists of hair shaft are probably due to the low activity of copper-dependent enzymes, which are important in creating disulfide bonds in hair keratin. Other hair shaft abnormalities are trichoclasis, trichorrhexis nodosa, and trichoptilosis [5].
In patients with Menkes disease, neurodegenerative signs, including seizures, feeding difficulties, hypotonia, and psychomotor retardation usually occur at 2-3 months of age [5]. Other common features are a jowly face with fair complexion, skin and joint laxity, arterial abnormalities, skeletal changes, and urinary tract infections caused by the diverticula of the bladder [5].
In therapeutic management, copper supplementation is the most important [5].

Björnstad Syndrome
Björnstad syndrome is an autosomal recessive or dominant condition caused by a missense mutation in the ubiquinol-cytochrome c reductase complex chaperone (BCS1L) gene [47]. It is characterized by the presence of pili torti and sensorineural hearing loss [47].
In Björnstad syndrome, pili torti develops during the first two years of life [20,21]. It usually affects exclusively the scalp hair. Eyebrows and eyelashes remain unaffected [20,21]. A positive correlation between severity of hair shaft abnormalities and hearing loss has been suggested [20].
Hair shaft abnormalities in Netherton syndrome are probably caused by disturbances in the keratinization process [50]. Pili torti is frequently observed, however trichorrhexis invaginata ("bamboo hair") is a pathognomonic feature. Other hair shaft defects, such as trichorrhexis nodosa, trichoschisis, and trichoptilosis may also be detected [35,36]. Hair shaft abnormalities in Netherton syndrome tend to improve with age. Complete resolution may occur [51,52]. The presence of hair shaft abnormalities is one of diagnostic criteria of Netherton syndrome, which emphasizes their importance in the diagnostic process [53].
Hair shaft abnormalities may be an initial presentation of Bazex-Dupré-Christol syndrome, and may precede the development of basal cell carcinomas [57]. They are reported in 85% of cases, and include pili torti and trichorrhexis nodosa [58]. Hypotrichosis is usually diffuse in boys, whereas abnormal hair is admixed with normal hair in girls. Eyebrows may also be affected [57].

Pili Torti in Ectodermal Dysplasias
Ectodermal dysplasias include a heterogenous group of inherited disorders, characterized by congenital defects in one or more ectodermal structures and their appendages (hair, teeth, nails, and sweat glands) [59]. Pili torti has been reported in numerous ectodermal dysplasias ( Table 2). The selected conditions are described below.

Rapp-Hodgkin Syndrome
Rapp-Hodgkin syndrome is a form of ectodermal dysplasia inherited as an autosomal dominant trait and characterized by anhidrotic ectodermal dysplasia, cleft lip, and cleft palate [80]. It is caused by the mutations in the Tumor Protein P63 (TP63) gene encoding p63 transcription factor [81].
It was hypothesized that hypoplastic adnexal structures, hypoplastic epidermis, folliculitis, atopy, and immunological disturbances in Rapp-Hodgkin syndrome contribute to scalp dermatitis, alopecia, and hair shaft abnormalities [82]. Hair shaft abnormalities in the disease include pili torti and pili canaliculi [74,75]. Scalp hair, eyebrows, eyelashes, and other body hair are affected. Alopecia usually does not affect the occipital and temporal areas [83,84]. Pili torti is one of the most distinctive clinical features in patients with Rapp-Hodgkin syndrome. Thus, it helps to discern it from other types of ectodermal dysplasia with dental abnormalities [85].

Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome
Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome is a form of ectodermal dysplasia inherited in an autosomal dominant fashion caused by mutations in TP63 gene [60].
Pili torti is a common finding in the disease, observed in up to 59% of cases [60]. Pili trianguli et canaliculi, and irregular indentation and shallow grooves are also commonly detected [60].
Other clinical features in ankyloblepharon-ectodermal defects-cleft lip/palate syndrome include abnormal fibrous strands of tissue that can partially or completely fuse the upper and lower eyelids (ankyloblepharon), mild to severe skin erosions, and cleft palate and/or cleft lip. Scalp erosions are considered as a main cause of morbidity in infants with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome [88].

Acquired Pili Torti
Acquired pili torti may be associated with numerous dermatological and systemic conditions (Table 3) or may be drug-induced (Table 4).

Pili Torti Associated with Cicatricial Alopecias
The term cicatricial alopecia corresponds to a heterogeneous group of disorders characterized by irreversible destruction of hair follicles with subsequent scarring [109]. It results in abnormal hair shaft formation with the presence of pili torti [7]. To date, data considering pili torti in cicatricial alopecias are limited. However, it may be suggested that the number of pili torti correlates with the severity and duration of inflammatory/fibrosis process.
The clinical and trichoscopic characteristics of cicatricial alopecias associated with pili torti are presented in Table 5.  The classic variant of lichen planopilaris is one of the most common forms of primary cicatricial alopecia [110]. The pathogenesis of the disease has not been fully elucidated [109]. However, a misdirected cellular immune response to an unknown antigen in the basement membrane zone, leading to the destruction of follicular stem cells in the bulge region of the hair follicle has mainly been suggested [109].

Frontal Fibrosing Alopecia
Frontal fibrosing alopecia is considered as a variant of lichen planopilaris [113,114]. The etiology and the pathogenesis of the disease are still unknown [114]. However, the role of sexual hormones in the development of frontal fibrosing alopecia has been proposed [114].
Pili torti is observed in 71.4% of patients with frontal fibrosing alopecia [89]. Its presence has been also described in the eyebrow area [115]. Similar to the classic variant of lichen planopilaris, perifollicular erythema and perifollicular scaling are the most characteristic trichoscopic features of frontal fibrosing alopecia [116].

Discoid Lupus Erythematosus
Discoid lupus erythematosus is the most common subtype of chronic cutaneous lupus erythematosus [114].

Pseudopelade of Brocq
Pseudopelade of Brocq is a form of lymphocytic primary scarring alopecia. There is still no clear consensus whether the disease is a distinct entity or represents the end stage of any given cicatricial scalp disorder [109,114].

Folliculitis Decalvans
Folliculitis decalvans is a form of primary neutrophilic cicatricial alopecia [114]. The frequent association with Staphylococcus aureus infections suggests that the disease is caused by an excessive inflammatory response to staphylococcal antigens [109].
Pili torti is identified in 47.1% of patients with folliculitis decalvans, regardless of the severity and stage of the disease [89,120]. Other characteristic trichoscopic features of the disease include hair tufts consisting of 5-20 hairs surrounded by yellowish tubular scaling [117].

Dissecting Cellulitis
Dissecting cellulitis is an infrequent form of primary neutrophilic cicatricial alopecia characterized by the occlusion of follicular openings [121].

Central Centrifugal Cicatricial Alopecia
Central centrifugal cicatricial alopecia is a form of lymphocyte-predominant cicatricial alopecia [123]. The pathogenesis of the disease has not been fully described. The role of genetic predisposition, use of chemical straighteners, traction hairstyles, bacterial or fungal infections of the scalp have been suggested [109].
Pili torti was described in a few cases of central centrifugal cicatricial alopecia [91]. The most specific trichoscopic feature of the disease is peripilar gray/white halo [124].

Pili Torti Associated with Secondary Cicatricial Alopecias Traction Alopecia
Traction alopecia is a form of acquired hair loss that results from persistent, pulling forces on the hair follicles associated with traction-inducing hairstyles [125]. In its early phase, areas of non-scarring hair loss are present. Subsequently, the disease may progress to scarring alopecia [125].
Pili torti is reported in 56% of patients with traction alopecia, and is present during the scarring stage of the disease [93]. Other trichoscopic findings of traction alopecia are non-specific [93].

Linear Scleroderma en Coup de Sabre
Linear scleroderma "en coup de sabre", a form of linear morphea, is one of the cause of secondary cicatricial alopecia.
In linear scleroderma "en coup de sabre", diffuse distribution of pili torti is observed [95]. Moreover, trichoscopy reveals scattered black dots, broken hairs, and short thick linear and branching tortuous vessels on the periphery of the lesion [95].

Pili Torti in Non-Cicatricial Alopecias Pili Torti in Alopecia Areata
Alopecia areata is an autoimmune form of non-scarring hair loss that may affect any hair-bearing area. It is caused by the infiltration of T helper cells, cytolytic T cells, natural killer cells, and plasmacytoid dendritic cells around the lower part of the hair bulb during the anagen phase, which induces the collapse of the hair follicle immune privilege and hair loss [126].
The pathogenesis of pili torti in alopecia areata has not been described [90]. It may be hypothesized that it results from perifollicular infiltrates that induce pressure on the epithelium and disrupt hair shaft formation. Pili torti in alopecia areata was reported in one study conducted by Park et al. [90] with the frequency 6% and 2% of patients with localized and diffuse hair loss, respectively. The most characteristic trichoscopic features of alopecia areata are exclamation mark hairs, while yellow dots and vellus hairs [2].

Pili Torti in Malignancies
Pili torti was described as the most common trichoscopic feature of the erythrodermic variants of cutaneous T-cell lymphoma present in 81% of cases [98]. It is characterized by high sensitivity and specificity of 81% and 93%, respectively [98]. It was hypothesized that in cutaneous lymphomas, pili torti results from folliculotropic inflammation without or with the mucinous degeneration of the hair follicle, which induces pressure on the epithelium, and, thus, affects hair shaft formation [98].
Moreover, one case report described a patient with scalp metastases of breast cancer, with the presence of pili torti on trichoscopic examination [97].
Pili torti is most commonly described after the use of epidermal growth factor receptor inhibitors. In an animal model, it was reported that epidermal growth factor receptor inhibitors impair DNA integrity and lead to apoptosis of both keratinocytes (interfollicular epidermis, outer root sheath, and matrix) and non-proliferative, differentiated cells of the hair shaft [127]. Inhibition of epidermal growth factor receptor pathways also interferes with transcription factor expression. Thus, it impairs proper differentiation cues for hair shaft cells, resulting in loss of the medulla layer. Moreover, in mice harboring a disruption of the epidermal growth factor receptor-allele it was showed that hair follicles fail to enter catagen, and remain in an aberrant anagen state [104]. Subsequently, the thinning or loss of the outer and inner root sheaths, together with perifollicular inflammation and fibrosis are detected. In a case series of patients treated with erlotinib, histological examination of the scalp showed irregular thinning of the outer root sheath and disintegration of the inner root sheath [104].
Other drugs which may induce pili torti are oral retinoids, sodium valproate, and carbamide perhydrate.
Retinoic acid plays an important role in hair follicle formation and patterning through the regulation of the homeobox genes [128]. It was suggested that retinoids influence the keratinization of the inner root sheaths of the hair follicle in the anagen phase, which leads to pili torti formation [129].
The mechanism of pili torti formation after valproate use is unclear. It may be associated with valproate chelating properties (copper, zinc, and magnesium) as well as the inhibition of metalloproteins [130].
Carbamide peroxide is a source of hydrogen peroxide, which affects the hair shaft by oxidation and decomposition of cysteine (which accounts for 20% of the amino acids of the hair keratin) as well as the formation of cysteic acid. Moreover, carbamide peroxide destroys the majority of the disulfide bridges of hair keratin [108].

Diagnosis
The diagnosis of pili torti is based on trichoscopic and microscopic examination. Trichoscopy, hair and scalp dermoscopy, is a rapid technique that is useful in the diagnosis of scalp and hair diseases as well as genetic disorders, including ectodermal dysplasias [10,131]. It can be performed with a manual dermoscope (10 magnification) or a videodermoscope (20-1000 magnification) [132]. This noninvasive method replaced light microscopy, which required pulling of multiple hairs for investigation. This is particularly burdensome in cases, where only few hairs might be affected [9]. In pili torti, low magnification trichoscopy reveals the hair shafts bent at different angles and at irregular intervals. Regular twists of the hair shaft along the long axis are observed at high magnification ( Figure 2). Microscopic examination shows groups of three or four regularly spaced twists at irregular intervals along the shaft [10].
Genetic diseases and syndromes should be excluded in every patient with pili torti. The search of other signs of underlying conditions should be performed in the case of acquired pili torti.

Treatment
There is no specific treatment of pili torti. The avoidance of trauma to the hair is recommended. Other forms of management include sleeping on a satin pillowcase, avoiding excessive grooming, braiding, heat treatments, and dying. Gentle shampoos may be beneficial [104,133].
Congenital pili torti may improve spontaneously after puberty. Drug-induced cases tend to resolve after the discontinuation of the offending agent [105,106]. In regard to acquired pili torti, the treatment of the underlying condition is most important.
Efficacy of pharmacological treatment in pili torti is limited [26]. Topical minoxidil has been suggested as a beneficial therapeutic option for patients with hair shaft abnormalities with increased fragility. However, it only has an impact on hair density and does not induce a causal treatment.

Conclusions
Pili torti is a rare condition, which may be associated with numerous congenital or acquired conditions. In every case of pili torti, the identification of the underlying disorder determines the therapeutic approach and prognosis.