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OFFICIAL JOURNAL OF THE SOCIETÀ ITALIANA DI DERMATOLOGIA MEDICA, CHIRURGICA, ESTETICA E DELLE MALATTIE SESSUALMENTE TRASMESSE (SIDeMaST)

VOLUME 149 - No. 1 - FEBRUARY 2014 Anno: 2014 Lavoro: 4731-MD Mese: Febraury titolo breve: Hair loss in infancy Volume: 149 primo autore: MORENO-ROMERO No: 1 pagine: 55-78 Rivista: GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA Cod Rivista: G ITAL DERMATOL VENEREOL

G ITAL DERMATOL VENEREOL 2014;149:55-78

Hair loss in infancy

J. A. MORENO-ROMERO 1, R. GRIMALT 2

Hair diseases represent a signifcant portion of cases seen 1Department of Dermatology by pediatric dermatologists although hair has always been Hospital General de Catalunya, Barcelona, Spain a secondary aspect in pediatricians and dermatologists 2Universitat de Barcelona training, on the erroneous basis that there is not much in- Universitat Internacional de Catalunya, Barcelona, Spain formation extractable from it. Dermatologists are in the enviable situation of being able to study many disorders with simple diagnostic techniques. The hair is easily ac- cessible to examination but, paradoxically, this approach is often disregarded by non-dermatologist. This paper has Embryology and normal hair development been written on the purpose of trying to serve in the diag- nostic process of daily practice, and trying to help, for ex- ample, to distinguish between certain acquired and some The full complement of hair follicles is present genetically determined hair diseases. We will focus on all at birth and no new hair follicles develop thereafter. the data that can be obtained from our patients’ hair and Each follicle is capable of producing three different try to help on using the messages given by hair for each types of hair: lanugo, vellus and terminal. Lanugo patient. Quite often it is extremely hard to distinguish between abnormality and normality in neonatal hair as- hairs are the neonatal non-pigmented, soft, fne hairs pects. We will specially focus in the most common physi- with no central medulla; vellus hairs are short, fne, ological changes that may mislead to an incorrect diagno- lightly pigmented and they are the hairs found over sis. Specifc treatment for those hair diseases that do have much of the adult body; terminal hairs are the long, one, and basic general approach to improve the cosmetic thick, strongly pigmented hairs found in the scalp appearance of hair, will be also be discussed for those hair disturbances that do not have a specifc treatment. and eyebrows of adults and children, as well as the Key words: Child - Alopecia - Hair diseases. axillary and pubic areas of adults and the chest and facial areas of adult males.1 Hair development begins in utero at 9th week, with air loss in children encompasses a wide range of the follicular units composed of epidermally derived Hconditions that can be congenital or acquired. A follicles and mesodermally derived papillae. Primary congenital hair abnormality may be an isolated fnd- hair follicles frst develop on the eyebrows, upper lip ing in an otherwise healthy child or may exist as a and chin. Later, hair follicles develop over the scalp feature of a clinical syndrome. The clinical presenta- in a frontal to occipital direction and over the body in tion of pediatric hair disorders ranges from subtle to a cephalocaudal direction. Secondary follicles then disfguring. A basic working knowledge of normal form at each side of the primary follicles, producing hair growth is necessary, including the embryology typical groups of three hairs on follicular units (Mei- and development of the hair. jeres trios). At 16 weeks of gestation, hair production begins in the follicles. All follicles produce lanugo 2 Corresponding author: J. A. Moreno-Romero, Department of Derma- hair that grows 2-3 cm in length. Fine lanugo hair tology, Hospital General de Catalunya, Barcelona, Spain. covers the scalp and proceeds to appear elsewhere

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Figure 2.—Alopecia areata may involve hair and nails.

months until the age of 2 years. This hair is coarser than lanugo hairs, but still are sparsely pigmented.6 At full term, there are two consecutive waves of hair on the scalp, each running from forehead to oc- ciput. Toward the end of the frst year of live, follow- ing the frst two synchronized waves of telogen, there Figure 1.—Transient neonatal hair loss (TNHL). In many cases this physiological condition is confused with a frictional alopecia. is a transition to a random mosaic pattern where each hair has its own intrinsic rhythm. This asynchrony continues throughout life unless modifed by preg- in a cephalocaudal direction, eventually covering nancy or illness. the entire fetus. This constitutes the frst anagen At puberty, the level of circulating adrenal andro- (growth) wave. At 26-28 weeks of gestation, the gens increases and elicits a site-specifc response body and most of the scalp hair follicles enter cata- from the hair follicles. On the scalp, hairs miniatur- gen and subsequently telogen in a programmed wave ize in response to androgens; however, the hairs of in a cephalocaudal direction in the body and a fron- the body enlarge, with the hairs of the axillary, pubic, tal to parietal direction on the scalp. Most of these chest and beard regions being more responsive. The telogen hairs are shed in utero,3 although this can be hair of these regions change from vellus to terminal delayed until after birth. A band-like area of occipi- hair, contributing to the development of the second- tal hair does not enter telogen until 8-12 weeks after ary sex characteristics.1 birth. These occipital hairs fall out, producing a well Hair leaves the scalp at precisely formed angles. Dis- defned area of alopecia, known as occipital alopecia placement of the scalp line occurs in a number of syn- of the newborn, seen at around 4-8 months of age.4 It dromes. A congenitally high anterior hairline is seen in has been recently renamed as transient neonatal hair myotonic dystrophy. A congenitally low posterior hair- loss (TNHL) (Figure 1).5 The duration of growth of line can occur in Turner and Noonan syndromes. A con- the scalp hairs extends, while that of the body hairs genitally low anterior hairline is found in Cornelia de shortens to produce hairs of 1 cm in length. These Lange syndrome, lipoatrophic diabetes, fetal hidantoin second body hairs grow for 4-8 weeks, then enter syndrome and Rubinstein-Taybi syndrome.6 telogen, and are shed during the frst 3-4 months of life to be replaced by a third coat of hair. Body hair progressively shorten into vellus hair, most of which Alopecia areata do not protrude from the follicle. Scalp hair enlarg- es progressively with each hair cycle into terminal Alopecia areata (AA) is a non-scarring, autoim- hair. Some infants display intermediate hair from 3 mune, infammatory, hair loss on the scalp and/or

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body. Recognized subgroups of this disease include those patients with the complete absence of terminal scalp hair (alopecia totalis) and those patients with total loss of terminal scalp and body hair (alopecia universalis) (Figures 2, 3).7 AA is common, the lifetime risk of AA in the gen- eral population is estimated to be 1.7%. The disease occurs in both genders and in all age groups, includ- ing children. AA presents before 16 years in approx- imately 20% of patients. In young infants, however, AA has been considered to be quite rare. Recent ar- ticles have suggested that this disorder may be more common in neonates and young infants than previ- ously supposed (Figure 4).8 Thus, AA can be clas- sifed as both an acquired and a congenital disorder. Earlier onset of AA may predispose the patient Figure 3.—When eyebrows and eyelashes are affected, the psy- to progression to more widespread disease. Walker chological involvement is enormous. and Rothman 9 reported that onset before puberty is correlated with severity, with 50% of his prepuber- except eyelashes, which are generally spared, usu- tal cases developing alopecia totalis compared with ally during the frst 3 months of life. Between the 23% who had an onset in the postpubertal period. Al- ages of 2 and 26 years, patients develop numerous though the trend toward disease severity in younger keratinous, papular cysts resembling milia on the patients is well established, it should be emphasized head, torso and extremities, distinguishing them that this cannot predict disease severity in an individ- from patients with alopecia totalis/alopecia uni- ual case and does not rule out future hair regrowth. versalis.8 The second rare condition to consider is Before the diagnosis of AA is made in infants with rickets resistant to 1.25-dihydroxyvitamin D. These patchy or initially patchy progressive hair loss, sev- patients present with loss of some or all scalp, body, eral other conditions must be considered. The cause and facial hair (with or without loss of eyelashes), of neonatal occipital alopecia may be synchronized typically within the frst 15 months of life. Affect- loss of telogen hairs on the occipital scalp at ap- ed children have clinical and radiological signs of proximately 8-12 weeks of age. Friction or pressure over the bony occipital prominence may contribute rickets, such as bowed limbs, extremity fractures, to this circumscribed hair loss.6 Alternatively, peri- and diffuse osteopenia, and laboratory abnormali- natal trauma associated with caput succedaneum ties. In the frst months of life, however, it may be can cause a pressure-induced alopecia, which often diffcult to distinguish vitamin D-resistant rickets presents as a “halo ring” of hair loss along the oc- from AA, because clinical signs of rickets may not cipital ridge. Other causes of circumscribed hair loss yet be apparent.8 to be considered include congenital nevi, congenital Although signifcant research on the pathogenesis triangular alopecia, aplasia cutis congenital, under- of AA has taken place, the evidence base for treat- lying meningocele or cystic lesion, and hair loss as- ment of AA is scant for adults and even less for chil- sociated with complex developmental disorders.8 dren. Childhood AA is relatively common and can Two rare conditions that are important to consid- be psychologically devastating. Although a conserv- er in the differential diagnosis of total or near-total ative approach is satisfactory to some, others strong- neonatal/infantile hair loss are atrichia with papular ly desire active treatment of their alopecia. Treat- lesions and vitamin-D resistant rickets. Both dis- ment of AA is not well researched in children, but eases are characterized by normal hair density at many options for pediatric treatment exist and are birth, followed by universal loss of hair, usually by commonly used at the present time. Corticosteroids 3-15 months of age, with no hair regrowth. Atrichia are commonly used for the treatment of AA and are with papular lesions is characterized by full hair at the frst-line choice for many dermatologists. Topi- birth with permanent loss of all scalp and body hair, cal corticosteroids are an attractive option for use in

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Figure 5.—Minoxidil in alopecia areata may induce excessive hair growth in adjacent areas.

transitional phase is characterized by regression of the lower transient half of the hair follicle. Less than 1% of scalp hairs are in catagen transitional phase, which lasts about three weeks. Approximately 5% to 10% of scalp hairs are in telogen resting phase, which lasts about 3 months, after which these hairs are shed. Furthermore, two new phases of the hair cycle Figure 4.—Neonatal alopecia areata is not so rare. have been described named kenogen and exogen. Kenogen indicates the physiological interval of the children because they may be applied painlessly and hair cycle in which the hair follicle remains empty have a benign side-effect profle. However, their ef- after the telogen hair has been extruded and before fcacy compared to placebo has not been proved and a new anagen hair emerges. Kenogen frequency and relapse with discontinuation of treatment appears to duration are greater in men and women with andro- be common. genetic alopecia.11 Exogen is the phase of the hair Minoxidil is commonly used in children, but data cycle describing the shedding of the club fber from on its effcacy in pediatrics are limited. Minoxidil its epithelial silo within the follicle.12 Normally, was used extensively in children without signifcant between 40 and 100 hairs are shed daily on a non- side effects, but use in children with widespread alo- shampoo day; twice as many are shed when the hair pecia is not without risk and requires regular follow- is shampooed. Shed hair is replaced by new hair that up (Figure 5). Other treatments for AA includes grows from the same follicle.13 topical immunotherapy, anthralin, phototherapy, im- Children are subject to the same causes of telogen munosuppresants and immunomodulators.10 and anagen loss as adults and should have a similar evaluation.

Disturbances of hair cycle Anagen loss Hair growth occurs in a 3-phase cycle: anagen Anagen loss is always abnormal and, with the ex- growth phase, catagen transitional phase, and telogen ception of loose anagen syndrome and alopecia ar- resting phase. The duration of the anagen growth phase eata, scalp anagen hair loss generally implies a toxic of scalp hair varies between 2 and 6 years. Individuals exposure. Hair loss is profound, as up to 90% of with a longer anagen growth phase are able to grow scalp hair is normally in anagen, and the loss gener- longer hair (Figure 6). Approximately 90% to 95% of ally occurs within days to weeks of the insult. scalp hairs are normally in the anagen phase. Catagen The most common and easily recognizable cause

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Figure 7.—In loose anagen hair condition, hair does not need to be cut. Figure 6.—Some patients may have a longer anagen phase that allows hair to grow down to the knees. from the hair follicle. Most hairs do not remain in the follicle for the full duration of anagen and so of anagen effuvium is radiotherapy or chemothera- do not grow to the normal lenght. Parents indicate py. Other causes of anagen loss include loose anagen that they do not need to cut their child’s hair (Fig- syndrome, alopecia areata and toxic exposure to bo- ure 7) because growth stop after it reaches a certain ric acid or heavy metals (mercury, arsenic, thallium). lenght.14-16 Very severe protein malnutrition may also give rise This condition is familial and most likely inher- to anagen effuvium, as can exposure to colchicine. ited in an autosomal dominant fashion. The normal- Loose anagen syndrome does not present as sudden appearing siblings and parents of the affected child diffuse sheding, and rarely alopecia areata does. Ti- may demonstrate easily plucked hair. Loose anagen pically, alopecia areata may result in some focal hair syndrome may be associated with several types of loss or fndings of exclamation point hairs that may ectodermal dysplasias. help to distinguish this from the other causes of ana- With light microscopy we can see hair with twist- gen effuvium.4 ed anagen roots without an inner root sheath. There is a characteristic presence of crumpling of the proximal hair cuticle (ruffng) although this is not Loose anagen syndrome confrmative and also occurs in normal hair (Fig- Loose anagen syndrome is characterized by ures 8, 9). lack of adhesion of the hair shaft to the hair folli- No treatment is necessary, as the hair reverts spon- cle. Since the growing anagen hair is not anchored taneously to normal with age. During childhood, normally, hairs can be easily an painlessly plucked gentle handling decreases hair shedding.

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Figure 8.—Scanning electron microscopy of the distrophyc roots Figure 9.—Scanning electron microscopy of the cuticular ruffing typical of loose anagen hair. that allows hair to be easily plucked with no pain.

Telogen effuvium gery, endocrine disorders, nutritional disorders, star- vation, malabsorption, hemorrhage, anemia, severe The stress on the anagen hair follicle necessary to emotional stress and immunization. The role of low trigger a telogen effuvium is milder than that with serum ferritin in the cause of diffuse hair shedding an anagen effuvium and, instead of triggering dam- is unclear.1 Recently, it has been reported two cases age to the matrix, it precipitates an abrupt transfor- of telogen effuvium occurring in two 11-year-old mation of anagen to telogen hair. children following bivalent human papillomavirus The diagnosis of telogen effuvium is confrmed (HPV) vaccine administration.17 The two children by fnding a positive hair pull test from multiple ar- began to lose their hair following the second HPV eas of the scalp, hair, when examined microscopi- vaccine dose. Alopecia worsened following the third cally, being found to be telogen. In total, 50-100 vaccine dose and then resolved spontaneously within telogen hair are normally shed per day, refecting a few months. the 10-15% of hair in telogen at any one time. In a In acute telogen effuvium the shedding resolves telogen effuvium, 100-300 hairs per day are usually in 3-6 months, and the hair may take another 6 shed and 20-50% of the scalp hairs may be in telogen months to return to normal density. If the shedding at a given time.4 continues past 6 months, it becomes chronic telo- Telogen effuvium is less common in children than gen effuvium. This is primarily a condition seen in adults, and in children is more likely to be related in middle-aged women.18 Chronic diffuse telogen to a sudden and transient illness than to the drugs and hair loss may occur in children with chronic star- hormonal fuctuations that commonly trigger this in vation, especially marasmus with sparse, dry, eas- adults. It must be emphasized that any drug can trig- ily plucked hair. Both hereditary and acquired zinc ger a telogen effuvium, just as any drug can cause defciency lead to sparse, brittle hair. Essential fatty a cutaneous allergic reaction. Different triggering acid defciency can also produce increased telogen factors may precipitate a telogen effuvium, as can hair shedding. It usually occurs in children with severe febrile illness, trauma, systemic illness, sur- prolonged parenteral alimentation with inadequate

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inclusion of supplemental essential fatty acids. tients in the context of obsessive-compulsive dis- Chronic telogen effuvium can also occur in thyroid order. Trichotemnomania is not purely voluntary, it disorders, pancreatic disease and other causes of is performed to relieve stress. Although it is a con- malabsorption. scious act, patients are resistant to admitting their habit. These patients may be embarrassed by their appearance and habit, and have feelings of guilt. Traumatic alopecia The hair is usually cut with scissors or shaved, and the diagnostic key is the presence of follicle open- ings with flled hairs shafts within a healthy-look- Trichotillomania ing scalp.21 Trichotillomania is defned by the Diagnostics Another type of artifcial hair loss, which results and Statistic Manual of Mental Disorders, 4th edi- from perpetual rubbing of the scalp causing fractur- tion, (DSM-IV) as “hair loss from a patient’s self- ing of the hair shafts is called trichoteiromania. Tri- pulling of hair”.19 Trichotillomania is classifed as an choteiromania presents with bald spots within hair of impulse control disorder, being a self-inficted com- different length, which may be similar to hair cutting pulsion or habit-tic to pull or pluck at the hair. with scissors. White tips are seen at the end of the The common presentation of trichotillomania is an hair shafts in the form of distal splitting. unusual pattern of hair loss with very short hairs of Another type of hair loss with associated psychi- irregular length in an area of normal scalp. The scalp atric comorbidity is trichodaganomania, which is and the eyebrows are the most common sites, but any characterized by the compulsive habit of biting one’s site may be involved. It is usually a non-permanent own hair. form of alopecia, but if the same area is persistently In adults a very selective type of trichophagia plucked, scarring may result, with persistent hair named trichorrhizophagia has been described, in loss.1 which the patient exclusively eats the root of the hair Three subsets appear to exist: preschool age chil- he plucked.22 dren, preadolescents to young adults, and adults.20 In the preschool age population, trichotillomania ap- Traction alopecia pears to be similar to a habit, such as nail biting or thumb sucking. These young children tend to have Traction alopecia, commonly occurring in fe- a benign course. Several reviews of childhood tri- males, is due to constant tension placed on the hair chotillomania relate the onset in young children to during styling, such as tight ponytails or braiding, stressful situations. The most common age of pres- rollers, or weaving of the hair. Short, broken hairs, entation for trichotillomania is in preadolescents to folliculitis and follicular papules may be seen. young adults. Mean age of onset is usually reported The alopecia is initially reversible if patients can between 9 and 13 years of age. There appears to be be persuaded to change their hairstyle. Prolonged, a female predominance in this group. Overall, these continuous traction may cause permanent scar- patients tend to have a more chronic and relapsing ring.1 course of hair pulling. The patient will often deny any role in the hair loss reminiscent of dermatitis ar- tefacta. They are secretive about their behavior, so Androgenetic alopecia in parents and the patient are often reluctant to accept children and adolescents such a diagnosis. Psychological intervention and counseling may help identify the underlying prob- Androgenetic alopecia (AGA) is the most com- lem and modify the behavior. Psychiatric referral is mon type of hair loss in adults. Although there are recommended in recalcitrant cases. differences in the age at onset, in both sexes the disease starts after puberty, when enough testoster- Trichotemnomania one is available to be transformed into dihydrotes- tosterone. The onset of AGA is, therefore, not ex- Trichotemnomania (froom Greek temnein, to pected to be seen in prepubertal patients without cut) is hair loss due to cutting or shaving by pa- abnormal androgen levels.23 Endocrine evaluation

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Figure 10.—Androgenetic alopecia in a 13-year-old girl.

Figure 11.—Androgenetic alopecia in a 12-year-old boy. is strongly recommended in children with AGA. The occurrence of AGA in healthy prepubertal children has rarely been reported in the literature, but second study provided data on 448 adolescents with it is probably not exceptional. Tosti et al. reported AGA. This group included 341 boys and 107 girls 20 prepubertal Caucasian children with AGA, 12 who sought treatment for their thinning hair.25 Hair girls and 8 boys, age range 6-10 years. In both boys loss in this population began between 7 and 17 years and girls, clinical examination showed hair loss with of age, with a mean age at onset of 14.8 years in boys thinning and widening of the central part of the scalp. and 13.8 years in girls. In 8 cases frontal accentuation and breach of frontal A careful clinical assessment is important to con- hairline were also present in the so called Christmas frm the absence of androgen excess. Laboratory tree pattern. There was a strong family history of tests or endocrine evaluation may be needed. AGA in all patients. Minoxidil topical solution appears to be an ef- AGA in adolescents is not uncommon (Figures 10, fective and well-tolerated treatment in adolescents 11). There are two studies that have documented the boys and girls with AGA. The percutaneous ab- prevalence and early age of onset of AGA. The frst sorption of minoxidil is similar to that observed study was a multicenter study to assess the preva- in adults. Finasteride has not been studied in the lence of AGA in 496 randomly selected, healthy treatment of men younger than 18 years, and thus boys.24 Approximately 15% showed early signs of the safety and effcacy of this drug in the treatment AGA and were rated as having stage 2 or greater hair of early onset adolescent AGA has not been deter- loss on the Hamilton-Norwood grading scale. The mined.26

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Figure 12.—Congenital hypotrichosis.

Figure 13.—Normal dentition in congenital hypotrichosis.

child may be born with complete absence of scalp and body hair, or the infant may progress to this stage over the frst 5 years of life (Figure 12). In an- other variant of the disease, the neonate is born with lanugo hair, which is shed in the frst few months of life and never replaced. Caution should be exer- cised to ensure that the hair abnormality is isolated, as other associations may be unveiled only with time (Figure 13). Congenital hypotrichosis is a less severe form of atrichia congenita, where hair is not absent, but it is diffusely thinned. It occurs usually as an isolated de- fect. Hypotrichosis may not be noticed until the age of two years because of variation in the quality and quantity of hair normally present at birth (Figure 14). Most cases of congenital hypotrichosis and atrichia congenita are autosomal recessive traits. Several au- tosomal dominant pedigrees have been identifed. When no family history is obtained, a scalp biopsy should be performed to exclude alopecia areata tota- Figure 14.—Late onset of congenital hypotrichosis. lis. The biopsy also provides information regarding the follicle architecture and count, and reveals any other cutaneous abnormalities. Hereditary and congenital hypotrichosis There is a very long list of conditions that present Congenital atrichia and hypotrichosis with hypotrichosis, but no complete alopecia, in in- fancy. The hypotrichosis may be secondary to follicu- Atrichia congenita is characterized by follicular lar hypoplasia or to faulty hair shaft production and agenesis or programmed follicular destruction. The breakage. Many of the ectodermal dysplasias are as-

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Figure 15.—Clinicogenetic classifcation of hypotrichoses. Using three clinical criteria, most patients with hypotrichosis can be as- signed to a group of molecularly defned hair disorders. ANE: alopecia, neurological defects and endocrinopathy; ARIH: autosomal recessive ichthyosis with hypotrichosis; DSG4: desmoglein 4; ED: ectodermal dysplasia; EDAR: ectodysplasin A receptor; EDAR- ADD: EDAR-associated death domain; HJMD: hypotrichosis with juvenile macular dystrophy; HRSV: hypotrichosis with recurrent vesicles; KRT85: keratin 85; LIPH: lipase H; LPAR6: lysophosphatidic acid receptor 6; NTS: Netherton syndrome. Adapted from Regina Betz et al.32 sociated with hypotrichosis but, unfortunately, most of conditions characterized by congenital alopecia or the hair shaft abnormalities have not been well char- hypotrichosis. In 1892, Bonnet 27 proposed the frst acterized; the abnormal hair is generally described known classifcation based on embryological prin- clinically only as “brittle”, “sparse” or “lustreless”. ciples. It has been widely used until nowadays and There have been numerous attempts to classify the roughly divides congenital hypotrichosis with nor-

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mal ectodermal structures from the ones with asso- tinctive combination of hair, facial and bone abnor- ciated teeth and nail defects. Afterwards, Cockayne malities with autosomal dominant inheritance. 28 and Muller 29, attempting a more critical analysis, 1. Trichorhinophalangeal syndrome type I. Type I proposed a working classifcation which allowed the TRPS is clinically characterized by the presence of currently named syndromes to be identifed, and pro- a variable congenital hypotrichosis, piriform (pear- vided a provisional status for those not yet character- shaped) nose, coniform epiphisis, subnasal fold, thin ized. In 1981 after the Berlin Congress, Sâlamon 30 lips, prognatia, and mandibular hypoplasia. The hair proposed a classifcation for the global problem of alterations consist of diffuse alopecia with a broad hair loss that is considered one of the most useful forehead and a partial alopecia of the lateral third of system for the study of congenital hypotrichosis. the eyebrows. Scanning electron-microscopic stud- During the past years, major breakthroughs in ies of the hair shaft can reveal fattened hair with an genomic techniques have facilitated considerable elliptoid transverse section pattern. Mechanical be- progress toward unraveling the molecular basis of in- havior of the hair might be abnormal with a signif- herited skin diseases. At present, over 6000 Mendelian cant increase in the viscous parameter, indicating a disorders are known, of which 560 involve skin abnor- decreased intermolecular bridging within the keratin malities and are associated with more than 500 unique matrix.34 protein-coding genes. More than 300 inherited disor- 2. Trichorhinophalangeal syndrome type II (Lang- ders featuring hair abnormalities have been catalogued er-Giedion syndrome). Patients with TRPS type II to date, and yet, in a substantial portion of these, no usually present hypotrichosis of the scalp hair, piri- genetic defect has been identifed.31 This new knowl- form nose and redundant skin as the type I, plus mul- edge is now resulting in a reorganization of the classif- tiple cartilaginous exostosis. In a recent article Lu cation systems in this group of diseases, which, instead et al.35 described associated alterations to this syn- of being solely founded on clinical fndings, now inte- drome including aplasia of the epiglottis and con- grates both clinical and molecular features. It is now genital nephrotic syndrome. possible to assign most forms of hypotrichosis to one 3. Trichorhinophalangeal syndrome type III. gene (or group of genes) on the basis of a very limited TRPS type III is a newly defned clinical entity 36 amount of information concerning three clinical fea- inherited as an autosomal dominant trait and clini- tures: mode of inheritance, the presence or absence of cally characterized by growth retardation, craniofa- associated features, and microscopic appearance of the cial abnormalities, severe brachydactyly and sparse hair shaft. Once these data are available, it is easy to hair. In addition, absence of mental retardation and decide about the optimal molecular diagnostic strategy cartilaginous exostoses are required for the diagnosis and genetic testing that is likely to lead to the correct of TRPS type III. Other associated abnormalities in- diagnosis. (Figure 15).32 clude a short stature, a thin upper lip and a prominent In this review, we will follow the practical classi- lower lip, a pear-shaped nose, stubby fngers and toes fcation based on the clinical observations proposed with cone-shaped epiphyses and sparse scalp hair. by Camacho et al.33 One should be aware, however, that within each of the groups there is a large clinical Dubowitz syndrome.—First described in 1965,37 spectrum and that these are not grouped on a patho- Dubowitz syndrome (DS) is characterized by a pe- genetic basis. The classifcation scheme shown in culiar face, eczema, small stature and mild micro- Table I is largely of didactic value. cephaly. The cutaneous fndings consist of an ecze- matous eruption affecting the face and fexural areas. Scalp hair is sparse and brittle and commonly affects Generalized congenital alopecia the lateral eyebrows. Patients affected by DS have a moderate mental defciency with a tendency toward Genodermatoses with non-scarring hypotrichosis hyperactivity, short attention span, stubbornness and shyness. They have also been characterized by their Genodermatoses with skeletal alterations high-pitched weak cry. Trichorhinophalangeal syndrome.—Trichorhi- Hallermann-Streiff syndrome.—Hallerman-Streiff no-phalangeal syndrome (TRPS) comprises a dis- syndrome is a rare congenital anomaly characterized

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by a peculiar bird face, mandibular and maxillary hy- Table II.—Ectodermal dysplasia subgroups proposed by Solo- poplasia, dyscephaly, congenital cataracts, microphtal- mon and Keuer. mia, hypotrichosis, skin atrophy, and short stature.38 Subgroups 1, 2, 3 and 4 (hair, teeth, nails and sweating defects) Dental abnormalities are present in 80% of the cases — Anhidrotic ectodermal dysplasia and include malocclusion, crowding, severe caries, su- — Rapp-Hodgkin — Ectrodactily-Ectpdermal dysplasia-Cleft palate syndrome pernumerary and neonatal teeth, enamel hypoplasia, — Popliteal web syndrome hypodontia, premature eruption of primary dentition, — Xeroderma-Talipes-Enamel defect syndrome agenesis of permanent teeth, and anterior displacement Subgroups 1, 2 and 3 (hair, teeth and nail defects) 39 or absence of condyles. — Clouston dysplasia — Trichodento-osseous syndrome — Ellis-van Creveld syndrome Genodermatoses with ectodermal alterations — Ankyloblepharon-Ectodermal defects-Cleft palate syndrome — Basan syndrome Ectodermal dysplasias — Tooth-nail syndrome Subgroups 1, 3 and 4 (hair, nails and sweating defects) The ectodermal dysplasias (EDs) are a heterogene- — Freire-Maia’s syndrome ous group of conditions primarily affecting the hair, — Subgroups 1 and 2 (Hair and teeth defects) — Orofaciodigital syndrome I teeth, nails, and skin, and are classifed according to — Sensenbrenner syndrome the tissue(s) affected. EDs are rare diseases with an — Trichodental syndrome 40 estimated incidence of 7/10.000 births. Of the 170 Subgroups 1 and 3 (hair and nail defect) EDs described so far, fewer than 30 have been ex- — Curly Hair-Ankyloblepharon-Nail Dysplasia syndrome plained at the molecular level with the identifcation — Onychotrichodysplasia with neutropenia of the causative gene. — Subgroups 1 (Hair defects) Trichorhinophalangeal syndromes — Dubowitz syndrome The term ectodermal dysplasia was originally ap- — Moynahan syndrome plied to anhidrotic ectodermal dysplasia in which hair, teeth, nails and sweat glands are defective. The classifcation proposed by Freire-Maia in 1977 41 was based on a primary defect of ectodermal deriva- in number, and characteristically the canines and inci- tives. Conditions in which the ectodermal changes sors are conical shaped. The absent or reduced sweat- are secondary, as in xeroderma pigmentosum are ing leads to heat intolerance, and unexplained pyrexia thus excluded from the EDs. According to the Freire- may be the presenting symptom in infancy. Carrier fe- Maia’s classifcations subgroup 1 is a hair dyspla- males may be clinically normal but may show in some sia, subgroup 2 a dental dysplasia, subgroup 3 a nail degree one or more of the features of the syndrome as dysplasia, subgroup 4 a sweat gland defect, and sub- conical teeth, hypotrichosis or heat intolerance. Oth- group 5 a defect of other ectodermal structures. erwise apparently normal carriers may show derma- Solomon and Keuer in 1980 42 defned subgroups toglyphic abnormalities, the presence of which may be of the EDs based on what ectodermal structures were a value in diagnosis.41 affected (Table II). EEC syndrome (ectrodactily, ectodermal dyspla- Anhidrotic ectodermal dysplasia (Christ-Siemen- sia and cleft lip and palate).—The association of Touraine syndrome).—In this X-linked syndrome ectrodactyly (lobster-claw deformity), ectodermal sweat glands and other ectodermal-derived appendag- dysplasia, and cleft lip and palate is a well defned es are absent or few in number. The full syndrome only autosomal dominant syndrome.43 occurs in males. Scalp and body hair is short, fne and Reported EEC syndrome cases show sparse hair, very sparse and often bright in colour, but may increase malformed teeth with early caries, ectrodactyly, cleft in quantity after puberty. Eyebrows and eyelashes may lip and/or palate, lacrimal duct stenosis and kidney also be sparse or absent but may be relatively little af- abnormalities, but not all defects are present in all fected. The prominent square forehead, saddle nose, affected individuals within a single family. thick lower lip and the pointed chin produce a distinc- tive face. The skin around the eyes is fnely wrinkled Hypotrichosis with juvenile macular dystrophy and may be pigmented. The teeth may be absent or few (HJMD).—Becker et al.44 described two sisters in a

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velopment, and an analysis of plucked hairs showed dysplastic and broken hair shafts. Polarizing micro- scopy and scanning electron microscopic studies re- vealed torsion, irregularities and impressions of the hair shaft, as seen in pili torti, trichorrhexis nodosa and pseudomonilethrix. Analysis of the amino-acid composition of the hair demonstrated a signifcant reduction of sulphonic cysteic acid and an elevated cysteine and lanthionine content.

Other genodermatoses with hypotrichosis.—Other genodermatoses with hypotrichosis include kid syn- drome (keratitis, ichthyosis and deafness).

KID syndrome (keratitis, ichthyosis, deaf- ness).—The KID syndrome is a congenital ectodermal disorder that affects not only the epidermis, but also other ectodermal-derived tissues such as the corneal epitheli- um and the inner ear. In a classic review,47 61 patients who met the criteria for this syndrome were identifed. All had cutaneous and auditory abnormalities, and 95% of them also had ophthalmologic defects. The most frequent clinical features were neurosensory deafness (90%), erythrokeratoderma (89%), vascularizing kerati- tis (79%), alopecia (79%), and reticulated hyperkeratosis Figure 16.—Hereditary hipotrichosis simplex. of the palms and soles (41%). In the same article, the authors state that the KID family of consanguineous parents with diffuse hy- acronym does not accurately defne this entity, since potrichosis of the head and visual impairment in the the disorder is not an ichthyosis, because scaling is context of a tricho-ocular malformation of an ecto- not the main cutaneous feature. In addition, not all dermal dysplasia. This entity is an autosomal reces- patients have keratitis. They suggest that this syn- sive disorder. Mutations in the P-cadherin (CDH3) drome should be included under the general heading gene have been shown to underlie HJMD. Because of congenital ectodermal defects as a keratoderma- P-cadherin is expressed not only in the hair follicle, tous ectodermal dysplasia (KED). but also in retinal pigmented epithelium of the eye, disruption of P-cadherin would lead to macular dys- Genodermatoses with hypotrichosis and tumors.— trophy of the retina.45 Genodermatoses with hypotrichosis and tumors in- clude Rombo syndrome, Bazex-Dupré-Christol’s Hypotrichoses with aminoacid metabolism altera- syndrome, hereditary hypotrichosis simplex. tions, ectodermal dysplasia.—Among the aminoacid metabolism alterations occurring in hypotrichoses Rombo syndrome.—First described by Michaëls- there are hair-shaff structure defects, hypercysteine son in 1981,48 Rombo syndrome is an autosomal dom- ahr and glucosuria. inant disease clinically characterized by hypotrichosis affecting the eyelashes and yellowish follicular facial Hypotrichosis, hair-shaft structure defects, papules. They also present cyanotic lips and multiple hypercysteine hair and glucosuria.—Blume- tricoepiteliomata and basal cell carcinomas.49 Peytavi et al.46 reported of two Turkish siblings with fragile and sparse scalp hair associated with gluco- Bazex-Dupré-Christol’s syndrome.—Bazex- suria without diabetes or kidney disease. Clinical ex- Dupré-Christol’s syndrome (BDCS) is an X-linked amination revealed normal physical and mental de- dominant disorder of the hair follicle characterized

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by follicular atrophoderma, multiple basal cell car- the ST14 gene underlie ichthyosis wit hypotrichosis cinomas, hypotrichosis, milia, and localized hypo- syndrome.45 hidrosis.50 Follicular atrophodermas are follicular de- The generalized form of HHS (GHHS) was pre- pressions (“ice pick marks”) seen most commonly on viously mapped to chromosome 18p11.32-p11.23. the dorsum of the hands and elbows. In a recent arti- Recently, a heterozygous mutation in the APCDD1 cle Kidd et al.51 described a Scottish family with this gene has been identifed in families with GHHS. syndrome, with fve affected members through three generations. The reported patients showed hypohid- Recently described syndromes (non-classifed dis- rosis confned to the face, coarse hair, dry skin, milia, orders).—In the last decade, several new hypotri- and follicular atrophoderma. All the adults had a his- chotic syndromes have been described with the title tory of multiple basal cell carcinomas. None of them of “A new genodermatosis?” or “A new syndrome?”. presented any skeletal feature suggestive of Gorlin’s These have yet to be classifed and included into the syndrome. The authors thus suggest that the BDCS older classifcation schemes. should be considered as a differential diagnosis in pa- tients with early onset or familial basal cell carcino- Congenital ichthyosis with follicular atrophode- mas. In 1994 Goeteyn et al.52 described 20 affected rma.—Lestringant et al.55 described fve Emirati sibs patients of a large family across four generations with (three girls and two boys), aged between 4 and 18 typical features of the BDCS. However, the clinical years, with normal stature, diffuse congenital ichthy- picture in that family differs with regard to gender osis, patchy follicular atrophoderma, generalized and and age, confrming an X-linked inheritance. diffuse non-scarring hypotrichosis, and marked hypo- hidrosis. Steroid sulfatase activity, assessed in the two Hereditary hypotrichosis simplex.—Heredi- boys, was found to be normal. Electron microscopic tary hypotrichosis simplex (HHS) is an uncommon studies of ichthyotic skin did not show any specifc group of familiar hypotrichias and atrichias, usually abnormality. The patients were thought to have Bazex non-scarring, which are not associated with other syndrome; however, ichthyosis is not a component dysplasias neither with internal abnormalities. HHS of Bazex syndrome. They concluded that congenital is an autosomal dominant hair disorder which is ichthyosis with follicular atrophoderma represents a characterized by progressive loss of hair starting in new autosomal recessive genodermatosis. the middle of the frst decade of life.45, 53 HHS can be largely classifed into the scalp limited Congenital atrichia, palmoplantar hyperk- form (HHSS) 54 and the generalized form (GHHS) eratosis mental retardation, and early loss in which facial and body hairs are also affected (Fig- of teeth ure 16). Steijlen et al.56 reported four siblings with con- HHSS was previously mapped to chromosome genital atrichia, palmoplantar hyperkeratosis, mental 6p21, and subsequently, heterozygous nonsense mu- retardation, and early loss of teeth. The pedigree in tations in the CDSN gene have been identifed in pa- that family suggested an autosomal recessive trait. tients with HHSS. Interestingly. It has recently been This combination of fndings has not been previous- shown that homozygous mutations in the CDSN gene ly reported and is therefore considered to be a new underlie an infammatory type of generalized peeling genetic entity. skin syndrome, which is characterized by erythema with peeling of the cornifed layer on the whole Keratoderma, hypotrichosis and leukonychia body. It is also known that mutations in other genes totalis functionally related with CDSN can show some hair phenotypes. Of these, Netherton syndrome is an au- Basaran et al.57 reported three relatives with con- tosomal recessive disorder characterized by ichthy- genital hypotrichosis, characterized by trichorrhexis osiform erythroderma, atopic manifestation and the nodosa and trichoptilosis, dry skin, keratosis pilaris hair shaft anomaly called bamboo hair (trichorrhexis and leukonychia totalis. The described patients also invaginata). The Netherton syndrome is caused by developed a progressive transgrediens type of pal- mutations in the SPINK5 gene. More recently, it has moplantar keratoderma, and hyperkeratotic lesions been reported that recessively inherited mutations in on the knees, elbows and perianal region.

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Alopecia-mental retardation syndrome asso- with coarse sparse hair and multiple milia on the ciated with convulsions and hypergonado- face, chest, axillae and pubic region. There are no tropic hypogonadism abnormalities of teeth and nails. Polarizing light mi- croscopy of hair shows an increased diameter of the 58 Devriendt et al. reported two brothers with total hair shaft. Rapelanoro et al.61 reported a large four congenital alopecia, mental retardation, childhood generations family where individuals presented with convulsions and hypergonadotropic hypogonadism. congenital hypotrichosis and multiple self-healing The authors believe that this association which has milia. not previously been reported represents a new auto- somal recessive condition. Marie-Unna hereditary hypotrichosis Universal congenital alopecia Typically, affected patients are born with normal to adequate, normal to coarse hair. With increasing Complete or partial congenital absence of hair age, the hair becomes increasingly coarse and wiry, may occur either in isolation or with associated ab- and has classically been likened to an “ill-ftting normalities. Most of the families with isolated con- wig” or “horse’s mane”. Patients most commonly genital alopecia have been reported to follow an au- have decreased or absent eyebrows, eyelashes, and tosomal-recessive inheritance. In an attempt to map body hair, including secondary sexual hair. Patients the gene for the autosomal recessive form, Nothem often demonstrate a progressive, nonscarring loss et al.59 performed genetic linkage analysis in a large of scalp hair that begins around pubert, particularly inbred family from Pakistan where affected individu- in the vertex and scalp margins. The condition may als showed a complete absence of hair. They mapped eventually result in only a sparse fringe of remaining the gene for this hereditary form of isolated con- hair along the scalp periphery.62 genital alopecia on chromosome 8p21-22 (ALUNC Marie-Unna heredirary hypotrichosis has only [alopecia universalis congenitalis]). In a more recent rarely been associated with other coexisting abnor- article,60 they reported an homozygous missense malities. Specifcally, up to 50% of affected indi- mutation in the human hairless gene. In addition, viduals may demonstrate exceptionally wide-spaced they found that the human hairless gene undergoes upper incisor teeth. Additionally, reports have been alternative splicing and that at least two isoforms made of associations with Ehlers-Danlos syndrome generated by alternative usage of exon 17 are found and juvenile macular degeneration. in human tissues. Interestingly, the isoform contain- On physical examination, gentle hair pull may ing exon 17 is the predominant isoform expressed result in extraction of multiple anagen hairs. Light in all tissues except the skin, where they observed microscopic examination may reveal hair shafts that exclusive expression of the shorter isoform. The au- are deeply pigmented and vary in diameter. Hairs thors speculate that this tissue-specifc difference in may also be twisted or bent at odd angles. Histologic the proportion of hairless transcripts lacking exon fndings include a signifcantly reduced number of 17 sequences could contribute to the tissue-specifc follicles per unit area that are often atrophic. A mild disease phenotype observed in individuals with this to moderate infammatory infltrate with limited f- type of isolated congenital alopecia. brosis and scarring may be present. Marie-Unna hypotrichosis was mapped to chro- Atrichia with papular lesions mosome 8p21.3, where the hairless gene (HR) is lo- cated. It is related to upregulation of the expression Atrichia with papular lesions (APL) is a rare au- of this gene.45 tosomal recessive disorder characterized by early onset of complete hair loss, which is followed by Genodermatoses with scarring alopecia papular eruptions due to formation of dermal cysts. It has been shown that loss-of-function mutations in Happle syndrome the hairless gene (HR) underlie APL.45 Previously, it has been reported patients with con- Gobello et al.63 described a 13-year-old girl with genital hypotrichosis and milia. This patient presents chondrodysplasia punctata, associated with ichthyosis

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arranged along Blaschko’s lines, follicular atrophode- Table III.—Classifcation of hair shaft disorders. rma, cicatricial alopecia and coarse, lustreless hair. — Hair shaft dysplasia with hair fragility The patient also showed a congenital cataract in the — Monilethrix right eye, dysplastic facial appearance and symmetri- — Pseudomonilethrix — Pili torti cal shortening of the tubular bones. The pathogenetic — Corkscrew hair concept of functional X-chromosome mosaicism in- — Menkes’ syndrome (kinky hair) troduced by Happle is used to name this syndrome. — Trichorrhexis invaginata (Netherton’s syndrome) — Trichothiodystrophy — Trichonodosis — Trichorrhexis nodosa Localized congenital alopecia — Bubble hair — Loose anagen hair Congenital triangular alopecia.—Congenital tri- — Hair shaft dysplasia without hair fragility angular alopecia (CTA),64 also known as temporal — Pili annulati (ringed hair) — Woolly hair triangular alopecia, is an unilateral or, less frequent- — Woolly hair nevus ly, bilateral patch of non-cicatricial and non-infam- — Acquired progressive kinking of the hair matory alopecia in the frontotemporal region. Al- — Diffuse partial woolly hair — Acquired partial curly hair though CTA is a congenital trait, it is usually noticed — Uncombable hair (Pili canaliculi) by the family when the child is above 2 years of age. Only about 74 cases have been reported,65 probably because the lesion is benign and nonprogressive. An estimated frequency of 0.11% is reported by García- Adams-Oliver syndrome.—Adams-Oliver syn- Hernández et al.66 Most cases are sporadic but the trait may affect, drome depends on the association of aplasia cutis by way of exception, several members of a family. with terminal digital abnormalities namely shorten- The hair loss is described as a “triangular”, “oval” ing of fngers and toes, absence of phalange or more or “lancet-shaped” temporal patch, covered only by rarely the absence of the entire extremity. A litera- 68 vellus hair. Recently, it has been described a central ture review revealed a rate of 13.4% for congeni- hair tuft in CTA as a typical feature of this disorder tal heart malformations in individuals with Adams- in a substantial proportion of cases.67 Oliver syndrome, suggesting that cardiac anomalies CTA usually occurs as an isolated anomaly but are a frequent manifestation of this syndrome. Thus, also several congenital diseases have been associ- all patients with Adams-Oliver syndrome should be ated: phakomatosis pigmentovascularis, Down syn- evaluated for cardiac abnormalities. drome, Dandy-Walker malformation, mental retar- dation and seizure, congenital heart diseases, and Aplasia cutis congenita, high myopia, and cone- bone and tooth abnormalities, multiples lentigines rod dysfunction.—Recently Gershoni-Baruch et al.69 and café-au-lait patches. reported two siblings with congenital nystagmus, cone-rod dysfunction, high myopia, and aplasia cutis Aplasia cutis congenita (Adams-Oliver syndrome congenita on the midline of the scalp vertex. The au- and other associations).—Aplasia cutis congenita is thors consider this familial oculocutaneous condi- a part of heterogeneous group of disorders character- tion as a new unique autosomal recessive disorder. ized by the absence of a portion of skin in a localized or widespread area of the scalp at birth. It most com- Nevus sebaceous.—Nevus sebaceus of Jadassohn monly manifests as a solitary defect on the scalp, but is a benign, congenital hamartoma of the folliculo- sometimes it may occur as multiple lesions. Aplasia sebaceous apocrine unit and epidermis that often cutis is a congenital condition in which skin, bone presents at birth, appears to regress in childhood, and and dura can be absent. The majority of cases affects grows during puberty, suggesting possible hormonal the scalp and are limited to the dermis and epidermis. control. In childhood, the lesion consists of a cir- Vertex aplasia cutis typically ranges in size from 0.5 cumscribed hairless yellow-orange-colored, waxy, to 3 cm. Ultrasound and magnetic resonance imag- pebble-like, papule or plaque often linear or round ing are helpful diagnostic tools for determining the or irregular. In puberty the lesion becomes verrucous extension of the lesion. and nodular. Nevus sebaceous may develop tumors

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in adulthood particularly, syringocystadenoma papil- Severity is highly variable and as a result there is a liferum and benign hair follicle tumors. Basal cell spectrum of clinical presentations, ranging from near carcinoma has been observed in about 5% of cases. normal hair, to hair that is no able to grow more than a few milimetres. At birth the hair is normal but after the frst shedding the replacement hairs are beaded, Hair shaft disorders fragile and break easily, arising from hyperkeratotic follicular papules. The age of onset is variable and This refers to malformations of the hair shaft. may be delayed until the teenage years. They are most likely due to single gene defects. There is no effective treatment for monilethrix. Most of these are congenital, and may be hereditary, Retinoids, glycolic acids and minoxidil may be help- whereas others are acquired. They may be localized ful in some cases. Monilethrix may improve with the or generalized and the defect may be simply local or years. Patients are advised to protect the fragile hair it may be a key diagnostic sign of a genodermato- from excessive combing, styling or friction. sis.70 It is often diffcult to draw a clear line between hypotrichoses and hair shaft disorders, as patients Pseudomonilethrix with diseases primarily resulting from abnormal hair structure often also manifest clinically with hypotri- This defect is inherited, also as a dominant trait. chosis. It involves a distinctive hair fragility to compulsive, The patients presents with an abnormality or sustained treatment of the hair by the normal ac- change in hair texture, appearance, manageability or tions of brushing and combing. This leads to dif- ability to grow hair long. A key feature of the clini- fuse or localized hypotrichosis with images of false cal evaluation is to determine if there is hair fragility nodes (fattened areas of irregular distribution) in with hair breakage (Table III). the hair shaft. It is not accompanied by hyperk- eratosis follicularis. It affects several members in Hair shaft abnormalities with increased fragility and the same family. It is a very rare defect, not to be breakage confused with iatrogenic or acquired pseudomoni- lethrix. Iatrogenic pseudomonilethrix is the same defect caused by previous improper handling of Monilethrix (beaded hair) the hair, generally caused by applying excessively Monilethrix is a distinctive rare hair shaft disorder strong pressure with the fngers or forceps when due to a mutation in the type II hair cortex keratins taking samples of hair which is also dysplastic for hHb6 and hHb1. When inherited as a dominant trait, microscopic observation. Monilethrix is usually due to mutations in genes en- coding hair keratins, including KRT81, KRT83, and Pili torti KRT86. When inherited as a recessive trait, Moni- lethrix is caused by mutations in DSG4, encoding Pili torti is a hair with a twisted appearance which desmoglein 4. shows regular angulations on its longitudinal axis. It is named after the resemblance of the affected The hair does not grow long and is easily broken, hair to a string of beads. The beaded appearance of patchy hair breakage and coarse stubble are typically the hair can be visualized by the naked eye, or with seen in the occiput and temporal areas due to friction. a dermatoscope, as alternating wide and constricted The twisted arrangement of this hair usually leads to segments along the hair shaft. The hair breaks spon- a distinctive shine depending on the incidence of the taneously or as a result of friction. The scalp is the light on this area. main site affected, especially in the occipital region, It is a familial defect of dominant inheritance but hair all over the body may be affected. The hair which may be isolated or associated with other con- appears short (a few milimetres) and beaded, so that ditions (Beare, Bazex, Crandall and Björnstad syn- shortly after it has emerged from the follicle it is dromes).71 fractured at the constrictions. It is accompanied by Atypical forms of pili torti have been found in local hyperkeratosis follicularis and it is also a com- Menkes syndrome (kinky hair) or isolated angula- mon fnding on the upper back and shoulders. tions in other hais dysplasias. It is commonly associ-

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ated with other congenital defects and therefore, if identifed, further evaluation for possible neurologi- cal and ectodermal disorders is an important part of the clinical evaluation. There is a range of heterogeneous disorders where half and three-quarter twists oh the hair are seen at irregular intervals rather than the 180º turns seen in pili torti. Acquired twisting is also invariable seen at the edge of a scarring alopecia where the hair follicle is distorted by the scarring process.1

Corkscrew hair This atypical acquired form of pili torti is clini- cally characterized by thick, dark scalp hairs that are coiled into a unique double spiral. It may be associ- ated with ordinary pili torti. Corkscrew hair has been associated with ectodermal dysplasia.72

Menkes syndrome (kinky hair) Menkes disease is a multisystemic lethal disorder due to impaired copper transport and metabolism Figure 17.—Bamboo hair patognomic of Netherton syndrome at with pili torti. As a result, this produces a general the Scanning Electron Microscopy. complex syndrome dominated by neurological signs, accompanied by hypothermia, psychomotor retarda- tion, quadriplegia, deafness, herniation, nanism, etc. sociated with Netherton’s syndrome, an autosomal These children have very distinctive facial features recessive inherited disorder that consists on the triad (partdridge profle) and their hair is light, very fne, of ichthyosis, atopic diathesis and trichorrhexis in- sparse and fragile. Death usually occurs at an early vaginata. The diagnosis of Netherton’s syndrome age due to neurological alterations. The kinky hair should always be entertained in “red scaly babies” is a polydysplastic hair with images of irregular pili who have sparse hair. torti, as well as images of monilethrix and/or trichor- There is no specifc treatment for trichorrhexis in- rhexis nodosa.73, 74 vaginata. Avoidance of trauma is important in this condition. Similar to the management of monilethrix, Trichorrhexis invaginata (Netherton’s syn- the only treatment available is cosmetic. Retinoids drome) and photochemotherapy have been reported to be of some value and the condition may spontaneously Netherton’s syndrome is caused by mutations improve with age. in SPINK5. As with monilethrix, the primary ab- normality involves a defect of keratinization of the hair shaft, allowing intussusception of the harder, Trichothiodystrophy keratinized distal portion of the hair into the softer proximal segment. This gives the typical bamboo Trichothiodystrophy (TTD) is a term that de- appearance under light microscopy, or the hair can scribes cystine-deficient brittle hair.76 Hair is an resemble a tulip if breakage of the distal hair shaft important clinical marker for this rare inherited occurs (Figure 17).75 disorder with a wide variety of phenotypes that Trichorrhexis invaginata can rarely occurs in trau- range from brittle hair only to a neuroectodermal matized, otherwise normal hair or with other con- symptom complex with severe intellectual and genital hair shaft dysplasias. Usually, however, is as- development impairment. It can be accompanied

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Trichorrhexis nodosa Trichorrhexis nodosa is the most common defect of the hair shaft leading to hair breakage. Trichor- rhexis nodosa describes a congenital or acquired de- fect. The affected hairs develop a disruption in the cuticle permitting cortical fber damage, fracture and fraying that resembles a nodal swelling. The nodes can be sited proximally or distally in the hair shaft. Distal nodes generally indicate hair weathering. Proximal nodes indicate increased hair fragility and increased susceptibility to weathering suggestive of an underlying hair shaft abnormality (Figure 18). Although congenital trichorrhexis nodosa can occur as an isolated fnding or with teeth and/or nail ab- normalities, its presence in an infant or young child should trigger a search for an underlying metabolic problem. It can be associated with argininosuccinic aciduria, citrullinaemia and it can also be present in Menkes disease. Figure 18.—Trichorrhexis nodosa under the Scanning Electron Wheathering refers to the structural damage of the Microscope. hair shaft caused by external forces. These forces may be cosmetic in nature, such as shampooing, grooming or styling, or environmental, such as UV by a characteristic facies, growth retardation, radiation, wetting and natural friction. Acquired urological malformations, onychodystrophy, ich- nodes resembling trichorrhexis nodosa are seen in thyosis and photosensitivity. TTD syndromes in- severe wheathering of the hair.1 clude BIDS (brittle hair, intellectual impairment, Management of congenital and acquired trich- decreased fertility, short stature), IBIDS (ichthyo- orrhexis nodosa os prevention of injury to the hair sis and BIDS), and PIBDS (photosensitivity and shaft. Avoidance of unnecessary hairdressing pro- IBIDS). cedures and styling products is advised. Protection The hair has markedly low cystine (sulphur) con- from sunlight exposure is also recommended.79-81 tent and presents characteristic light and polarized features, the so-called “tiger tail” pattern. There may Bubble hair be the typical trichoschisis fractures. This is an acquired abnormality of the hair shaft due to the presence of air bubbles within the shaft. Trichonodosis This phenomenon seems to be caused by the direct Trichonodosis is the name used to refer to the pres- effect of excessively high temperatures from styl- ing with blow dyers or curling irons. It is seen above ence of knots on the hair shaft. Although it may be all in women in the from of localized hypotrichosic seem to be a rare fnding, in reality it is frequent but plaques or as a focal area of unruly and fy-away area is diffcult to detect. It may be suspected when one in the vertex.82, 83 observes that a hair suddenly forms an angle which indicates a change of direction. It is more common in individuals with curly hair and has been associated Hair shaft abnormalities without increased fragility with localized trauma, scratching or tics. It may ap- pear in axillary and pubic hair. At the latter location Pili annulati (ringed hair) it has been described associated with pediculosis and Ringed hair is, together with bubble hair, a disease also with acarophobia.77, 78 that affects the hair medulla. It consists of the pres-

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Figure 19.—Diffuse partial wooly hair may be confused with ac- quired progressive kinking of hair. ence of alternating dilatations of the medulla, which is shown clinically by the ringed appearance of the hair. After detailed observation, a series of light and Figure 20.—Scanning electron microscopy. Pili trianguli. dark bands are visible on the hair. There is no fragil- ity, and the hair can grow long. gene causes an autosomal recessively-inherited hy- Observation with light microscopy reveals that potrichosis in isolated Russian populations. Impor- in fact there is a regular alternating pattern of light tantly, it has recently turned out that LIPH mutations and dark bands (dilatations of the medulla flled also show the woolly hair phenotype, thus the LIPH with air). gene can be regarded as a causative gene for not only Pili annulati is inherited in an autosomal dominant hypotrichosis, but also autosomal recessive woolly fashion and may also appear sporadically. It consti- hair.45 tutes an esthetic defect which may be well-accepted Woolly hair can occur as an isolated fnding or in by the patient, depending on the fashion.84 association with various genetic syndromes. There may be associated ocular defects, deafness, kerato- Woolly hair syndrome sis pilaris atrophicans, enamel hypoplasia and Noo- nan syndrome. Congenital localized woolly hair Woolly hair is defned as hair which is thinner than nevus occurs sporadically. Is characterized by a dis- normal, curly and fat. It is normally found in the crete area of tightly curled hair in an otherwise nor- white race, as the hair of black individuals is usually mal scalp. In about half the reported cases, woolly fat and curly, but of normal size. hair nevus is associated with linear nevi. The pig- Woolly hair may be localized, diffuse, congeni- mentary or epidermal nevi are usually on the neck, tal or acquired. The congenital diffuse form can be arms or trunk, and not on the scalp. In general, it is inherited in an autosomal dominant pattern or, less an isolated fnding, but woolly hair nevus has been frequently, an autosomal recessive fashion. It is well reported to occur with neurological defects, ocular known that the surface of the hair shaft cuticle is abnormalities, bone disorders, and other mesoder- covered by a lipid layer which is believed to play a mal defects. role in protecting the hair shaft as a barrier. However, Acquired progressive woolly hair may herald the additional roles of lipids in the hair follicle had re- onset of androgenetic alopecia or be observed as a mained unknown. Kazantseva et al.85 have reported side effect of etretinate drug treatment. that a large deletion mutation in the lipase H (LIPH) There is no specifc treatment and in the congen-

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Table IV.—Conditions associated with focal scarring hair loss in children.

Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome Aplasia cutis congenita — Single anomaly — Associated with other anomalies — 41) Associated with limb abnormalities — 42) 46 XY genotype/gonadal dysgenesis — 43) “Lumpy” scalp syndrome — 44) Trisomy 13 — 45) 4p syndrome — 46) Ectodermal dysplasia of Carey — 47) Ectodermal dysplasia of Tuffi — 48) Hallerman-Streiff syndrome — 49) ANOTHER syndrome — 10) Focal dermal hypoplasia — 11) Johansson-Blizzard syndrome Birth trauma Congenital ectodermal dysplasia of the face Conradi-Hünermann chondrodysplasia punctata Epidermal or organoid nevus — CHILD syndrome (congenital hemidysplasia with ichthyo- siform erythroderma and limb defects) Epidermolysis bullosa Hallerman-Streiff syndrome Incontinentia pigmenti Keratosis follicularis spinulosa decalvans Kerion KID syndrome (keratitis, ichthyosis, deafness) Neoplasia Prolonged pressure Primary cutaneous disease Tufted folliculitis

Uncombable hair (pili canaliculi) Figure 21.—Scanning electron microscopy. Pili canaliculi. Uncombable hair syndrome presents with charac- teristic unruly hair that is diffcult to style and has the appearance of standing away from the scalp. It ital diffuse form, the hair may relax from curly to affects young individuals or children with abundant waxy with age.1 hair. The hair is arranged in bundles pointing in dif- ferent directions which make it impossible to man- Acquired progressive kinking of the hair age or comb. It is also known as “spunglass hair”. Usually it is a dominant familial condition which Acquired progressive kinking of the hair is a non- may be sporadic. Cases of localized uncombable familial acquired form of curly hair. It primarily af- fects young males near puberty (Figure 19). Multi- hair have also been described. ple areas of hair gradually becomes kinky, mainly In all cases the clinical aspect of uncombable affecting the occipital area. It does not seem to be hair involves a characteristic hair shaft dysplasia: related to external causes and it gradually evolves pili canaliculi. On light microscopic examina- into androgenetic alopecia. A localized form in the tion, the shaft may have a canal-like longitudinal temporal regions is known as circumscribed sym- groove along one or two facets. When hair cross- metric allotrichia (“whisker hair”). Cases of ac- sections are examined the characteristic triangular quired curling of hair can be drug induced (retin- or kidney-shaped appearance of the hair shaft is oids).86 diagnostic (Figures 20, 21).

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There is a spontaneous tendency to improve over time. bene i capelli abbiano rivestito sempre un aspetto secon- The use of a shampoo with zinc piritione and silicone- dario nella formazione di pediatri e dermatologi, partendo 70, 86 del presupposto erroneo che non sia possibile ricavare una based conditioners may help in managing the hair. grande quantità di informazioni da essi. I dermatologi si trovano nell’invidiabile posizione di poter studiare nu- merosi disturbi attraverso tecniche diagnostiche semplici. Scarring alopecia I capelli si prestano facilmente a essere analizzati; para- dossalmente, però, tale approccio è spesso trascurato dai medici non dermatologi. Obiettivo del presente articolo è Scarring alopecia can be either focal or diffuse. In stato quello di cercare di contribuire al processo diagno- an infant, there are four main causes of focal scarring stico nella pratica quotidiana, aiutando a distinguere, ad hair loss: trauma (including prolonged pressure), esempio, tra alcune patologie dei capelli acquisite e altre aplasia cutis congenita, underlying nevus (or neopla- determinate geneticamente. Presteremo particolare atten- sia) or as a part os a syndrome (Table IV). zione a tutti i dati che sono stati ottenuti dai capelli dei nostri pazienti e cercheremo di mettere a frutto le infor- The most common primary cicatricial alopecias, mazioni ricavate dai capelli per ciascun paziente. Spesso, i.e., lupus erythematosus, lichen planopilaris, fol- è estremamente diffcile distinguere tra normalità e anor- liculitis decalvans and pseudopelade of Brocq, are malità nell’aspetto dei capelli neonatali. Ci concentreremo rare in children. However, the group of disorders in particolare sulle alterazioni fsiologiche più comuni che characterized by keratosis pilaris and scarring alo- potrebbero condurre a una diagnosi erronea. Discuteremo anche dei trattamenti specifci per le patologie dei capelli pecia, termed keratosis pilaris atrophicans, typically che è possibile trattare e dell’approccio basilare generico have their onset in childhood. One of these, keratosis per migliorare l’aspetto estetico dei capelli in quei disturbi follicularis spinulosa decalvans begins with kerato- che non hanno un trattamento specifco. sis pilaris in infancy and is accompanied by photo- Parole chiave: Età pediatrica - Alopecia - Capelli, malattie. phobia, corneal changes and progressive alopecia of the scalp, eyebrows and/or eyelashes.4 References 1. Harrison S, Sinclair R. Optimal management of hair loss (Alopecia) Conclusions in children. Am J Clin Dermatol 2003;4:757-70. 2. Lavker RM, Bertolino AP, Klein LM. Biology of hair follicles. In: Fitzpatrick TB, Eisen AZ, Wollf K, et al. editors. Dermatology in gen- The psychological and cosmetic importance of hair eral medicine. 5th ed. Boston, MA: McGraw-Hill; 1993. p. 230-8. is immense in our society. Disruption in the normal 3. Cutrone M, Grimalt R. Where has all that hair gone? Clin Exp Der- appearance of hair can predispose to low self-esteem matol 2006;31:136-7. 4. Olsen E. Hair disorders. In: Harper J, Oranje A, Proje N, editors. and negative body image. A detailed clinical history Textbook of pediatric dermatology. 2nd ed. Malden, MA: Blackwell and examination accompanied by hair microscopy is Publishing Ltd.; 2006. p. 1753-822. 5. Cutrone M, Grimalt R. Transient neonatal hair loss. European Jour- essential for accurate diagnosis of the condition. In nal of Pediatrics 2005;164:630-2. pediatric hair disorders it is important that the par- 6. Sinclair RD, Banfeld CC, Dawber RP. Hair structure and function. ents are given a clear understanding of the etiology In: Sinclair RD, Banfeld CC, Dawber RP, editors. Handbook of dis- eases of the hair and scalp. Oxford: Blackwell Science; 1999. p. 3-23. and natural history of the disease and are offered ge- 7. Wasserman D, Guzman-Sanchez DA, Scott K, Scott K, McMichael netic counseling if the disease is hereditary. A. Alopecia areata. Int J Dermatol 2007;46:121-31. Unfortunately, for many hair disorders there is no ef- 8. Crowder JA, Frieden I, Price V. Alopecia areata in infants and new- borns. Pediatric Dermatology 2002;19:155-8. fective, reliable therapy; in reversible conditions such in 9. Walker SA, Rothman S. Alopecia areata: a statistical study and consid- infections, treatment is mandatory. Some conditions are eration of endocrine infuences. J Invest Dermatol 1950;14:403-13. amenable to surgical correction. Cosmetic solutions such 10. Mukherjee N, Burkhart CN, Morrell DS. Treatment of alopecia ar- eata in children. Pediatric Annals 2009;38:388-95. as wigs can provide satisfactory camoufage if surgery is 11. Guarrera M, Rebora A. Kenogen in female androgenetic alopecia. A not an option and medical therapies fail.1 longitudinal study. Dermatology 2005;210:1818-20. 12. Higgins CA, Westgate GE, Jahoda C. Modulation in protelolytic activity is identifed as a hallmark of exogen by transcriptional pro- fling of hair follicles. J Inv Dermatol 2011;131:2349-57. Riassunto 13. Price VH. Treatment of hair loss. N Eng J Med 1999;341:964-73. 14. Price VH, Gummer CL. Loose anagen hair. J Am Acad Dermatol Alopecia infantile 1989;20:249-56. 15. Grimalt R, Barbareschi M, Menni S. Loose anagen hair of child- Le patologie dei capelli rappresentano una frazione im- hood: report of a case and review of the literature. Eur J Dermatol portante dei casi osservati dai dermatologi pediatrici, seb- 1992;2:570-2.

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American Psychiatric Association. Diagnostic and statistics manual Orfanos CE. Hypotrichosis, hair structure defects, hypercysteine of mental disorders. 4th ed. Text revision. Washington, DC: Ameri- hair and glucosuria: a new genetic syndrome? Br J Dermatol can Psychiatric Association; 2000. 1996;134:319-24. 20. Sah D, Koo J, Price V. Trichotillomania. Dermatologic Therapy 47. Cáceres-Ríos H, Tamayo-Sanchez L, Duran-Mckinster C, de la Luz 2008;21:13-21. Orozco M, Ruiz-Maldonado R. Keratitis, ichthyosis, and deafness 21. Orgaz-Molina J, Husein-ElAhmed H, Soriano-Hernández MI, Arias- (KID syndrome): review of the literature and proposal of a new ter- Santiago S. Trichotemnomania: hair loss mediated by a compulsive minology. Pediatr Dermatol 1996;13:105-13. habit not admitted by patients. Act Derm Venereol 2012;92:183-4. 48. Michaëlsson G, Olsson E, Westermark P. The Rombo syndrome: a 22. Grimalt R, Happle R. Trichorrhizophagia. 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