Pédiatrie and Developmental Pathology 17, 36-43, 2014 DOI: 10.2350/13-09-1375-OA.1 © 2014 Society for Pédiatrie Pathology
Light Microscopic Hair Abnormalities in Children: Retrospective Review of 119 Cases in a 10-Year Period LEI SHAO^* AND BRANDON NEWELL^ ^Department of Pathology, Children's Mercy Hospitals and Clinics, Kansas City, MO, USA ^Section of Dermatology, Children's Mercy Hospitais and Clinics, Kansas City, MO, USA
Received September 6, 2013; accepted November 17, 2013; published online November 18, 2013.
ABSTRACT Abnormalities in the hair can be congenital or acquired conditions. Examples of genetic disorders with associated hair abnormalities include Menkes syndrome, Netherton syndrome, uncombable hair syndrome, trichothiodystrophy, and loose anagen hair syndrome. Acquired hair abnormalities can be associated with grooming or use of various hair products. There are many patterns of hair abnormalities that can be readily identified under a light microscope. We performed a retrospective review of 129 hair mount samples from 119 patients submitted to the pathology department for microscopic examination over a 10-year span (from January 2002 to December 2011). Of the 119 patients, 63 (53%) had morphologic changes in the hair samples. Thirty-seven patients (31%) showed morphologic changes compatible with specific diagnoses of various genetic conditions, including 25 cases of loose anagen hair syndrome, 6 cases of uncombable hair syndrome, 2 cases of Netherton syndrome, 3 cases of Menkes syndrome, and 1 case of trichothiodystrophy. The other changes were considered nonspecific or nondiagnostic, with trichorrhexis nodosa in 13 patients, presence of loose anagen hairs in 12 patients, and pili torti in 1 patient. We describe the light microscopic patterns of hair abnormalities, clinical findings, and molecular defects related to those genetic conditions. Our study indicates that hair examination can be a lst-line investigation on various pédiatrie conditions. Key words: hair, hair abnormality, light microscopy
INTRODUCTION Examination of hair samples under light microscopy may reveal distinct patterns of hair abnormalities and therefore facilitate accurate diagnosis of underlying conditions. Patients with Menkes syndrome typically have multiple twists in the hair shaft at irregular intervals (pili torti). * Corresponding author, e-mail: [email protected]
Nodular swelling with a cup-like expansion of the proximal hair cortex that surrounds the distal segment (trichorrhexis invaginata) is considered diagnostic of Netherton syndrome. Longitudinal grooves along the hair shaft (pili canaliculti et trianguli) are seen in uncombable hair syndrome. Alternating light and dark banding under polarized light (tiger-tail banding) is characteristically found in patients with trichothiodystrophy (TTD). In patients with loose anagen hair syndrome (LAHS), anagen hairs are easily pulled out, and they show misshapen hair bulbs, ruffied cuticles at the suprabulbar zone, and absent root sheaths (loose anagen hair [LAH]). Foci of ruptured cuticle with frayed cortical fibers (trichorrhexis nodosa) are usually associated with trauma to the hair shaft in a normal individual and rarely in someone with inherited weakness of the hair shaft. Hair follicles are derived from hair germ cells in the ectoderm in a developing embryo. There are 2 major types of hair follicles in children based on the size and color ofthe hairs they produce. The terminal hair follicles are deep rooted in the subcutaneous tissue, and they make long, pigmented hairs such as those on the scalp. Vellus hair follicles are located in the superficial dermis. Vellus hair follicles produce short and nonpigmented hairs that are present throughout the human body surface except for the palms, the soles, and mucosa-covered areas. Human hair grows in cycles through a poorly understood, complicated signaling mechanism. Each growth cycle begins with the appearance of a new hair shaft from its hair follicle and ends with spontaneous shedding of the hair shaft as the follicle enters its resting stage. Each follicular life cycle, regardless of the type of the hair follicles, is divided into 3 phases: the anagen, catagen, and telogen phases. The anagen phase consists of active hair growth with rapidly dividing cells in the hair follicles. The catagen phase marks follicular regression, and the telogen phase represents spontaneous hair shedding and a resting period before a new growth cycle begins. The anagen phase of the scalp terminal hair follicles varies from 2 to 7 years among different
B
Figure 1. Light microscopic pictures of anagen and telogen hairs. An anagen hair (A) contains nucleated keratinocytes in tbe bair bulb and attached root sbeatbs. The hair bulb of a telogen hair (B) is completely cornified, without surroundinq root sheaths.
individuals. The catagen phase generally lasts 1-3 weeks and the telogen phase 1-3 months. In the scalp, approximately 90% of the terminal hair follicles are in the anagen phase, and 10% are in the telogen phase. Less than 1% ofthe terminal sealp hair follicles are in the catagen phase. The hair shaft is made of keratinized dead cells and hard proteins called keratins. The hair shaft has 3 layers. The center, called the medulla, is surrounded by cortex. The cuticle is on the outer surface of the hair shaft. The cuticle is the strongest layer, and it is formed by tightly packed dead cells lined up like roof shingles. The difference in straight, wavy, and eurly hair lies in the shape of the hair shaft. Straight hair is eircular or nearly circular in cross section. Wavy hair has an oval-shaped eross seetion, and eurly hair has an elliptieal eross seetion. The hair root is embedded within a hair follicle in the skin. The most proximal, expanded extremity of the hair root is called a hair bulb. The hair at anagen phase is firmly anchored to the sealp by the hair folliele and the surrounding anchoring structures, including the inner root sheath, outer root sheath, vitrous layer, and fibrous root sheath. Removal of a normal anagen hair from the human scalp is painful and requires forcible plucking. A telogen hair is separated from the anehoring stmctures and sheds spontaneously. Under light microscopy, an anagen hair root contains nucleated cells in the hair bulb and attached root sheaths (Fig. lA). A telogen hair shows a completely comified hair bulb without attached root sheaths (Fig. 1B).
A catagen hair is also completely comified in the hair bulb like a telogen hair, but with attached root sheaths, as seen in an anagen hair. In this study, we reviewed the hair samples of 119 pédiatrie patients submitted to the pathology department at Children's Mercy Hospital and Clinics for hair examination in a 10-year period. We also collected clinical infonnation for eorrelation with the mieroseopie hair findings. A review ofthe literature revealed 1 similar study [1] that ineluded both pédiatrie and adult patients. The aim of our study is to examine, retrospeetively, the usefulness of hair examination in a ehildren's hospital. Our results indicate that light microscopic examination of hair samples is a simple, noninvasive, and valuable tool that should be used more widely in various pédiatrie patients. MATERIALS AND METHODS A search of eomputerized datahases identified all hair samples received between January 2002 and December 2011 in the Department of Pathology at Children's Mercy Hospital and Clinics (Kansas City, MO). There are 2 types of hair samples in our study. A clipped hair sample contains hair shaft only, and the sample is colleeted by eutting hair close to the skin with a pair of seissors. A gently pulled hair sample is eolleeted by a gentle but firm pull, grasping about 5-10 hairs from an ~1-em-diameter area of the scalp. Typically 2-3 regions are sampled. A pulled hair sample has both hair bulbs and hair shaft. Hair
LIGHT MICROSCOPIC HAIR ABNORMALITIES IN CHILDREN
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Table 1. Summary of clinical indications for hair examination, morphologic patterns of hair examination, and final diagnosis of all the patients in the study Clinical indications (No. of eases) Hair abnormality only {N = 87)
Erythroderma or diffuse eczematous dermatitis (iV= 16) Neurological symptoms (iV= 9) Ectodermal dysplasia (TV =4) Immunological or hematological symptoms (iV=3)
Patterns of morphologic findings (No. of cases) >5 Hair bulbs and >50% loose anagen hairs {N = 25) 50% loose anagen hairs (LAHs) in a gently pulled hair sample to be diagnostic of LAHS, provided there was a clinical suspicion of this condition.
RESULTS A total of 129 hair samples were accessioned from 119 patients. Ninety patients were female and 29 were male. The median age at the time of hair examination was
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L. SHAO AND B . NEWELL
Specific diagnosis (No. of cases)
Netherton syndrome (N = 2)
4.3 years and the mean age was 6.0 years, with a range from 10 days to 16.8 years. Five cases consisted of eyebrow hairs and the rest comprised scalp hairs. Four patients had 2 samples collected on different dates as the result of having a different type of hair sample or because of an inadequate prior sample. Six patients had both clipped and pulled scalp hair samples colleeted at the same time. The combined microscopic findings were used for these patients with more than 1 sample. Sixty-five hair samples were pulled. The remaining 64 were clipped hair samples. Of the 119 patients, 87 presented clinically with hair abnormalities only, 16 with erythroderma or diffuse eczematous dermatitis, 9 patients with neurological symptoms, 4 with clinical suspicion of ectodermal dysplasia, and 3 with immunological or hematological symptoms. In the group of patients with isolated hair abnormality, 56 cases showed morphologic changes in the hair samples and 31 cases had normal hairs. The morphologic findings were diagnostic of specific genetic conditions in 31 patients, including 25 patients who met the criteria for LAHS and 6 patients with uncombable hair syndrome. The microscopic changes were considered nonspecific or nondiagnostic in 25 patients. Of the 25 patients with nondiagnostie/nonspecific findings, LAHs were present in 12 patients and trichorrhexis nodosa was present in 13 patients. In the other 4 groups of 32 patients, the hair samples in 25 patients were unremarkable. The microscopic findings were considered compatible with specific genetic conditions in 6 patients when combined with other clinical findings. Three of the 6 patients had Menkes syndrome, 2 had Netherton syndrome, and 1 patient had TTD. One patient with eetodermal dysplasia had pili torti, whieh was considered nondiagnostic/
Figure 2. Loose anagen hair syndrome. A 4-year-old girl with blond, thinner, listless hair (A) that can be painlessly extracted with a gentle hair pull. A loose anagen hair has an appearance of a "hockey stick" due to kinking at the suprabubar zone. Ruffling of the cuticle is also common under light microscopy (B).
nonspecific. Overall, 37 patients (31%) had hair abnormalities that were diagnostie of or eompatible with specific genetic conditions. The clinical indications for hair examination, patterns of morphologic findings in the hair samples, and final diagnoses were summarized in Table 1. There were 25 patients with the diagnosis of LAHS in our study. The medium age was 4.2 years (mean, 4.6 years; range, 2.0-9.8 years). Three of the 25 patients were male and 22 were female, with a maleifemale ratio of approximately 1:7. The hair color of 2 patients was dark brown, and the rest of the patients had blond or light brown hair. A loose anagen hair under the light microscope is devoid of root sheaths, with frequent kinking of the suprabulbar zone and a ruffled cuticle in the proximal hair shaft. A typieal patient with LAHS and
a representative hair sample with many LAHs are shown in Figure 2. The number of LAHs in the hair samples of the 25 pafients with LAHS was variable. In the 13 cases with 5-9 hair bulbs in the hair samples, 100% LAHs were found in 11 cases. The other 2 cases contained 86% and 89% LAHs, with total numbers of hair bulbs of 7 and 9, respectively. Twelve patients with LAHS had 10-20 hair bulbs in the submitted hair samples, and 64-100% of the hairs were LAHs. In the 12 patients who did not meet our diagnostic criteria of LAHS, 11 patients had 2-A hair bulbs in the hair samples. One hundred percent LAHs were found in 8 patients (4 patients with 4 LAHs, 2 patients with 3 LAHs, and 2 patients with 2 LAHs). In 3 patients, 4 hairs bulbs were present in the samples, with 50-75% being LAHs. The last patient had 9 hair bulbs, with 3 LAHs and 6 telogen hairs.
Figure 3. Uncombable hair syndrome. A 5-year-old female with frizzy hair that is difficult to comb and style (A). The hair shaft shows longitudinal grooving under light microscopy (B) and scanning electron microscopy (C). LIGHT MICROSCOPIC HAIR ABNORMALITIES IN CHILDREN
39
Figure 4. Netherton syndrome. A 5-month-old male infant with short, broken hair in the scalp and eyebrow (A) and a skin rash with double-edged scald in the right foot (B). A hair sample showed nodes of trichorrhexis invaginata and multiple breaks of the hair shaft at the nodes (C, D).
Six patients in our study showed pili canaliculti et trianuuli, which is diagnostic of uncombable hair syndrome. Five of the 6 patients were female, and 1 patient was male. The mean age was 5.1 years (range, 1.4-13.3 years). Four patients had blond hair, and 2 had light brown hair. Two female patients were siblings. Light microscopic examination revealed longitudinal grooves in 5 patients. One patient did not have hair mount slides on file. The report stated that this patient had nonnal hair under light microscopic examination, and scanning electron microscopic study demonstrated longitudinal grooves in the hair shaft. Confirmatory or diagnostic scanning electron microscopy studies were performed in 2 other cases at the time of hair examination. Figure 3 illustrates the typical clinical appearance and light microscopic and scanning electron microscopic findings of uncombable hair sjoidrome. Two patients in the group of erythroderma/diffuse eczematous dermatitis had trichorrhexia invaginata in their hair samples, diagnostic of Netherton syndrome. One patient had a medical history of severe hypematremia and diffuse desquamation of the skin shortly after birth. He had short brittle hair and a characteristic skin rash with double-edged scale (ichthyosis linearis circumsflexa) on the legs and feet at 2 months of age. A clipped
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eyebrow sample at that time was normal. A clipped scalp hair at 5 months of age showed trichorrhexis invaginata. The clinical and light microscopic changes in his hair sample are shown in Figure 4. A molecular test later showed homozygous deletion of a single " A " nucleotide in exon 26 of the SPINK5 gene compatible with Netherton syndrome. The 2nd patient was a boy with severe eczema and poor growth. A hair sample was submitted for light microscopic examination. Trichorrhexia invaginata was identified in the hair sample. In the group of patients with neurological symptoms, one patient who had been followed by pédiatrie genetics for ataxia and tremor since 2 years of age was diagnosed with trichothiodystrophy after hair examination. She also had brittle hair, bilateral cataracts, developmental delay, photosensitivity of the skin, and abnormal brain magnetic resonance imaging with changes of abnormal myelination. She had a negative workup for various genetic or metabolic conditions. Her hair examination at 5 years of age revealed tiger-tail banding under polarized light (Fig. 5A). Amino acid analysis of a hair sample later showed a sulfur content of 3.8% (normal reference, 5%). Three male patients with neurological symptoms showed pili torti (Fig. 5B). The hair examination for all 3 patients was performed at the initial clinical workup for metabolic
A
B
Figure 5. Hair shaft abnormalities. Under polarized light, alternating light and dark banding (tiger-tail banding) are present in a patient witb tricbotbiodystropby (A). Multiple twists of the bair shaft (pili torti) are seen in a patient with Menkes syndrome (B). A fragile node of trichorrhexis nodosa shows a ruptured cuticle witb frayed cortical fibers (C).
or neurological disease. The diagnosis of Menkes syndrome was made based on the physical examination, hair examination, and laboratory testing. Moleeular tests were performed later and eonfirmed the diagnosis. The elinieal findings and molecular test results for these 3 patients are summarized in Table 2. An example of triehorrhexis nodosa seen in 13 patients is shown in Figure 5C. DISCUSSION In our study of hair samples from 119 patients in the 10year period, the presence of LAHs in gently pulled hair samples is the most common microscopic finding, seen in 37 patients. Loose anagen hair syndrome is a type of selflimiting, noninflammatory, nonscaring alopecia in which anagen hairs are easily and painlessly extraeted. It is seen in up to 10% of ehildren presenting with hair loss or alopeeia [2]. The elinieal findings of patients with LAHS are quite heterogeneous. Many patients have slowgrowing hair that seldom requires eutting. Other patients have sparse growth of thin, fine hair and diffuse or patehy alopeeia. Gentle traetion results in hair that is painlessly removed. Loose anagen hair syndrome is an inherited eondition in an autosomal-dominant pattem [3,4]. The
eondition typieally affeets young girls, often those with light-eolored hair. Based on hairstyle ehoiees, LAHS is likely underdiagnosed [5] in male patients. The pathogenesis of LAHS is unelear but likely involves defeetive anehorage of the hair shaft to the hair folliele. Premature keratinization of the inner root sheath in the presenee of K6hf mutation in some patients with LAHS might lead to defective anchorage [3]. Diagnosis of LAHS relies primarily on the elinieal findings, the number and pereentage of LAHs from hair samples. The hallmark feature of LAHS is the ability to extraet anagen hairs easily and painlessly with gentle pulling on physical examination (a "pull test"). The gently pulled hair samples are examined under the microscope for the percentage of loose anagen hairs. The diagnostie eriteria have been evolving in reeent years. In 1997 Tosti and colleagues [6] proposed diagnostic criteria for LAHS, as follows: (1) positive pull test results with painless extraction of at least 10 LAHs and (2) the presence of more than 80% LAHs on trichogram. The same group later revised the eriteria after they found that a positive pull test was present only in the severely affeeted patients. The revised eriteria in 2002 [7] only required the presenee 70% LAHs on triehogram. In 2009 Cantatore-Francis and Orlow [2] used the presence of
Table 2.
Clinical and molecular findings in the 3 patients with Menkes syndrome
Patient
Presenting symptoms
Age at presentation (month)
Mutation in ATP7A
Age of demise (month)
1
Seizure, loss of developmental milestones Developmental delay Seizure
4
P.P852L (C.2555OT)
48
8 2
P.E336X (c.l006G>T) IVS7-1OC
15 44
2 3
LIGHT MICROSCOPIC HAIR ABNORMALITIES IN CHILDREN
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50% of LAHs from a gently pulled hair sample as the diagnostic criteria for LAHS in their study; however, there was no specified minimal number of total hairs required in the study. Rare LAHs can be present in gently pulled hair samples from "normal" children. Olsen and colleagues [8] reported that LAHs were seen in 14 of 23 hair pull samples from normal children below 10 year of age. On average, 1-2 LAHs were present in normal children, compared to more than 3, and often more than 10, LAHs in patients with LAHS. The samples used in the study were gently pulled with at least 5 hair bulbs. Based on the published data, in our retrospective review we establish the criteria that a hair sample with 5 or more hair bulbs and at least 50% LAHs in the presence of clinical suspicion is diagnostic of LAHS. The minimum requirement of 5 hair bulbs with >50% LAHs will likely prevent overdiagnosis of LAHS when rare LAHs are present in a gently pulled hair sample. In our study of 37 cases with LAHs, 25 patients met the above criteria. Twelve cases were considered nondiagnostic due to either fewer than 5 hair bulbs or less than 50% LAHs in the samples. They either represented patients with LAHS with inadequate hair sampling for light microscopic diagnosis or normal children with dystrophic LAHs found in a pull test. Netherton syndrome is a rare autosomal-recessive disease with variable expression. It is characterized by the triad of ichthyosis linearis circumfiexa, trichorrhexis invaginata, and an atopic diathesis. Many children with Netherton syndrome develop congenital erythroderma at birth or during the first weeks of life. Dehydration, hypematremia, failure to thrive, and recurrent infections may be present at a young age. Ichthyosis linearis circumfiexa, which consists of erythematous, migratory polycyclic patches surrounded by double-edged scales, is typically noted at 1-2 years of age and ean be transient at times. Symptoms of atopic diathesis include atopic dermatitis, elevated serum immunoglobulin E, and food allergies. Patients with Netherton syndrome may have abnormal sparse, short, and brittle hair. Trichorrhexis invaginata (or bamboo hair), the result of an intermittent keratinizing defect of the hair cortex, is pathognomonic of Netherton syndrome. The characteristic hair findings are also seen in eyebrow hairs [9]. It is common to have multiple hair samples examined before the diagnostic microscopic finding is identified. Netherton syndrome is due to genetie mutations of the SPINK5 gene on chromosome 5q31-32 [10]. The SPINK5 gene eneodes a serine protease inhibitor (lympho-epithelial Kazal-typerelated inhibitor LEKTI) [11]. LEKTI contributes to the balance of desquamation and keratinization in the epidermis and hair follieles [12]. Many different mutations have been reported, and the wide range of mutations is responsible for variable clinical manifestation in the patients. The pathogenesis of Netherton syndrome and its association with SPINK 5 mutation were supported by knockout mice with LEKTI deficiency [13]. Patients with uncombable hair syndrome present at an early age with "unruly," frizzy hair that is difficult to
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style and comb. Rarely, juvenile cataract, ectodermal dystrophy, or LAHS are reported [14,15]. The color of the hair is typically blond or light brown, as was the case for the 6 children in our study. Light microscopic examination of the hair shaft may reveal longitudinal grooves, but this finding may not be noted in all the reported cases. Scanning electron microscopy revealed longitudinal grooves in over 50% of the hairs in patients with uncombable hair syndrome [16], and it is considered the gold standard for the diagnosis of this condition. The cross sections of hair shaft embedded in paraffin are triangular or kidney shaped in patients with uncombable hair syndrome. Some authors [17] proposed to use this cheaper, but technically challenging, option for the diagnosis of uncombable hair syndrome. In our study, longitudinal grooves are identified in all 5 cases with available hair mount slides. The grooves of the hair shaft can be very subtle, focal, and easily overlooked. We found that examination of hair samples without a condenser, at medium power of magnification (preferably with a X20 object lens) and constant adjustment of miero-focus will make the grooves more visible. The pathogenesis of uncombable hair is unknown. It is believed to be an autosomal-dominant condition with variable penetrance. Trichothiodystrophy is a rare, inherited, autosomalrecessive disorder with impaired nucleotide excision pathway for DNA repair, but without increased frequeney of skin cancers, as seen in xeroderma pigmentosum. All TTD patients have brittle hair and variable neuroectodermal symptoms, including skin photosensitivity, ichthyosis, short stature, and intelleetual and developmental impairment. The diagnosis of TTD can be made by careful examination of hair shaft with polarized light and clinical examination of the patients [18]. Tiger-tail banding is the hallmark hair abnormality in TTD patients. Other hair abnormalities reported are nonspecific including trichoschosis, trichorrhexis nodosa-like fractures and ribboning. Liang and colleagues [19] reported that TTD hair samples have reduced cysteine that parallels the low total sulfur content by amino-acid analysis in 15 patients. A study of hair samples in patients with hair fragility and neurological symptoms, tiger-tail banding can have normal cysteine content [20]. Pili torti is an etiologically less specific hair finding seen in Menkes syndrome, Bjorstad's syndrome, Bazex syndrome, Rapp-Hodgkin syndrome, Crandall syndrome, and occasionally in normal individuals. Menkes syndrome is a lethal x-linked recessive disorder due to impaired copper transport and metabolism. Patients have defective activity of copper-dependent enzymes affecting multiple organs. After the normal-appearing newborn period, patients develop short, coarse, sparse, and hypopigmented hair and progressive, severe neurological deterioration leading to death at an early age. The molecular defect is in the ATP7A gene, which encodes a copper-transporting ATPase [21]. Because normal copper transportation is essential to formation of disulfide bonds in hair keratin, defective keratin production may
cause twisting of the hair. Although less specific, pili torti in a young male infant with neurological symptoms should prompt other laboratory testing and early clinical evaluation for the diagnosis of Menkes syndrome. In many ehildren's hospitals in the United States, light mieroscopic examination of hair samples is perfomied by dermatologists using dry mount hair preparation (hairs are cover-slipped without any mounting medium). The hair samples are not kept or stored after examination, and the microscopic findings are likely recorded in the clinical notes. In our hospital, pédiatrie pathologists have been involved in the vast majority of light microscopic examination of hair samples for over a deeade. Since hair sample collection is relatively simple, physieians in neurology, geneties, hematology, and other services may submit samples directly for light microscopic examination. The findings of the hair examination are reported in formal pathology reports, and the hair mount slides have been stored in the pathology archives for future reference. Our study demonstrated that 31% of our cases showed light mieroseopie ehanges that were diagnostic of or compatible with speeific genetie eonditions. Hair examination is a quiek, noninvasive, and valuable test. It should be eonsidered a eonvenient and inexpressive 1stline investigation in the diagnosis of many pédiatrie systemic genetic conditions, such as Menkes syndrome, TTD, and Netherton syndrome. It is also an indispensable test for many genetic conditions that affect hair only, such as uncombable hair syndrome and LAHS. REFERENCES 1. Smith V, Anderson G, Malone M, Sebire NJ. Light microscopic examination of scalp hair samples as an aid in the diagnosis of paediatric disorders: retrospective review of more than 300 cases from a single centre. J Clin Fathol 2005;58:1294-1298. 2. Cantatore-Francis JL, Orlow SJ. Practical guidelines for evaluation of loose anagen hair syndrome. Arch Dermatol 2009; 145:11231128. 3. Chapalain V, Winter H, Langbein L, et al. Is the loose anagen hair syndrome a keratin disorder? A clinical and molecular study. Arch Dermatol 2002;138:501-506. 4. Sinclair R, Cargnello J, Chow CW. Loose anagen syndrome. Exp Dermatol 1999;8:297-298.
5. Pham CM, Krejci-Manwaring J. Loose anagen hair syndrome: an underdiagnosed condition in males. Pediatr Dermatol 2010;27:408409. 6. Tosti A, Peluso AM, Misciali C, et al. Loose anagen hair. Arch Dermatol 1997;133:10S9-1093. 7. Tosti A, Piraccini BM. Loose anagen hair syndrome and loose anagen hair. Arch Dermatol 2002;138:521-522. 8. Olsen EA, Bettencourt MS, Coté NL. The presence of loose anagen hairs obtained by hair pull in the normal population. J Investig Dermatol Symp Proc 1999;4:258-260. 9. Powell J, Dawber RP, Ferguson DJ, Griffiths WA. Netherton's syndrome: increased likelihood of diagnosis by examining eyebrow hairs. Br J Dermatol 1999;141:544-546. 10. Chavanas S, Gamer G, Bodemer C, et al. Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping. Am J Hum Genet 2000;66:914-921. n . Ong C, O'Toole EA, Ghali L, et al. LEKTI demonstrable by immunohistochemistry of the skin: a potential diagnostic skin test for Netherton syndrome. Br J Dermatol 2004;151:1253-1257. 12. Bitoun E, Micheloni A, Lamant L, et al. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Hum Mol Genet 2003; 12:2417-2430. 13. Descargues P, Déraison C, Bonnart C, et al. Spink 5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat Genet 2005;37:56-65. 14. Lee AJ, Maino KL, Cohen B, Sperling L. A girl with loose anagen hair syndrome and uncombable, sptin-glass hair. Pediatr Dermatol 2005;22;230-233. 15. Fritz TM, Trueb RM. Uncombable hair syndrome with angel-shaped phalango-epiphyseal dysplasia. Pediatr Dermatol 2000;17:21-24. 16. Rest EB, Fretzin DF. Quantitative assessment of scanning electron microscope defects in uncombable-hair syndrome. Pediatr Dermatol 1990;7:93-96. 17. Weinstein JM, Chamlin SL. Uncombable hair syndrome: light microscopy diagnosis. Pediatr Dermatol 2005;22:369-370. 18. Price VH, Odom RB, Ward WH, Jones FT. Tdchothiodystrophy: sulfur-deficient brittle hair as a marker for a neuroectodermal symptom complex. Arch Dermatol 1980;l 16:1375-1384. 19. Liang C, Morris A, Schlucker S, et al. Structural and molecular hair abnonnalities in trichothiodystrophy. J Invest Dermatol 2006; 126: 2210-2216. 20. Cheng S, Stone J, de Berker D. Trichothiodystrophy and fragile hair: the distinction between diagnostic signs and diagnostic labels in childhood hair disease. Br J Dermatol 2009;161:1379-1383. 21. Vulpe C, Levinson B, Whitney S, et al. Isolation of a candidate gene for Menkes disease and evidence that it encodes a coppertransporting ATPase. Nat Genet 1993;3:7-13.
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Light Microscopic Hair Abnormalities in Children: Retrospective Review of 119 Cases in a 10-Year Period LEI SHAO^* AND BRANDON NEWELL^ ^Department of Pathology, Children's Mercy Hospitals and Clinics, Kansas City, MO, USA ^Section of Dermatology, Children's Mercy Hospitais and Clinics, Kansas City, MO, USA
Received September 6, 2013; accepted November 17, 2013; published online November 18, 2013.
ABSTRACT Abnormalities in the hair can be congenital or acquired conditions. Examples of genetic disorders with associated hair abnormalities include Menkes syndrome, Netherton syndrome, uncombable hair syndrome, trichothiodystrophy, and loose anagen hair syndrome. Acquired hair abnormalities can be associated with grooming or use of various hair products. There are many patterns of hair abnormalities that can be readily identified under a light microscope. We performed a retrospective review of 129 hair mount samples from 119 patients submitted to the pathology department for microscopic examination over a 10-year span (from January 2002 to December 2011). Of the 119 patients, 63 (53%) had morphologic changes in the hair samples. Thirty-seven patients (31%) showed morphologic changes compatible with specific diagnoses of various genetic conditions, including 25 cases of loose anagen hair syndrome, 6 cases of uncombable hair syndrome, 2 cases of Netherton syndrome, 3 cases of Menkes syndrome, and 1 case of trichothiodystrophy. The other changes were considered nonspecific or nondiagnostic, with trichorrhexis nodosa in 13 patients, presence of loose anagen hairs in 12 patients, and pili torti in 1 patient. We describe the light microscopic patterns of hair abnormalities, clinical findings, and molecular defects related to those genetic conditions. Our study indicates that hair examination can be a lst-line investigation on various pédiatrie conditions. Key words: hair, hair abnormality, light microscopy
INTRODUCTION Examination of hair samples under light microscopy may reveal distinct patterns of hair abnormalities and therefore facilitate accurate diagnosis of underlying conditions. Patients with Menkes syndrome typically have multiple twists in the hair shaft at irregular intervals (pili torti). * Corresponding author, e-mail: [email protected]
Nodular swelling with a cup-like expansion of the proximal hair cortex that surrounds the distal segment (trichorrhexis invaginata) is considered diagnostic of Netherton syndrome. Longitudinal grooves along the hair shaft (pili canaliculti et trianguli) are seen in uncombable hair syndrome. Alternating light and dark banding under polarized light (tiger-tail banding) is characteristically found in patients with trichothiodystrophy (TTD). In patients with loose anagen hair syndrome (LAHS), anagen hairs are easily pulled out, and they show misshapen hair bulbs, ruffied cuticles at the suprabulbar zone, and absent root sheaths (loose anagen hair [LAH]). Foci of ruptured cuticle with frayed cortical fibers (trichorrhexis nodosa) are usually associated with trauma to the hair shaft in a normal individual and rarely in someone with inherited weakness of the hair shaft. Hair follicles are derived from hair germ cells in the ectoderm in a developing embryo. There are 2 major types of hair follicles in children based on the size and color ofthe hairs they produce. The terminal hair follicles are deep rooted in the subcutaneous tissue, and they make long, pigmented hairs such as those on the scalp. Vellus hair follicles are located in the superficial dermis. Vellus hair follicles produce short and nonpigmented hairs that are present throughout the human body surface except for the palms, the soles, and mucosa-covered areas. Human hair grows in cycles through a poorly understood, complicated signaling mechanism. Each growth cycle begins with the appearance of a new hair shaft from its hair follicle and ends with spontaneous shedding of the hair shaft as the follicle enters its resting stage. Each follicular life cycle, regardless of the type of the hair follicles, is divided into 3 phases: the anagen, catagen, and telogen phases. The anagen phase consists of active hair growth with rapidly dividing cells in the hair follicles. The catagen phase marks follicular regression, and the telogen phase represents spontaneous hair shedding and a resting period before a new growth cycle begins. The anagen phase of the scalp terminal hair follicles varies from 2 to 7 years among different
B
Figure 1. Light microscopic pictures of anagen and telogen hairs. An anagen hair (A) contains nucleated keratinocytes in tbe bair bulb and attached root sbeatbs. The hair bulb of a telogen hair (B) is completely cornified, without surroundinq root sheaths.
individuals. The catagen phase generally lasts 1-3 weeks and the telogen phase 1-3 months. In the scalp, approximately 90% of the terminal hair follicles are in the anagen phase, and 10% are in the telogen phase. Less than 1% ofthe terminal sealp hair follicles are in the catagen phase. The hair shaft is made of keratinized dead cells and hard proteins called keratins. The hair shaft has 3 layers. The center, called the medulla, is surrounded by cortex. The cuticle is on the outer surface of the hair shaft. The cuticle is the strongest layer, and it is formed by tightly packed dead cells lined up like roof shingles. The difference in straight, wavy, and eurly hair lies in the shape of the hair shaft. Straight hair is eircular or nearly circular in cross section. Wavy hair has an oval-shaped eross seetion, and eurly hair has an elliptieal eross seetion. The hair root is embedded within a hair follicle in the skin. The most proximal, expanded extremity of the hair root is called a hair bulb. The hair at anagen phase is firmly anchored to the sealp by the hair folliele and the surrounding anchoring structures, including the inner root sheath, outer root sheath, vitrous layer, and fibrous root sheath. Removal of a normal anagen hair from the human scalp is painful and requires forcible plucking. A telogen hair is separated from the anehoring stmctures and sheds spontaneously. Under light microscopy, an anagen hair root contains nucleated cells in the hair bulb and attached root sheaths (Fig. lA). A telogen hair shows a completely comified hair bulb without attached root sheaths (Fig. 1B).
A catagen hair is also completely comified in the hair bulb like a telogen hair, but with attached root sheaths, as seen in an anagen hair. In this study, we reviewed the hair samples of 119 pédiatrie patients submitted to the pathology department at Children's Mercy Hospital and Clinics for hair examination in a 10-year period. We also collected clinical infonnation for eorrelation with the mieroseopie hair findings. A review ofthe literature revealed 1 similar study [1] that ineluded both pédiatrie and adult patients. The aim of our study is to examine, retrospeetively, the usefulness of hair examination in a ehildren's hospital. Our results indicate that light microscopic examination of hair samples is a simple, noninvasive, and valuable tool that should be used more widely in various pédiatrie patients. MATERIALS AND METHODS A search of eomputerized datahases identified all hair samples received between January 2002 and December 2011 in the Department of Pathology at Children's Mercy Hospital and Clinics (Kansas City, MO). There are 2 types of hair samples in our study. A clipped hair sample contains hair shaft only, and the sample is colleeted by eutting hair close to the skin with a pair of seissors. A gently pulled hair sample is eolleeted by a gentle but firm pull, grasping about 5-10 hairs from an ~1-em-diameter area of the scalp. Typically 2-3 regions are sampled. A pulled hair sample has both hair bulbs and hair shaft. Hair
LIGHT MICROSCOPIC HAIR ABNORMALITIES IN CHILDREN
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Table 1. Summary of clinical indications for hair examination, morphologic patterns of hair examination, and final diagnosis of all the patients in the study Clinical indications (No. of eases) Hair abnormality only {N = 87)
Erythroderma or diffuse eczematous dermatitis (iV= 16) Neurological symptoms (iV= 9) Ectodermal dysplasia (TV =4) Immunological or hematological symptoms (iV=3)
Patterns of morphologic findings (No. of cases) >5 Hair bulbs and >50% loose anagen hairs {N = 25) 50% loose anagen hairs (LAHs) in a gently pulled hair sample to be diagnostic of LAHS, provided there was a clinical suspicion of this condition.
RESULTS A total of 129 hair samples were accessioned from 119 patients. Ninety patients were female and 29 were male. The median age at the time of hair examination was
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L. SHAO AND B . NEWELL
Specific diagnosis (No. of cases)
Netherton syndrome (N = 2)
4.3 years and the mean age was 6.0 years, with a range from 10 days to 16.8 years. Five cases consisted of eyebrow hairs and the rest comprised scalp hairs. Four patients had 2 samples collected on different dates as the result of having a different type of hair sample or because of an inadequate prior sample. Six patients had both clipped and pulled scalp hair samples colleeted at the same time. The combined microscopic findings were used for these patients with more than 1 sample. Sixty-five hair samples were pulled. The remaining 64 were clipped hair samples. Of the 119 patients, 87 presented clinically with hair abnormalities only, 16 with erythroderma or diffuse eczematous dermatitis, 9 patients with neurological symptoms, 4 with clinical suspicion of ectodermal dysplasia, and 3 with immunological or hematological symptoms. In the group of patients with isolated hair abnormality, 56 cases showed morphologic changes in the hair samples and 31 cases had normal hairs. The morphologic findings were diagnostic of specific genetic conditions in 31 patients, including 25 patients who met the criteria for LAHS and 6 patients with uncombable hair syndrome. The microscopic changes were considered nonspecific or nondiagnostic in 25 patients. Of the 25 patients with nondiagnostie/nonspecific findings, LAHs were present in 12 patients and trichorrhexis nodosa was present in 13 patients. In the other 4 groups of 32 patients, the hair samples in 25 patients were unremarkable. The microscopic findings were considered compatible with specific genetic conditions in 6 patients when combined with other clinical findings. Three of the 6 patients had Menkes syndrome, 2 had Netherton syndrome, and 1 patient had TTD. One patient with eetodermal dysplasia had pili torti, whieh was considered nondiagnostic/
Figure 2. Loose anagen hair syndrome. A 4-year-old girl with blond, thinner, listless hair (A) that can be painlessly extracted with a gentle hair pull. A loose anagen hair has an appearance of a "hockey stick" due to kinking at the suprabubar zone. Ruffling of the cuticle is also common under light microscopy (B).
nonspecific. Overall, 37 patients (31%) had hair abnormalities that were diagnostie of or eompatible with specific genetic conditions. The clinical indications for hair examination, patterns of morphologic findings in the hair samples, and final diagnoses were summarized in Table 1. There were 25 patients with the diagnosis of LAHS in our study. The medium age was 4.2 years (mean, 4.6 years; range, 2.0-9.8 years). Three of the 25 patients were male and 22 were female, with a maleifemale ratio of approximately 1:7. The hair color of 2 patients was dark brown, and the rest of the patients had blond or light brown hair. A loose anagen hair under the light microscope is devoid of root sheaths, with frequent kinking of the suprabulbar zone and a ruffled cuticle in the proximal hair shaft. A typieal patient with LAHS and
a representative hair sample with many LAHs are shown in Figure 2. The number of LAHs in the hair samples of the 25 pafients with LAHS was variable. In the 13 cases with 5-9 hair bulbs in the hair samples, 100% LAHs were found in 11 cases. The other 2 cases contained 86% and 89% LAHs, with total numbers of hair bulbs of 7 and 9, respectively. Twelve patients with LAHS had 10-20 hair bulbs in the submitted hair samples, and 64-100% of the hairs were LAHs. In the 12 patients who did not meet our diagnostic criteria of LAHS, 11 patients had 2-A hair bulbs in the hair samples. One hundred percent LAHs were found in 8 patients (4 patients with 4 LAHs, 2 patients with 3 LAHs, and 2 patients with 2 LAHs). In 3 patients, 4 hairs bulbs were present in the samples, with 50-75% being LAHs. The last patient had 9 hair bulbs, with 3 LAHs and 6 telogen hairs.
Figure 3. Uncombable hair syndrome. A 5-year-old female with frizzy hair that is difficult to comb and style (A). The hair shaft shows longitudinal grooving under light microscopy (B) and scanning electron microscopy (C). LIGHT MICROSCOPIC HAIR ABNORMALITIES IN CHILDREN
39
Figure 4. Netherton syndrome. A 5-month-old male infant with short, broken hair in the scalp and eyebrow (A) and a skin rash with double-edged scald in the right foot (B). A hair sample showed nodes of trichorrhexis invaginata and multiple breaks of the hair shaft at the nodes (C, D).
Six patients in our study showed pili canaliculti et trianuuli, which is diagnostic of uncombable hair syndrome. Five of the 6 patients were female, and 1 patient was male. The mean age was 5.1 years (range, 1.4-13.3 years). Four patients had blond hair, and 2 had light brown hair. Two female patients were siblings. Light microscopic examination revealed longitudinal grooves in 5 patients. One patient did not have hair mount slides on file. The report stated that this patient had nonnal hair under light microscopic examination, and scanning electron microscopic study demonstrated longitudinal grooves in the hair shaft. Confirmatory or diagnostic scanning electron microscopy studies were performed in 2 other cases at the time of hair examination. Figure 3 illustrates the typical clinical appearance and light microscopic and scanning electron microscopic findings of uncombable hair sjoidrome. Two patients in the group of erythroderma/diffuse eczematous dermatitis had trichorrhexia invaginata in their hair samples, diagnostic of Netherton syndrome. One patient had a medical history of severe hypematremia and diffuse desquamation of the skin shortly after birth. He had short brittle hair and a characteristic skin rash with double-edged scale (ichthyosis linearis circumsflexa) on the legs and feet at 2 months of age. A clipped
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L. SHAO AND B . NEWELL
eyebrow sample at that time was normal. A clipped scalp hair at 5 months of age showed trichorrhexis invaginata. The clinical and light microscopic changes in his hair sample are shown in Figure 4. A molecular test later showed homozygous deletion of a single " A " nucleotide in exon 26 of the SPINK5 gene compatible with Netherton syndrome. The 2nd patient was a boy with severe eczema and poor growth. A hair sample was submitted for light microscopic examination. Trichorrhexia invaginata was identified in the hair sample. In the group of patients with neurological symptoms, one patient who had been followed by pédiatrie genetics for ataxia and tremor since 2 years of age was diagnosed with trichothiodystrophy after hair examination. She also had brittle hair, bilateral cataracts, developmental delay, photosensitivity of the skin, and abnormal brain magnetic resonance imaging with changes of abnormal myelination. She had a negative workup for various genetic or metabolic conditions. Her hair examination at 5 years of age revealed tiger-tail banding under polarized light (Fig. 5A). Amino acid analysis of a hair sample later showed a sulfur content of 3.8% (normal reference, 5%). Three male patients with neurological symptoms showed pili torti (Fig. 5B). The hair examination for all 3 patients was performed at the initial clinical workup for metabolic
A
B
Figure 5. Hair shaft abnormalities. Under polarized light, alternating light and dark banding (tiger-tail banding) are present in a patient witb tricbotbiodystropby (A). Multiple twists of the bair shaft (pili torti) are seen in a patient with Menkes syndrome (B). A fragile node of trichorrhexis nodosa shows a ruptured cuticle witb frayed cortical fibers (C).
or neurological disease. The diagnosis of Menkes syndrome was made based on the physical examination, hair examination, and laboratory testing. Moleeular tests were performed later and eonfirmed the diagnosis. The elinieal findings and molecular test results for these 3 patients are summarized in Table 2. An example of triehorrhexis nodosa seen in 13 patients is shown in Figure 5C. DISCUSSION In our study of hair samples from 119 patients in the 10year period, the presence of LAHs in gently pulled hair samples is the most common microscopic finding, seen in 37 patients. Loose anagen hair syndrome is a type of selflimiting, noninflammatory, nonscaring alopecia in which anagen hairs are easily and painlessly extraeted. It is seen in up to 10% of ehildren presenting with hair loss or alopeeia [2]. The elinieal findings of patients with LAHS are quite heterogeneous. Many patients have slowgrowing hair that seldom requires eutting. Other patients have sparse growth of thin, fine hair and diffuse or patehy alopeeia. Gentle traetion results in hair that is painlessly removed. Loose anagen hair syndrome is an inherited eondition in an autosomal-dominant pattem [3,4]. The
eondition typieally affeets young girls, often those with light-eolored hair. Based on hairstyle ehoiees, LAHS is likely underdiagnosed [5] in male patients. The pathogenesis of LAHS is unelear but likely involves defeetive anehorage of the hair shaft to the hair folliele. Premature keratinization of the inner root sheath in the presenee of K6hf mutation in some patients with LAHS might lead to defective anchorage [3]. Diagnosis of LAHS relies primarily on the elinieal findings, the number and pereentage of LAHs from hair samples. The hallmark feature of LAHS is the ability to extraet anagen hairs easily and painlessly with gentle pulling on physical examination (a "pull test"). The gently pulled hair samples are examined under the microscope for the percentage of loose anagen hairs. The diagnostie eriteria have been evolving in reeent years. In 1997 Tosti and colleagues [6] proposed diagnostic criteria for LAHS, as follows: (1) positive pull test results with painless extraction of at least 10 LAHs and (2) the presence of more than 80% LAHs on trichogram. The same group later revised the eriteria after they found that a positive pull test was present only in the severely affeeted patients. The revised eriteria in 2002 [7] only required the presenee 70% LAHs on triehogram. In 2009 Cantatore-Francis and Orlow [2] used the presence of
Table 2.
Clinical and molecular findings in the 3 patients with Menkes syndrome
Patient
Presenting symptoms
Age at presentation (month)
Mutation in ATP7A
Age of demise (month)
1
Seizure, loss of developmental milestones Developmental delay Seizure
4
P.P852L (C.2555OT)
48
8 2
P.E336X (c.l006G>T) IVS7-1OC
15 44
2 3
LIGHT MICROSCOPIC HAIR ABNORMALITIES IN CHILDREN
41
50% of LAHs from a gently pulled hair sample as the diagnostic criteria for LAHS in their study; however, there was no specified minimal number of total hairs required in the study. Rare LAHs can be present in gently pulled hair samples from "normal" children. Olsen and colleagues [8] reported that LAHs were seen in 14 of 23 hair pull samples from normal children below 10 year of age. On average, 1-2 LAHs were present in normal children, compared to more than 3, and often more than 10, LAHs in patients with LAHS. The samples used in the study were gently pulled with at least 5 hair bulbs. Based on the published data, in our retrospective review we establish the criteria that a hair sample with 5 or more hair bulbs and at least 50% LAHs in the presence of clinical suspicion is diagnostic of LAHS. The minimum requirement of 5 hair bulbs with >50% LAHs will likely prevent overdiagnosis of LAHS when rare LAHs are present in a gently pulled hair sample. In our study of 37 cases with LAHs, 25 patients met the above criteria. Twelve cases were considered nondiagnostic due to either fewer than 5 hair bulbs or less than 50% LAHs in the samples. They either represented patients with LAHS with inadequate hair sampling for light microscopic diagnosis or normal children with dystrophic LAHs found in a pull test. Netherton syndrome is a rare autosomal-recessive disease with variable expression. It is characterized by the triad of ichthyosis linearis circumfiexa, trichorrhexis invaginata, and an atopic diathesis. Many children with Netherton syndrome develop congenital erythroderma at birth or during the first weeks of life. Dehydration, hypematremia, failure to thrive, and recurrent infections may be present at a young age. Ichthyosis linearis circumfiexa, which consists of erythematous, migratory polycyclic patches surrounded by double-edged scales, is typically noted at 1-2 years of age and ean be transient at times. Symptoms of atopic diathesis include atopic dermatitis, elevated serum immunoglobulin E, and food allergies. Patients with Netherton syndrome may have abnormal sparse, short, and brittle hair. Trichorrhexis invaginata (or bamboo hair), the result of an intermittent keratinizing defect of the hair cortex, is pathognomonic of Netherton syndrome. The characteristic hair findings are also seen in eyebrow hairs [9]. It is common to have multiple hair samples examined before the diagnostic microscopic finding is identified. Netherton syndrome is due to genetie mutations of the SPINK5 gene on chromosome 5q31-32 [10]. The SPINK5 gene eneodes a serine protease inhibitor (lympho-epithelial Kazal-typerelated inhibitor LEKTI) [11]. LEKTI contributes to the balance of desquamation and keratinization in the epidermis and hair follieles [12]. Many different mutations have been reported, and the wide range of mutations is responsible for variable clinical manifestation in the patients. The pathogenesis of Netherton syndrome and its association with SPINK 5 mutation were supported by knockout mice with LEKTI deficiency [13]. Patients with uncombable hair syndrome present at an early age with "unruly," frizzy hair that is difficult to
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L. SHAO AND B . NEWELL
style and comb. Rarely, juvenile cataract, ectodermal dystrophy, or LAHS are reported [14,15]. The color of the hair is typically blond or light brown, as was the case for the 6 children in our study. Light microscopic examination of the hair shaft may reveal longitudinal grooves, but this finding may not be noted in all the reported cases. Scanning electron microscopy revealed longitudinal grooves in over 50% of the hairs in patients with uncombable hair syndrome [16], and it is considered the gold standard for the diagnosis of this condition. The cross sections of hair shaft embedded in paraffin are triangular or kidney shaped in patients with uncombable hair syndrome. Some authors [17] proposed to use this cheaper, but technically challenging, option for the diagnosis of uncombable hair syndrome. In our study, longitudinal grooves are identified in all 5 cases with available hair mount slides. The grooves of the hair shaft can be very subtle, focal, and easily overlooked. We found that examination of hair samples without a condenser, at medium power of magnification (preferably with a X20 object lens) and constant adjustment of miero-focus will make the grooves more visible. The pathogenesis of uncombable hair is unknown. It is believed to be an autosomal-dominant condition with variable penetrance. Trichothiodystrophy is a rare, inherited, autosomalrecessive disorder with impaired nucleotide excision pathway for DNA repair, but without increased frequeney of skin cancers, as seen in xeroderma pigmentosum. All TTD patients have brittle hair and variable neuroectodermal symptoms, including skin photosensitivity, ichthyosis, short stature, and intelleetual and developmental impairment. The diagnosis of TTD can be made by careful examination of hair shaft with polarized light and clinical examination of the patients [18]. Tiger-tail banding is the hallmark hair abnormality in TTD patients. Other hair abnormalities reported are nonspecific including trichoschosis, trichorrhexis nodosa-like fractures and ribboning. Liang and colleagues [19] reported that TTD hair samples have reduced cysteine that parallels the low total sulfur content by amino-acid analysis in 15 patients. A study of hair samples in patients with hair fragility and neurological symptoms, tiger-tail banding can have normal cysteine content [20]. Pili torti is an etiologically less specific hair finding seen in Menkes syndrome, Bjorstad's syndrome, Bazex syndrome, Rapp-Hodgkin syndrome, Crandall syndrome, and occasionally in normal individuals. Menkes syndrome is a lethal x-linked recessive disorder due to impaired copper transport and metabolism. Patients have defective activity of copper-dependent enzymes affecting multiple organs. After the normal-appearing newborn period, patients develop short, coarse, sparse, and hypopigmented hair and progressive, severe neurological deterioration leading to death at an early age. The molecular defect is in the ATP7A gene, which encodes a copper-transporting ATPase [21]. Because normal copper transportation is essential to formation of disulfide bonds in hair keratin, defective keratin production may
cause twisting of the hair. Although less specific, pili torti in a young male infant with neurological symptoms should prompt other laboratory testing and early clinical evaluation for the diagnosis of Menkes syndrome. In many ehildren's hospitals in the United States, light mieroscopic examination of hair samples is perfomied by dermatologists using dry mount hair preparation (hairs are cover-slipped without any mounting medium). The hair samples are not kept or stored after examination, and the microscopic findings are likely recorded in the clinical notes. In our hospital, pédiatrie pathologists have been involved in the vast majority of light microscopic examination of hair samples for over a deeade. Since hair sample collection is relatively simple, physieians in neurology, geneties, hematology, and other services may submit samples directly for light microscopic examination. The findings of the hair examination are reported in formal pathology reports, and the hair mount slides have been stored in the pathology archives for future reference. Our study demonstrated that 31% of our cases showed light mieroseopie ehanges that were diagnostic of or compatible with speeific genetie eonditions. Hair examination is a quiek, noninvasive, and valuable test. It should be eonsidered a eonvenient and inexpressive 1stline investigation in the diagnosis of many pédiatrie systemic genetic conditions, such as Menkes syndrome, TTD, and Netherton syndrome. It is also an indispensable test for many genetic conditions that affect hair only, such as uncombable hair syndrome and LAHS. REFERENCES 1. Smith V, Anderson G, Malone M, Sebire NJ. Light microscopic examination of scalp hair samples as an aid in the diagnosis of paediatric disorders: retrospective review of more than 300 cases from a single centre. J Clin Fathol 2005;58:1294-1298. 2. Cantatore-Francis JL, Orlow SJ. Practical guidelines for evaluation of loose anagen hair syndrome. Arch Dermatol 2009; 145:11231128. 3. Chapalain V, Winter H, Langbein L, et al. Is the loose anagen hair syndrome a keratin disorder? A clinical and molecular study. Arch Dermatol 2002;138:501-506. 4. Sinclair R, Cargnello J, Chow CW. Loose anagen syndrome. Exp Dermatol 1999;8:297-298.
5. Pham CM, Krejci-Manwaring J. Loose anagen hair syndrome: an underdiagnosed condition in males. Pediatr Dermatol 2010;27:408409. 6. Tosti A, Peluso AM, Misciali C, et al. Loose anagen hair. Arch Dermatol 1997;133:10S9-1093. 7. Tosti A, Piraccini BM. Loose anagen hair syndrome and loose anagen hair. Arch Dermatol 2002;138:521-522. 8. Olsen EA, Bettencourt MS, Coté NL. The presence of loose anagen hairs obtained by hair pull in the normal population. J Investig Dermatol Symp Proc 1999;4:258-260. 9. Powell J, Dawber RP, Ferguson DJ, Griffiths WA. Netherton's syndrome: increased likelihood of diagnosis by examining eyebrow hairs. Br J Dermatol 1999;141:544-546. 10. Chavanas S, Gamer G, Bodemer C, et al. Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping. Am J Hum Genet 2000;66:914-921. n . Ong C, O'Toole EA, Ghali L, et al. LEKTI demonstrable by immunohistochemistry of the skin: a potential diagnostic skin test for Netherton syndrome. Br J Dermatol 2004;151:1253-1257. 12. Bitoun E, Micheloni A, Lamant L, et al. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Hum Mol Genet 2003; 12:2417-2430. 13. Descargues P, Déraison C, Bonnart C, et al. Spink 5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat Genet 2005;37:56-65. 14. Lee AJ, Maino KL, Cohen B, Sperling L. A girl with loose anagen hair syndrome and uncombable, sptin-glass hair. Pediatr Dermatol 2005;22;230-233. 15. Fritz TM, Trueb RM. Uncombable hair syndrome with angel-shaped phalango-epiphyseal dysplasia. Pediatr Dermatol 2000;17:21-24. 16. Rest EB, Fretzin DF. Quantitative assessment of scanning electron microscope defects in uncombable-hair syndrome. Pediatr Dermatol 1990;7:93-96. 17. Weinstein JM, Chamlin SL. Uncombable hair syndrome: light microscopy diagnosis. Pediatr Dermatol 2005;22:369-370. 18. Price VH, Odom RB, Ward WH, Jones FT. Tdchothiodystrophy: sulfur-deficient brittle hair as a marker for a neuroectodermal symptom complex. Arch Dermatol 1980;l 16:1375-1384. 19. Liang C, Morris A, Schlucker S, et al. Structural and molecular hair abnonnalities in trichothiodystrophy. J Invest Dermatol 2006; 126: 2210-2216. 20. Cheng S, Stone J, de Berker D. Trichothiodystrophy and fragile hair: the distinction between diagnostic signs and diagnostic labels in childhood hair disease. Br J Dermatol 2009;161:1379-1383. 21. Vulpe C, Levinson B, Whitney S, et al. Isolation of a candidate gene for Menkes disease and evidence that it encodes a coppertransporting ATPase. Nat Genet 1993;3:7-13.
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