Is the Loose Anagen Hair Syndrome a Keratin Disorder? a Clinical and Molecular Study

STUDY Is the Loose Anagen Hair Syndrome a Keratin Disorder? A Clinical and Molecular Study

Vale´rie Chapalain, MD; Hermelita Winter, PhD; Lutz Langbein, PhD; Jean-Michel Le Roy, MD; Christine Labre`ze, MD; Milos Nikolic, MD; Ju¨rgen Schweizer, PhD; Alain Taı¨eb, MD

Objectives: To report the clinical features of the loose seldom cut their hair, and 4 had unmanageable hair. One anagen hair syndrome and to test the hypothesis that the patient had hypodontia. Two patients had an additional typical gap between the hair and the inner root sheath clinical phenotype of diffuse partial woolly hair. The fam- may result from hereditary defects in the inner root sheath ily history was positive for loose anagen hair syndrome or the apposed companion layer. in 5 patients. Marked improvement was noted after treatment with 5% minoxidil lotion in 7 of the 11 patients Design: Case series. treated. Polymerase chain reaction analysis of the gene segments encoding the ␣-helical 1A and 2B subdomains Setting: A pediatric dermatology unit (referral center). of K6hf, the type II cytokeratin exclusively expressed in the companion layer, was performed in 9 families. In Patients: A consecutive sample of 17 children (13 girls). 3 of these 9 families, a heterozygous glutamic acid and For 9 of them and their first-degree relatives, molecular lysine mutation, E337K, was identified in the L2 linker analyses were performed in the K6HF gene with 50 ap- region of K6HF. propriate controls. Conclusions: Diffuse partial woolly hair can be associ- Intervention: Minoxidil therapy (5% lotion) in 11 pa- ated with loose anagen hair syndrome. A keratin muta- tients for 1 to 12 months. tion, E337K in K6HF, was possibly causative in 3 of the 9 families studied. Another keratin, and possibly the type Main Outcome Measures: Clinical and follow-up fea- I partner of K6hf, could be responsible for loose anagen tures and determination of mutations in the K6HF gene. hair syndrome in other patients, or the gene involved may be a minor gene. Results: Most patients had easily pluckable hair with no sign of scalp inflammation or scarring. Ten patients Arch Dermatol. 2002;138:501-506

INCE 1990, it has been known pulling, to painlessly extract anagen hairs that mutations in keratin genes that lack the inner root sheath (IRS) and can cause various hereditary the outer root sheath. epithelialdisorders.Thedelete- rious mutations are not ran- For editorial comment domlyS distributed along a keratin molecule, see page 521 From Unite´ de Dermatologie but occur preferentially in those parts of the Pe´diatrique, Hoˆpital molecule that are essential for ordered fila- Previous analyses of hair morpho- Pellegrin-Enfants, Bordeaux, ment formation. The main areas involved in logic features in patients with LAHS have France (Drs Chapalain, Le Roy, this process are the helix initiation motif or shown that the main defect is a gap be- Labre`ze, and Taı¨eb); the the helix termination motif. The hereditary tween the cuticle of the IRS and the cu- German Cancer Research hair disease monilethrix can be caused by ticle of the hair, without abnormalities of Center, Heidelberg, Germany a mutation in hair keratins.1 the hair follicle structure. We hypoth- (Drs Winter, Langbein, and Loose anagen hair syndrome (LAHS) esized that the typical gap between the hair Schweizer); and the is a recently described hair disease, char- and the IRS may result from defects in the Department of Dermatology, acterized by easily pluckable hair. It was IRS or in the apposed companion layer University Hospital, Belgrade, first reported by Zaun in 1984,2 and then (CL). Both compartments are tightly con- Yugoslavia (Dr Nikolic). 3 Dr Taı¨eb is now with the by No¨dl et al in 1986, and was then pub- nected and are thought to stabilize the Service de Dermatologie, lished in the US literature by Hamm and growing hair. Thus, mutations in kerat- Hoˆpital St Andre´, Bordeaux, Traupe4 and Price and Gummer5 in 1989. ins expressed in these follicular compart- France. The essential finding is the ability, by gentle ments may compromise the stable anchor-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Summary of the Clinical Findings in the 17 Children PATIENTS AND METHODS Variable Findings* Female-male ratio 13:4 PATIENTS Age, y At the initial visit, mean 4.3 (2.0-8.5) From January 1988 to December 1998, 17 cases of (range) LAHS originating from 17 different families were di- At onset Birth to 7 agnosed in our unit because of easily pluckable hair, Family history Positive for LAHS (n = 5) alopecia, and/or slow-growing hairs. The diagnosis Associated findings Hypodontia (n = 1), fragile nails was established on clinical grounds associated with (n = 1), atopic dermatitis (n = 2), a trichogram in 16 patients. More than 50% of dys- and psoriasis guttata (n = 1) trophic anagen hairs in the trichogram was consid- Trichogram (obtained in Mostly dystrophic anagen hairs ered as diagnostic of LAHS in 14 of the 16 patients 16 patients) (n = 14), 56.5%-99.0%; and investigated. associated with DPWH (n = 2) Course of the disease Follow-up, 3.0 mo to 6.5 y (n = 15): DNA natural improvement (n = 10) and stable (n = 5) Minoxidil therapy (5% lotion twice a After ethic committee approval, blood was drawn day), 1 mo to1y(n=11): 7 from consenting affected and unaffected members patients showed improvement of 9 nuclear families (the propositus and parents and sometimes brothers and sisters) of this series *LAHS indicates loose anagen hair syndrome; DPWH, diffuse partial and from 50 unrelated healthy individuals, without woolly hair. a history of hair disorder, to whom the aim and nature of the study had been explained. Genomic tions in these keratins should result in disorders other DNA was isolated (Blood and Tissue Culture DNA Extraction System; QIAGEN GmbH, Hilden, than loose anagen. Germany). We describe 17 consecutive patients with LAHS who were referred to our department from January 1988 to MUTATION ANALYSIS December 1998. For 9 of them and their first-degree relatives, molecular analyses were performed in the K6HF The gene segments encoding the ␣-helical 1A and 2B gene to look at possible causative mutations. subdomains of K6HF were amplified by the polymerase chain reaction using the primer pairs 5Ј- TCAGTGGCCCCAGCTTCCCCTGTT-3Ј (forward RESULTS primer) and 5Ј-TGTTCCTCAGTTCAGCTTCAA- GCCTGC-3Ј (reverse primer) for amplification of the CLINICAL FINDINGS 1A region and the primer pairs 5Ј-GGCAGGCTT- GAAGCTGAACTGAGGA-3Ј(forward primer) and 5Ј- The main complaint for 13 patients was easily pluck- GGAGACAAACTTGACGCTAGAACCA-3Ј (reverse able hair. The number of haircuts ranged from none from primer) for amplification of the 2B region. Polymer- birth to 1 every 2 months. Nine patients had thin, lus- ase chain reaction analysis was performed (Expand terless, and/or dry hair. Unmanageable hair was noted Long Template PCR System; Roche, Mannheim, in 4 patients; hair was described as being rough, messed Germany). The polymerase chain reaction condi- up, or hard to comb. It was more evident in the occipital tions consisted of incubation for 2 minutes at 94°C, region in 2 patients. Last, when noted, hair length was followed by 30 cycles for 10 seconds at 94°C, 30 sec- reported as short or variable. It did not exceed 20 cm. onds at 60°C, and 2 minutes at 68°C. Polymerase chain All children were in good health. Eyebrows and eye- reaction products were separated by agarose gel elec- trophoresis, purified using silica gel beads (Roche), and lashes were normal. Nails were normal, except for one sequenced directly according to a radiolabeled chain patient who had fragile nails. One patient had hypodon- terminator cycle-sequencing protocol (Thermo Se- tia, and lacked incisors and premolars (Table). quenase; Amersham Biosciences, Braunschweig, Ger- A trichogram was obtained in 16 patients accord- many) by using the gene-specific primers as sequencing to a routine technique of sampling hairs in 3 sites ing primers. (frontal, temporal, and occipital). Examination by light microscopy revealed a prevalence of dystrophic anagen hairs, and a low count of telogen hairs for 14 of the 16 patients (Table). These dystrophic anagen hairs were de- void of root sheaths, had a distorted bulb, and had a ta- age of the hair in the follicle. Unfortunately, the keratins pered end (Figure 1). For the 2 other patients, results expressed in the different layers of the IRS are not known. showed mostly normal anagen hairs. Nevertheless, dys- In contrast, the keratins expressed in the CL are known. trophic anagen hairs were still numerous (37.3% and The major keratin is the recently discovered type II cy- 19.3%, respectively) and clinical examination and pull tokeratin K6hf, which is exclusively expressed in the CL.6 test results were positive for LAHS. The other cytokeratins of the CL are keratin pairs, K6a/ The family history was positive for LAHS in 5 pa- K16 and K6b/K17.7 These keratin pairs are also ex- tients. Three of them had 1 adult relative (1 mother, 1 pressed in the outer root sheath and, therefore, muta- father, or 1 paternal aunt) who displayed clinical signs

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Figure 1. A, A typical trichogram showing almost only dystrophic anagen hairs. B, Detail showing ruffled cuticles and distorted bulbs.

of LAHS. The 2 other patients with a positive family his- I tory of LAHS (1 brother for one; a father, a brother, and 1 2 a sister for the other one, corresponding to family 7 de- Family 2 tailed in Figure 2) displayed, among normal or loose II anagen hairs, a special type of curly hairs. These were 1 2 shorter, hypopigmented, and easy to pluck, correspond- I ing to the clinical phenotype of diffuse partial woolly hair 1 2 (DPWH) (Figure 3). Family 3 II 1 2 INDIRECT IMMUNOFLUORESCENCE MICROSCOPY STUDIES I 1 2 Sections of a scalp biopsy specimen of a patient with Family 7 II LAHS (patient 2) were reacted with specific K6 and 1 2 3 K6hf antibodies. Figure 4 shows a near-longitudinal Figure 2. Pedigrees of families 2, 3, and 7 who are affected by loose anagen section in which the K6hf antibody decorated the entire hair syndrome. DNA samples were obtained from all individuals. Black CL. K6 was coexpressed with K6hf in the CL; however, symbols indicate clinically affected members of the families; gray symbols, this occurred only above the widening of the outer root individuals who are clinically not affected but carry the K6HF E337K mutation; and open symbols, individuals who are not clinically affected and sheath. At this level, the outer root sheath also started who do not carry the mutation. In family 7, diffuse partial woolly hair was to be positive for K6. The appearance of the CL is not diagnosed in I:1, II:1, II:2, and II:3. visibly different from that published previously for hair follicles of healthy individuals.6 of family 3. While the T→C mutation was silent, the G→A IDENTIFICATION OF A GLUTAMIC ACID mutation led to an E337K substitution in the K6HF mol- AND LYSINE MUTATION, E337K, ecule (Figure 5). Whereas both point mutations were IN THE L2 LINKER REGION OF K6HF clearly absent in clinically unaffected control individual I:1 of the family (sequence ladder a in Figure 5), the same The pedigrees of the 3 families positive for LAHS (fami- mutation pattern, including the silent T→C mutation, lies 2, 3, and 7) are shown in Figure 2. Analysis of the could be detected in clinically unaffected individuals I:2 region encoding the helix initiation motif of K6HF did and II:2 of family 3. The G→A point mutation affects the not reveal alterations from the reported sequence in af- fourth amino acid position (glutamic acid) of the short fected and unaffected members of the 9 families stud- L2 linker region, which spans from S334 to W341 of kera- ied. The primer pair used amplifies not only the helix ini- tin K6hf (Figure 5). Investigations in 50 healthy indi- tiation motif coding region but also considerable parts viduals did not reveal the presence of the T→Corthe coding for the head domain and the ␣-helical 1A subdo- G→A mutation in the K6HF gene (results not shown). main of K6HF. Except for some polymorphisms, these The results of subsequent analysis for the K6HF sequences were identical in all families. The same holds E337K mutation in the other families were completely true for the K6HF helix termination motif coding region negative for members of families 1, 4 to 6, 8, and 9. In contained in the approximately 9000–base pair polymer- contrast, in family 7, the G→A mutation and the result- ase chain reaction product obtained with primer pair 2 ing E337K substitution could clearly be detected in clini- (results not shown). However, successive sequence analy- cally affected individual I:2 and children II:1, II:2, and sis of the 9000–base pair segment, which spans from exon II:3. None of these individuals exhibited the silent T→C 2toexon9oftheK6HF gene, revealed a heterozygous point mutation observed in some members of family 3. G→A point mutation and an adjacent T→C mutation (se- In family 2, the K6HF E337K mutation was clearly quence ladder b in Figure 5) in affected individual II:1 present in affected individual II:2 and in the clinically

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Figure 3. A patient with partial diffuse woolly hair. A, Clinical features showing a mixture of curly and straight hairs. B, Polarizing microscopy: torsion of a hair shaft in a woolly hair.

unaffected father I:2. As expected, the mutation was ently normal straight hairs and abnormal curly hairs dif- absent from the unaffected mother I:1. It also clearly fusely intermingled. Some characteristics of LAHS and of was lacking in the child II:1. This child was first seen at DPWH are quite similar (age at onset, female predomi- the age of 12 months, with alopecia of the occipital nance, hair loss, thin hair, curly or unmanageable hair, and area, possibly due to the pillow. A trichogram was longitudinal grooves on microscopic examination). These obtained at the age of 3 years and showed many dystro- 2 diseases may, therefore, be somehow related. Further- phic anagen hairs (43%). However, the occipital alope- more, Sinclair et al8 recently noted a woolly hair appear- cia had completely regressed. Other signs of LAHS were ance for 21 of their 24 patients studied. totally absent (there was normal growth with regular Based on the pathological features of LAHS, we an- cuts, no easy plucking, no sparse hair, no patch of alo- ticipated that mutations in hair keratins should not be pecia, and a negative pull test result). The diagnosis of the cause for the syndrome. Indeed, mutation analyses LAHS was then excluded. of all known hair keratins of both types in the available families with LAHS did not reveal alterations of the gene COMMENT structure in affected individuals (results not shown). In view of the cleavage zone between the IRS and the hair Loose anagen hair syndrome may not be as rare as has shaft in the hair follicles of persons with LAHS, we specu- been thought. Sinclair et al,8 in a large series of 43 lated that mutations in keratins expressed in the IRS might patients, estimated the incidence to be 2 to 2.25 cases be responsible for the observed defect. Unfortunately, ker- per million per year. The clinical presentation of chil- atins expressed in the IRS are not yet known. In con- dren in our series is similar to that of other cases trast, in the apposed CL, connected via desmosomal junc- reported in the literature.4,5,8-20 The children have slow- tions with the Henle layer of the IRS, a specific keratin, growing hair that seldom requires cutting.4,5,8-19,21,22 Par- K6hf, has recently been described.6 Indeed, mutation ents may also be worried by the patients’ diffuse hair analysis of the K6HF gene revealed a G→A substitution loss or localized patches of alopecia.4,5,8-16,19,22,23 They in the region coding for the L2 linker of the rod domain may have easily pluckable hair, although this sign is not of K6HF, leading to a replacement of glutamic acid resi- 9,10,12-15,19,21,23 always obvious. However, as in our series, due 337 by lysine in 3 of the 9 families analyzed. Up to the pull test result is usually positive, with more than now, keratin mutations in linker regions, causative for 50% of dystrophic anagen hairs per pull in pediatric epidermal genodermatoses, ie, the Weber-Cockayne syn- cases of LAHS. The presence of loose anagen hairs in drome type epidermolysis bullosa, have only been re- children on a gentle hair pull is not diagnostic of LAHS ported for linker L1/2.28 However, because recent inves- when 1 to 2 dystrophic anagens per hair pull are tigations emphasized the importance of the highly 20 found. Additional findings include thin, dry, luster- conserved linker L2 for the correct axial alignment of kera- 8,9,12,13,17-19 less,* or unmanageable hair, with the occipital tin molecules,29 mutations in this non–␣-helicoidal part area being the most frequently affected region. Some- of the K6HF rod domain may also affect intermediate fila- 5,11 8 times, hair is also reported as sticky or tacky. ment assembly. Because our immunofluorescence stud- Loose hair anagen syndrome may be an inherited con- ies did not reveal discernible alterations of the CL in the dition. The pattern of affected family members seems to 5,8-10,21,24 follicles of those with LAHS, it might be that, unlike mu- be that of an autosomal dominant inheritance. In tations in the helix initiation or termination motif of the our series, 5 children had 1 or more affected family mem- rod domain of keratins, the observed L2 mutation does bers. For 3 of them, relatives displayed clinical character- not lead to a visible breakdown of the intermediate fila- istics of LAHS. For the 2 others, family members had hairs 25-27 ment network, but rather to a general destabilization of of the DPWH type. The anomaly comprises appar- the latter. Based on molecular studies, a dominant inherit- *References 4, 9, 10, 12-14, 16, 18, 19, 21-23. ance of LAHS was confirmed in the 3 families in whom

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 3' C A Y342 a b T G ACGT ACGT G W341 T C C S340 T G A E339 ORSsb G T C A338 G G A E337K G or A C or T C A336 b ORS G G G R335 C C G S334 A C G R333 C C co A N332 cl A 5'

Figure 5. Mutation analysis of the type II keratin K6HF gene in family 3, affected by loose anagen hair syndrome. Excerpts from DNA sequencing gels show K6HF sequences from either unaffected individual I:1 (a) or affected individual II:1 (b). The affected individual is heterozygous for a silent C→T transition (solid arrow) and an adjacent G→A transition (open arrow), which leads to a E337K substitution in the L2 linker region of K6HF (amino acid residues S334 through W341).

ciated DPWH. This could be due to a variable pen- etrance of the condition. Another explanation could be provided, for the father of family 3 only, by the natural improvement of LAHS. When comparing phenotypically tested patients according to the presence or absence of the E337K mutation of K6HF, characteristics were not different (age at onset, hair growth, positive family history of LAHS, association with the DPWH phenotype, and trichogram results). An- other gene may, therefore, be implicated in the patients dp who tested negative for the mutation. Because the type I partner of K6hf is still unknown, we restricted our muta- Figure 4. Expression studies of K6hf and K6 in a follicle with loose anagen tion analysis to the K6HF gene. Another explanation could hair syndrome (LAHS). A near-longitudinal section of a follicle with LAHS be provided by the coexistence of major and minor genes. was reacted with an antibody against K6hf (red) and K6 (green), as The K6HF gene involved may be one of the minor ones, described by Winter et al.6 ORSsb indicates outer root sheath, suprabasal; the major one yet to be discovered. ORSb, outer root sheath, basal; cl, companion layer; co, cortex; and dp, dermal papilla. Loose anagen hair syndrome is a recently described hair disease, well defined by its clinical findings and trichogram characteristics. The results in our series of 17 pedi- the mutation was found, because both children and fa- atric patients are similar to other findings in the litera- thers bore the mutation. However, father I:2 and child ture. Other hair disorders, such as DPWH, may be II:2 in family 3 seemed clinically unaffected. In family associated with LAHS, or even linked in a yet unknown 7, in which the association of LAHS and DPWH was found manner. Future case reports may confirm our findings. Our in propositus II:1, the father (I:2) had DPWH and the experience with minoxidil therapy is encouraging, but other children (II:2 and II:3) had mild LAHS and asso- needs to be confirmed in a controlled trial. We have, for

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 the first time to our knowledge, authenticated a keratin 9. Baden HP, Kvedar JC, Magro CM. Loose anagen hair as a cause of hereditary mutation, E337K in K6HF, in patients with LAHS, which hair loss in children. Arch Dermatol. 1992;128:1349-1353. 10. Tosti A, Peluso AM, Misciali C, Venturo N, Patrizi A, Fanti PA. Loose anagen hair. is possibly causative for this syndrome in 3 of the 9 fami- Arch Dermatol. 1997;133:1089-1093. lies studied. It remains to be seen if another keratin, and 11. Thomas L, Robart S, Balme B, Moulin G. Syndrome des cheveux anage`nes ca- possibly the type I partner of K6hf, is responsible for LAHS ducs. Ann Dermatol Venereol. 1993;120:535-537. in other patients or if the gene involved is a minor gene, 12. Pride HB, Tunnessen WW Jr. Picture of the month: loose anagen syndrome. 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