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 treat- ment 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 Sdomly 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- (REPRINTED) ARCH DERMATOL / VOL 138, APR 2002 WWW.ARCHDERMATOL.COM 501 ©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 rela- tives, 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 polymer- ase 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 sequenc- ing 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 (REPRINTED) ARCH DERMATOL / VOL 138, APR 2002 WWW.ARCHDERMATOL.COM 502 ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 A B 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.