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Medical genetics Two cases of autosomal recessive woolly hair with LIPH gene mutations Kazutoshi Harada 1 , MD, Takashi Inozume 1 , MD, Tatsuyoshi Kawamura 1 , MD, Naotaka Shibagaki 1 , MD, Tomoko Kinoshita 2 , MD, Nobuhiro Deguchi 3 , MD, and Shinji Shimada 1 , MD 1 Department of Dermatology, Faculty of Medicine, University of Yamanashi, Chuo-shi, 2 Enzan Skin Clinic, Kohshu-shi, and 3 Department of Dermatology, Yamanashi Kosei Hospital, Yamanashi-shi, Japan Corresspondence Dr Kazutoshi Harada, MD 1110 Shimokato Chuo-shi Yamanashi 409-3898 Japan E-mail: [email protected] Conflict of Interest: None. Abstract Background Woolly hair is a hereditary disorder characterized by fine and tightly curled hair. Autosomal recessive woolly hair (ARWH) was recently determined to result from mutations in either the lipase H (LIPH) or the LPAR6 (P2RY5) gene. Case report An 8-year-old boy (proband) and his 11-year-old brother presented with tightly coiled and sparse scalp hair. The boys did not have cardiomyopathy, palmoplantar keratoderma, or facial dysmorphism. Their parents had normal hair growth and no woolly hair. The sequence analysis of their genomic DNA revealed that the proband and his brother had a homozygous mutation of c.736T > A in the LIPH gene. On the basis of these findings, these patients were diagnosed with ARWH. Conclusions To the best of our knowledge, only 20 cases of ARWH have been previously reported in Japan. However, several reports showed that one mutation was detected in the 4/200 normal and unrelated alleles in healthy Japanese control individuals, indicating the presence of ARWH in patients with extremely mild symptoms. Introduction Woolly hair is a hereditary disorder characterized by fine and tightly curled hair. Woolly hair occurs with or with- out other physical findings or syndromes. 1 It has recently been reported that mutations in either lipase H (LIPH) or LPAR6 (P2RY5) genes underlie non-syndromic forms of autosomal recessive woolly hair (ARWH: MIM no. 278150) with or without hypotrichosis. 24 Herein, we describe a case of Japanese siblings with ARWH associated with LIPH gene mutations. Case report An 8-year-old boy (proband) and his 11-year-old brother, both showing sparse and woolly hair, were referred to our clinic. Clinical examination showed that their scalp hair was tightly coiled and sparse (Fig. 1a). The proband’s clinical symptoms were more severe than his brother’s (Fig. 1b). Their hair grew slowly and only several inches. Eyebrow hair was slightly reduced, while eyelashes, nails (Fig. 1c), and teeth (Fig. 1d) were normal. They had never experienced anhidrosis. Clinical manifestations, including cardiomyopathy, palmoplantar keratoderma, and facial dysmorphism, were absent. Although preg- nancy and birth were normal and no abnormal clinical finding was observed at birth, their woolly hair became apparent postnatally. Their parents had normal hair growth and no woolly hair (Fig. 2). There was no family history of consanguineous marriages, sparse/coiled hair, cancer, heart disease, or neurological disorders. On the basis of these findings, these patients were diagnosed as having ARWH. Recently, causative genes of ARWH, namely LIPH and LPAR6 (P2RY5), have been identi- fied. 5 To date, LIPH mutations have been identified in more than 20 Japanese patients with ARWH. 6 Therefore, we searched for mutations in LIPH in these patients. This examination was approved by the ethics committee of the University of Yamanashi. Peripheral blood samples were collected from the boys and their parents after obtaining informed consent. Genomic DNA was extracted, and all exons and adjacent exonintron boundaries of LIPH were amplified by polymerase chain reaction using gene-specific primers. 7 We performed direct sequence analyses of the amplified DNA. As shown in Figure 3, the same missense mutation (c.736T > A, p.Cys246Ser) was detected homozygously in our patients and heterozygously in their parents. International Journal of Dermatology 2013, 52, 572–574 ª 2013 The International Society of Dermatology 572

Two cases of autosomal recessive woolly hair with LIPH gene mutations

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Page 1: Two cases of autosomal recessive woolly hair with               LIPH               gene mutations

Medical genetics

Two cases of autosomal recessive woolly hair with LIPH

gene mutations

Kazutoshi Harada1, MD, Takashi Inozume1, MD, Tatsuyoshi Kawamura1, MD,Naotaka Shibagaki1, MD, Tomoko Kinoshita2, MD, Nobuhiro Deguchi3, MD, andShinji Shimada1, MD

1Department of Dermatology, Faculty of

Medicine, University of Yamanashi,

Chuo-shi, 2Enzan Skin Clinic, Kohshu-shi,

and 3Department of Dermatology,

Yamanashi Kosei Hospital, Yamanashi-shi,

Japan

Corresspondence

Dr Kazutoshi Harada, MD

1110 Shimokato

Chuo-shi

Yamanashi 409-3898

Japan

E-mail: [email protected]

Conflict of Interest: None.

Abstract

Background Woolly hair is a hereditary disorder characterized by fine and tightly curled

hair. Autosomal recessive woolly hair (ARWH) was recently determined to result from

mutations in either the lipase H (LIPH) or the LPAR6 (P2RY5) gene.

Case report An 8-year-old boy (proband) and his 11-year-old brother presented with tightly

coiled and sparse scalp hair. The boys did not have cardiomyopathy, palmoplantar

keratoderma, or facial dysmorphism. Their parents had normal hair growth and no woolly

hair. The sequence analysis of their genomic DNA revealed that the proband and his

brother had a homozygous mutation of c.736T > A in the LIPH gene. On the basis of

these findings, these patients were diagnosed with ARWH.

Conclusions To the best of our knowledge, only 20 cases of ARWH have been previously

reported in Japan. However, several reports showed that one mutation was detected in the

4/200 normal and unrelated alleles in healthy Japanese control individuals, indicating the

presence of ARWH in patients with extremely mild symptoms.

Introduction

Woolly hair is a hereditary disorder characterized by fineand tightly curled hair. Woolly hair occurs with or with-out other physical findings or syndromes.1 It has recentlybeen reported that mutations in either lipase H (LIPH) orLPAR6 (P2RY5) genes underlie non-syndromic forms ofautosomal recessive woolly hair (ARWH: MIM no.278150) with or without hypotrichosis.2–4 Herein,we describe a case of Japanese siblings with ARWHassociated with LIPH gene mutations.

Case report

An 8-year-old boy (proband) and his 11-year-old brother,both showing sparse and woolly hair, were referred toour clinic. Clinical examination showed that their scalphair was tightly coiled and sparse (Fig. 1a). The proband’sclinical symptoms were more severe than his brother’s(Fig. 1b). Their hair grew slowly and only several inches.Eyebrow hair was slightly reduced, while eyelashes, nails(Fig. 1c), and teeth (Fig. 1d) were normal. They hadnever experienced anhidrosis. Clinical manifestations,including cardiomyopathy, palmoplantar keratoderma,

and facial dysmorphism, were absent. Although preg-nancy and birth were normal and no abnormal clinicalfinding was observed at birth, their woolly hair becameapparent postnatally. Their parents had normal hairgrowth and no woolly hair (Fig. 2). There was no familyhistory of consanguineous marriages, sparse/coiled hair,cancer, heart disease, or neurological disorders. On thebasis of these findings, these patients were diagnosed ashaving ARWH. Recently, causative genes of ARWH,namely LIPH and LPAR6 (P2RY5), have been identi-fied.5 To date, LIPH mutations have been identified inmore than 20 Japanese patients with ARWH.6 Therefore,we searched for mutations in LIPH in these patients. Thisexamination was approved by the ethics committee of theUniversity of Yamanashi. Peripheral blood samples werecollected from the boys and their parents after obtaininginformed consent. Genomic DNA was extracted, and allexons and adjacent exon–intron boundaries of LIPH wereamplified by polymerase chain reaction using gene-specificprimers.7 We performed direct sequence analyses of theamplified DNA. As shown in Figure 3, the same missensemutation (c.736T > A, p.Cys246Ser) was detectedhomozygously in our patients and heterozygously in theirparents.

International Journal of Dermatology 2013, 52, 572–574 ª 2013 The International Society of Dermatology

572

Page 2: Two cases of autosomal recessive woolly hair with               LIPH               gene mutations

Discussion

Recent genetic studies have revealed that LIPH andLPAR6 mutations are responsible for ARWH.2–4 LIPH

gene encodes membrane-associated phosphatidic acid-preferring phospholipaseA1a. This enzyme associates withthe cell membrane and hydrolyzes phosphatidic acid,

which is a major constituent of cell membranes and pro-duces 2-acyl-lysophosphatidic acid, which is a ligand forthe G-protein-coupled receptor P2Y5 (LPA6) encoded byLPAR6 gene.8 These findings indicate that the phospholi-paseA1a-lysophosphatidic acid-P2Y5 axis regulates thedifferentiation and maturation of hair follicles. Shinkumaet al. also demonstrated that a p.Cys246Ser-phospho-lipase A1a mutant, which is identical to the cases reportedhere, showed complete abolition of hydrolytic activityand no P2Y5 activation ability.5 Moreover, phospho-lipase A1a-deficient mice, produced by gene-targetingtechnology, showed wavy hair owing to the aberrant for-mation of the inner root sheath of hair follicles.8 Morethan 10 different LIPH mutations have been reportedworldwide, with no clear genotype–phenotype correla-tions. The c.736T > A (p.C246S) and c.742C > A(p.H248N) mutations are highly specific and common inJapanese patients, including our cases.6 Interestingly, theARWH phenotype severity varied among individualswithin a single family. Consistently, the phenotype of ourproband was more severe than his brother’s. Only 20cases have been previously reported in Japan. However,Shinkuma et al. reported that one mutation was found in4/200 normal and unrelated alleles in healthy Japanesecontrol individuals, suggesting that about one in 10,000babies in Japan are born with ARWH.6 Further clinicalinvestigations may identify patients with ARWH withextremely mild phenotypes who cannot be distinguishedfrom normal persons.

(a) (b)

(c) (d)

Figure 1 Tightly coiled and sparse hair was observed in an8-year-old boy (proband) (a) and his 11-year-old brother (b).The clinical symptoms of the proband were more severe thanthat of his brother’s. Their nails (c) and teeth (d) werecompletely normal

Figure 2 Pedigree of the family including the affected siblings

Figure 3 The LIPH gene 736T>A transition that causes theamino acid change of C246S was detected homozygously inthe patients and heterozygously in their parents

ª 2013 The International Society of Dermatology International Journal of Dermatology 2013, 52, 572–574

Harada et al. Two cases of ARWH Medical genetics 573

Page 3: Two cases of autosomal recessive woolly hair with               LIPH               gene mutations

References

1 Chien AJ, Valentine MC, Sybert VP. Hereditary woollyhair and keratosis pilaris. J Am Acad Dermatol 2006; 54:S35–S39.

2 Kazantseva A, Goltsov A, Zinchenko R, et al. Human hairgrowth deficiency is linked to a genetic defect in thephospholipase gene LIPH. Science 2006; 314: 982–985.

3 Shimomura Y, Wajid M, Ishii Y, et al. Disruption ofP2RY5, an orphan G protein-coupled receptor, underliesautosomal recessive woolly hair. Nat Genet 2008; 40:335–339.

4 Pasternack SM, von Kugelgen I, Aboud KA, et al. Gprotein-coupled receptor P2Y5 and its ligand LPA areinvolved in maintenance of human hair growth. Nat Genet

2008; 40: 329–334.

5 Shinkuma S, Akiyama M, Inoue A, et al. Prevalent LIPHfounder mutations lead to loss of P2Y5 activation abilityof PA-PLA1alpha in autosomal recessive hypotrichosis.Hum Mutat 2010; 31: 602–610.

6 Shimomura Y. Congenital hair loss disorders: rare, but nottoo rare. J Dermatol 2011; 39: 3–10.

7 Shimomura Y, Wajid M, Petukhova L, et al. Mutations inthe lipase H gene underlie autosomal recessive woolly hair/hypotrichosis. J Invest Dermatol 2009; 129: 622–628.

8 Inoue A, Arima N, Ishiguro J, et al. LPA-producingenzyme PA-PLAalpha regulates hair follicle developmentby modulating EGFR signalling. EMBO J 2011; 30: 4248–4260.

International Journal of Dermatology 2013, 52, 572–574 ª 2013 The International Society of Dermatology

Medical genetics Two cases of ARWH Harada et al.574