156
Letters to the Editor / Journal of Dermatological Science 78 (2015) 149–164
Letter to the Editor Two Japanese familial cases of punctate palmoplantar keratoderma caused by a novel AAGAB mutation, c.191_194delCAAA
Keywords: Palmoplantar keratoderma; Punctate; AAGAB; Etretinate; Bleomycin; Japanese
Punctate palmoplantar keratoderma type 1 (PPPK1, OMIN 148600), also known as Buschke–Fischer–Brauer syndrome, is an autosomal dominant disorder characterized by multiple discrete hyperkeratotic lesions on the palms and soles that usually start in adolescence. Lesions increase in size and number with advancing age, and coalesce to form diffuse, painful hyperkeratotic plaques on
the pressure-bearing areas of the plantar skin [1,2]. Recently, two consecutive studies identified that PPPK1 was caused by mutations in the AAGAB gene, encoding alpha- and gamma-adaptin binding protein p34 (p34) [1,2]. Subsequently, several AAGAB mutations were reported in PPPK1 families from Europe, the Middle East, and Asia [1–8]. Here, we describe two Japanese PPPK1 pedigrees harboring the same, novel AAGAB mutation. This work was conducted in accordance with the Declaration of Helsinki principles. Blood samples were collected after obtaining written informed consent, and DNA was extracted using standard protocols with QIAamp DNA Blood Maxi Kit (QIAGEN). Polymerase chain reaction amplification and Sanger sequencing were performed to screen all exons and exon/intron boundaries of the AAGAB gene, as described previously [1]. In family 1, proband 1 is a 49-year-old Japanese female who was referred to our department with a 5-year history of progressive development of tender callosities on her soles. Physical examination revealed multiple tiny hyperkeratotic lesions on her palms (Fig. 1A), and diffuse hyperkeratosis on the weight-bearing areas of her soles (Fig. 1B). Central depressions characteristic of PPPK1 were also observed on her palms. The proband’s mother and
Fig. 1. Clinical manifestations of the palms (A) and soles (B) of proband 1. Family tree of pedigree 1 (C); the arrow indicates the proband. Genomic DNA sequence of wild-type (D) and mutant alleles (E) of exon 2 in AAGAB. The arrow indicates initiation of the frameshift.
Letters to the Editor / Journal of Dermatological Science 78 (2015) 149–164
157
Fig. 2. Clinical manifestations of the palms (A) and soles (B) of proband 2. Family tree of pedigree 2 (C); the arrow indicates the proband. Histopathological findings of a skin biopsy specimen obtained from tiny hyperkeratotic plaques on the proband’s sole (D). Clinical manifestations of the left palm of proband 2 before starting the treatment (E) and 6 months after initiation of oral etretinate and intralesional injection of bleomycin therapy (F).
daughter displayed similar lesions on their palms and soles (Fig. 1C). Histological examination of a biopsy specimen from the proband’s right sole revealed a markedly thickened stratum corneum with compact orthokeratosis and thickening of the stratum granulosum. Direct sequencing identified an unreported heterozygous 4-base pair deletion in exon 2 of AAGAB, c.191_194delCAAA, resulting in a premature-termination codon (p.Lys66Phefs*43) within proband 1 (Fig. 1D and E). This mutation was detected in neither of the unaffected family members nor in 100 ethnically matched control individuals. Topical ointment of 10% salicylic acid and urea were not effective. Although we began a treatment of oral etretinate (0.5 mg kg1 day1), it had to be discontinued owing to gastrointestinal side effects. In family 2, proband 2 is a 45-year-old Japanese male who suffered from multiple hyperkeratotic lesions of the palmoplantar skin for 15 years. Physical examination revealed multiple tiny hyperkeratotic lesions distributed on the palmoplantar regions (Fig. 2A). Some of the papules were coalesced to form larger hyperkeratotic plaques in the weight-bearing regions of his soles (Fig. 2B). His father was also similarly affected by hyperkeratotic lesions (Fig. 2C). Histopathology of the papules sampled from the left palm showed compact hyperkeratosis with a discrete central epidermal depression and a reduced granular layer (Fig. 2D). The same deletion c.191_194delCAAA mutation that was identified in proband 1 was detected in proband 2 (Fig. 1D and E). Forty milligrams per day of oral etretinate and topical injection of bleomycin to the large plaques markedly ameliorated the palmar hyperkeratotic lesions in proband 2 within 6 months (Fig. 2E and F). AAGAB encodes p34, a 315-amino acid cytosolic protein. Although the function of p34 is not fully elucidated, it contains a Rab-like GTPase domain; therefore, it might play a pivotal role as a chaperone in clathrin-coated vesicle trafficking [1,2]. Pohler et al. reported that knockdown of p34 in HaCaT cells led to increased cell division, which was linked to elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation, and they hypothesized that p34 deficiency may impair endocytic recycling of EGFR, leading to increased signaling and cellular proliferation [4]. In addition, Giehl et al. demonstrated that
granular staining of p34 was widely reduced in the skin of affected individuals, and they speculated that p34 plays an important role in skin integrity [2]. To our knowledge, 27 distinct AAGAB mutations were previously reported in familial and sporadic cases of PPPK1, including 11 deletion, nine nonsense, three splice site, three insertion, and one insertion–deletion mutation [1–8]. All of these were heterozygous loss-of-function mutations except for one splice-site mutation, c.451 + 1G > A, leading to an in-frame deletion that is expected to result in the loss of 30 amino acids in p34, corresponding to the entire exon 4 in AAGAB [5]. In this study, we reported a novel deletion mutation, c.191_194delCAAA, in exon 2 of the AAGAB gene in two unrelated Japanese pedigrees. Two AAGAB mutations have been detected previously in Japanese PPPK1 families to date [1,7]. Therefore, the mutation identified in the present cases might be a recurrent mutation in the Japanese population. There are several case reports describing the successful treatment of PPK1 with etretinate or acitretin, and chemotherapeutic agents [7,9,10]. Our case report provides further evidence that administration of a systemic retinoid is an effective therapeutic option for treating PPPK1. In addition, this is the first case report demonstrating that local injection of bleomycin effectively resolved PPPK1 lesions. Intralesional injection of bleomycin is generally used in therapy for some types of cancers, benign tumors, keloid and hypertrophic scars, lymphangiomas, and recalcitrant warts in the dermatological field. Bleomycin is a glycopeptide antibiotic used as an anticancer agent. It acts by induction of DNA strands break and suppresses cell proliferation. In PPPK1, bleomycin might attenuate hyperkeratosis by reducing proliferation of basal keratinocytes. Even though careful management is necessary to prevent serious adverse effects of bleomycin, including interstitial pneumonia and lung fibrosis, intralesional bleomycin injection can be considered as a therapeutic option for PPPK1. In conclusion, we report two unrelated Japanese PPPK1 pedigrees harboring the novel AAGAB mutation c.191_194delCAAA. Our study will enrich the database of AAGAB mutations and contribute to improving the genetic diagnosis of PPPK1. In addition, we suggest efficient oral etretinate and local injection
158
Letters to the Editor / Journal of Dermatological Science 78 (2015) 149–164
of bleomycin as therapeutic options for PPPK1. Including our study, there are few reports describing therapy for PPPK1; therefore, analysis of more cases will aid in improving the understanding of PPPK1 pathogenesis, which will, in turn, help in the development of an effective treatment of this intractable disease.
[6]
[7]
Acknowledgment
[8]
This work was supported by a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science, No. 30436034.
[9]
[10]
palmoplantar keratoderma and congenital dysplasia of the hip in a large family. Clin Exp Dermatol 2014;39:182–6. Furniss M, Higgins CA, Martinez-Mir A, Horev L, Petukhova L, Stanimirovic´ A, et al. Identification of distinct mutations in AAGAB in families with type 1 punctate palmoplantar keratoderma. J Invest Dermatol 2014;134:1749–52. Nomura T, Yoneta A, Pohler E, Suzuki S, Osawa R, Mizuno O, et al. Punctate palmoplantar keratoderma type 1: a novel AAGAB mutation and efficacy of etretinate. Acta Derm Venereol 2014. http://dx.doi.org/10.2340/00015555-1832. Pohler E, Huber M, Boonen SE, Zamiri M, Gregersen PA, Sommerlund M, et al. New and recurrent AAGAB mutations in punctate palmoplantar keratoderma. Br J Dermatol 2014;171:433–6. Erkek E, Erdogan S, Tuncez F, Kurtipek GS, Bagci Y, Ozoguz P, et al. Type I hereditary punctate keratoderma associated with widespread lentigo simplex and successfully treated with low-dose oral acitretin. Arch Dermatol 2006;142:1076–7. Lienemann AO, Colucci VJ, Jones MS, Trauscht JM. Treatment of palmoplantar keratoderma with continuous infusion 5-fluorouracil. Cutis 2004;73: 303–308.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jdermsci.2015. 02.004. References [1] Pohler E, Mamai O, Hirst J, Zamiri M, Horn H, Nomura T, et al. Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nat Genet 2012;44:1272–8. [2] Giehl KA, Eckstein GN, Pasternack SM, Praetzel-Wunder S, Ruzicka T, Lichtner P, et al. Nonsense mutation in AAGAB cause punctuate palmoplantar keratoderma type Buschke–Fischer–Brauer. Am J Hum Genet 2012;91:754–9. [3] Cui H, Gao M, Wang W, Xiao R, Chen G, Zhang Q, et al. Six mutations in AAGAB confirm its pathogenic role in Chinese punctuate palomoplantar keratoderma patients. J Invest Dermatol 2013;133:2631–4. [4] Po¨hler E, Zamiri M, Harkins CP, Salas-Alanis JC, Perkins W, Smith FJ, et al. Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling. J Invest Dermatol 2013;113:2805–8. [5] Eytan O, Sarig O, Israeli S, Mevorah B, Basel-Vanagaite L, Sprecher E. A novel splice-site mutation in the AAGAB gene segregates with hereditary punctate
Eijiro Akasakaa,1, Yuko Okawab,1, Hajime Nakanoa,*, Noriko Takiyoshia, Daiki Rokunohea, Yuka Toyomakia, Daisuke. Sawamuraa, Hirohiko Suekic a Department of Dermatology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; bDivision of Dermatology, Showa University Northern Yokohama Hospital, Yokohama, Japan; c Department of Dermatology, Showa University Graduate School of Medicine, Tokyo, Japan *Corresponding author. Tel.: +81 172 39 5087; fax: +81 172 37 6060 E-mail address: [email protected] (H. Nakano). 1
These authors contributed equally to the work.
Received 9 December 2014 http://dx.doi.org/10.1016/j.jdermsci.2015.02.004
Letter to the Editor Ichthyosis and Kallmann syndrome: Not always a contiguous gene syndrome To the Editor, Ichthyoses comprise a heterogeneous group of genetic disorders of cornification characterized by scaling of the skin, which can be either isolated or syndromic. Mutations in more than 30 different genetic loci have been associated to this condition showing both autosomal (dominant and recessive) or X-linked patterns of inheritance. Common forms of ichthyosis include the autosomal semidominant ichthyosis vulgaris (MIM#146700), which is caused by mutations of the filaggrin gene on 1q21.3, and the X-linked recessive ichthyosis (XLI) (MIM#308100) that is due to mutations of the STS gene on Xp22.31 encoding steroid sulphatase [1]. Kallmann syndrome (KS) is a genetically heterogeneous disease characterized by hypogonadotropic hypogonadism, anosmia or hyposmia and a variable association of other non-reproductive findings, including unilateral renal agenesis. KS occurs in both sporadic and inherited forms showing different modes of transmission, namely the X-linked form (MIM# #308700) which is caused by mutations in the KAL1 gene on Xp22.31, but also autosomal dominant forms, recessive monogenic or digenic/oligogenic conditions [2]. A number of patients manifest both KS and XLI as a consequence of a contiguous gene syndrome characterized by large deletions in the Xp22.3 region leading to the loss of neighbouring genes, §
Funding: This research was supported by the Italian Ministry of Health grant no GR-2009-1578914 and by a grant from Fondazione CARIPARO.
including both KAL1 and the locus encoding the steroid sulphatase that is about 1.2 Mb apart [3,4]. Here we report a boy with this peculiar phenotype who did not present with the classical deletion but instead harboured two distinct mutations in KAL1 and STS. The patient was referred to our clinic at 9 years of age because of ichthyosis, left kidney agenesis and hypogonadotropic hypogonadism. Close examination of the patient’s family history revealed an apparently X-linked pattern of ichthyosis with three affected male relatives of the mother (her father, her paternal uncle and a first cousin once-removed) (Fig. 1). At birth generalized ichthyosis
Fig. 1. Pedigree of the three-generation family, showing the propositus (indicated by the arrow) affected by ichthyosis and Kallmann syndrome and the three male relatives affected by ichthyosis. The patient was born to non-consanguineous parents.
Letters to the Editor / Journal of Dermatological Science 78 (2015) 149–164
Letter to the Editor Two Japanese familial cases of punctate palmoplantar keratoderma caused by a novel AAGAB mutation, c.191_194delCAAA
Keywords: Palmoplantar keratoderma; Punctate; AAGAB; Etretinate; Bleomycin; Japanese
Punctate palmoplantar keratoderma type 1 (PPPK1, OMIN 148600), also known as Buschke–Fischer–Brauer syndrome, is an autosomal dominant disorder characterized by multiple discrete hyperkeratotic lesions on the palms and soles that usually start in adolescence. Lesions increase in size and number with advancing age, and coalesce to form diffuse, painful hyperkeratotic plaques on
the pressure-bearing areas of the plantar skin [1,2]. Recently, two consecutive studies identified that PPPK1 was caused by mutations in the AAGAB gene, encoding alpha- and gamma-adaptin binding protein p34 (p34) [1,2]. Subsequently, several AAGAB mutations were reported in PPPK1 families from Europe, the Middle East, and Asia [1–8]. Here, we describe two Japanese PPPK1 pedigrees harboring the same, novel AAGAB mutation. This work was conducted in accordance with the Declaration of Helsinki principles. Blood samples were collected after obtaining written informed consent, and DNA was extracted using standard protocols with QIAamp DNA Blood Maxi Kit (QIAGEN). Polymerase chain reaction amplification and Sanger sequencing were performed to screen all exons and exon/intron boundaries of the AAGAB gene, as described previously [1]. In family 1, proband 1 is a 49-year-old Japanese female who was referred to our department with a 5-year history of progressive development of tender callosities on her soles. Physical examination revealed multiple tiny hyperkeratotic lesions on her palms (Fig. 1A), and diffuse hyperkeratosis on the weight-bearing areas of her soles (Fig. 1B). Central depressions characteristic of PPPK1 were also observed on her palms. The proband’s mother and
Fig. 1. Clinical manifestations of the palms (A) and soles (B) of proband 1. Family tree of pedigree 1 (C); the arrow indicates the proband. Genomic DNA sequence of wild-type (D) and mutant alleles (E) of exon 2 in AAGAB. The arrow indicates initiation of the frameshift.
Letters to the Editor / Journal of Dermatological Science 78 (2015) 149–164
157
Fig. 2. Clinical manifestations of the palms (A) and soles (B) of proband 2. Family tree of pedigree 2 (C); the arrow indicates the proband. Histopathological findings of a skin biopsy specimen obtained from tiny hyperkeratotic plaques on the proband’s sole (D). Clinical manifestations of the left palm of proband 2 before starting the treatment (E) and 6 months after initiation of oral etretinate and intralesional injection of bleomycin therapy (F).
daughter displayed similar lesions on their palms and soles (Fig. 1C). Histological examination of a biopsy specimen from the proband’s right sole revealed a markedly thickened stratum corneum with compact orthokeratosis and thickening of the stratum granulosum. Direct sequencing identified an unreported heterozygous 4-base pair deletion in exon 2 of AAGAB, c.191_194delCAAA, resulting in a premature-termination codon (p.Lys66Phefs*43) within proband 1 (Fig. 1D and E). This mutation was detected in neither of the unaffected family members nor in 100 ethnically matched control individuals. Topical ointment of 10% salicylic acid and urea were not effective. Although we began a treatment of oral etretinate (0.5 mg kg1 day1), it had to be discontinued owing to gastrointestinal side effects. In family 2, proband 2 is a 45-year-old Japanese male who suffered from multiple hyperkeratotic lesions of the palmoplantar skin for 15 years. Physical examination revealed multiple tiny hyperkeratotic lesions distributed on the palmoplantar regions (Fig. 2A). Some of the papules were coalesced to form larger hyperkeratotic plaques in the weight-bearing regions of his soles (Fig. 2B). His father was also similarly affected by hyperkeratotic lesions (Fig. 2C). Histopathology of the papules sampled from the left palm showed compact hyperkeratosis with a discrete central epidermal depression and a reduced granular layer (Fig. 2D). The same deletion c.191_194delCAAA mutation that was identified in proband 1 was detected in proband 2 (Fig. 1D and E). Forty milligrams per day of oral etretinate and topical injection of bleomycin to the large plaques markedly ameliorated the palmar hyperkeratotic lesions in proband 2 within 6 months (Fig. 2E and F). AAGAB encodes p34, a 315-amino acid cytosolic protein. Although the function of p34 is not fully elucidated, it contains a Rab-like GTPase domain; therefore, it might play a pivotal role as a chaperone in clathrin-coated vesicle trafficking [1,2]. Pohler et al. reported that knockdown of p34 in HaCaT cells led to increased cell division, which was linked to elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation, and they hypothesized that p34 deficiency may impair endocytic recycling of EGFR, leading to increased signaling and cellular proliferation [4]. In addition, Giehl et al. demonstrated that
granular staining of p34 was widely reduced in the skin of affected individuals, and they speculated that p34 plays an important role in skin integrity [2]. To our knowledge, 27 distinct AAGAB mutations were previously reported in familial and sporadic cases of PPPK1, including 11 deletion, nine nonsense, three splice site, three insertion, and one insertion–deletion mutation [1–8]. All of these were heterozygous loss-of-function mutations except for one splice-site mutation, c.451 + 1G > A, leading to an in-frame deletion that is expected to result in the loss of 30 amino acids in p34, corresponding to the entire exon 4 in AAGAB [5]. In this study, we reported a novel deletion mutation, c.191_194delCAAA, in exon 2 of the AAGAB gene in two unrelated Japanese pedigrees. Two AAGAB mutations have been detected previously in Japanese PPPK1 families to date [1,7]. Therefore, the mutation identified in the present cases might be a recurrent mutation in the Japanese population. There are several case reports describing the successful treatment of PPK1 with etretinate or acitretin, and chemotherapeutic agents [7,9,10]. Our case report provides further evidence that administration of a systemic retinoid is an effective therapeutic option for treating PPPK1. In addition, this is the first case report demonstrating that local injection of bleomycin effectively resolved PPPK1 lesions. Intralesional injection of bleomycin is generally used in therapy for some types of cancers, benign tumors, keloid and hypertrophic scars, lymphangiomas, and recalcitrant warts in the dermatological field. Bleomycin is a glycopeptide antibiotic used as an anticancer agent. It acts by induction of DNA strands break and suppresses cell proliferation. In PPPK1, bleomycin might attenuate hyperkeratosis by reducing proliferation of basal keratinocytes. Even though careful management is necessary to prevent serious adverse effects of bleomycin, including interstitial pneumonia and lung fibrosis, intralesional bleomycin injection can be considered as a therapeutic option for PPPK1. In conclusion, we report two unrelated Japanese PPPK1 pedigrees harboring the novel AAGAB mutation c.191_194delCAAA. Our study will enrich the database of AAGAB mutations and contribute to improving the genetic diagnosis of PPPK1. In addition, we suggest efficient oral etretinate and local injection
158
Letters to the Editor / Journal of Dermatological Science 78 (2015) 149–164
of bleomycin as therapeutic options for PPPK1. Including our study, there are few reports describing therapy for PPPK1; therefore, analysis of more cases will aid in improving the understanding of PPPK1 pathogenesis, which will, in turn, help in the development of an effective treatment of this intractable disease.
[6]
[7]
Acknowledgment
[8]
This work was supported by a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science, No. 30436034.
[9]
[10]
palmoplantar keratoderma and congenital dysplasia of the hip in a large family. Clin Exp Dermatol 2014;39:182–6. Furniss M, Higgins CA, Martinez-Mir A, Horev L, Petukhova L, Stanimirovic´ A, et al. Identification of distinct mutations in AAGAB in families with type 1 punctate palmoplantar keratoderma. J Invest Dermatol 2014;134:1749–52. Nomura T, Yoneta A, Pohler E, Suzuki S, Osawa R, Mizuno O, et al. Punctate palmoplantar keratoderma type 1: a novel AAGAB mutation and efficacy of etretinate. Acta Derm Venereol 2014. http://dx.doi.org/10.2340/00015555-1832. Pohler E, Huber M, Boonen SE, Zamiri M, Gregersen PA, Sommerlund M, et al. New and recurrent AAGAB mutations in punctate palmoplantar keratoderma. Br J Dermatol 2014;171:433–6. Erkek E, Erdogan S, Tuncez F, Kurtipek GS, Bagci Y, Ozoguz P, et al. Type I hereditary punctate keratoderma associated with widespread lentigo simplex and successfully treated with low-dose oral acitretin. Arch Dermatol 2006;142:1076–7. Lienemann AO, Colucci VJ, Jones MS, Trauscht JM. Treatment of palmoplantar keratoderma with continuous infusion 5-fluorouracil. Cutis 2004;73: 303–308.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jdermsci.2015. 02.004. References [1] Pohler E, Mamai O, Hirst J, Zamiri M, Horn H, Nomura T, et al. Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nat Genet 2012;44:1272–8. [2] Giehl KA, Eckstein GN, Pasternack SM, Praetzel-Wunder S, Ruzicka T, Lichtner P, et al. Nonsense mutation in AAGAB cause punctuate palmoplantar keratoderma type Buschke–Fischer–Brauer. Am J Hum Genet 2012;91:754–9. [3] Cui H, Gao M, Wang W, Xiao R, Chen G, Zhang Q, et al. Six mutations in AAGAB confirm its pathogenic role in Chinese punctuate palomoplantar keratoderma patients. J Invest Dermatol 2013;133:2631–4. [4] Po¨hler E, Zamiri M, Harkins CP, Salas-Alanis JC, Perkins W, Smith FJ, et al. Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling. J Invest Dermatol 2013;113:2805–8. [5] Eytan O, Sarig O, Israeli S, Mevorah B, Basel-Vanagaite L, Sprecher E. A novel splice-site mutation in the AAGAB gene segregates with hereditary punctate
Eijiro Akasakaa,1, Yuko Okawab,1, Hajime Nakanoa,*, Noriko Takiyoshia, Daiki Rokunohea, Yuka Toyomakia, Daisuke. Sawamuraa, Hirohiko Suekic a Department of Dermatology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; bDivision of Dermatology, Showa University Northern Yokohama Hospital, Yokohama, Japan; c Department of Dermatology, Showa University Graduate School of Medicine, Tokyo, Japan *Corresponding author. Tel.: +81 172 39 5087; fax: +81 172 37 6060 E-mail address: [email protected] (H. Nakano). 1
These authors contributed equally to the work.
Received 9 December 2014 http://dx.doi.org/10.1016/j.jdermsci.2015.02.004
Letter to the Editor Ichthyosis and Kallmann syndrome: Not always a contiguous gene syndrome To the Editor, Ichthyoses comprise a heterogeneous group of genetic disorders of cornification characterized by scaling of the skin, which can be either isolated or syndromic. Mutations in more than 30 different genetic loci have been associated to this condition showing both autosomal (dominant and recessive) or X-linked patterns of inheritance. Common forms of ichthyosis include the autosomal semidominant ichthyosis vulgaris (MIM#146700), which is caused by mutations of the filaggrin gene on 1q21.3, and the X-linked recessive ichthyosis (XLI) (MIM#308100) that is due to mutations of the STS gene on Xp22.31 encoding steroid sulphatase [1]. Kallmann syndrome (KS) is a genetically heterogeneous disease characterized by hypogonadotropic hypogonadism, anosmia or hyposmia and a variable association of other non-reproductive findings, including unilateral renal agenesis. KS occurs in both sporadic and inherited forms showing different modes of transmission, namely the X-linked form (MIM# #308700) which is caused by mutations in the KAL1 gene on Xp22.31, but also autosomal dominant forms, recessive monogenic or digenic/oligogenic conditions [2]. A number of patients manifest both KS and XLI as a consequence of a contiguous gene syndrome characterized by large deletions in the Xp22.3 region leading to the loss of neighbouring genes, §
Funding: This research was supported by the Italian Ministry of Health grant no GR-2009-1578914 and by a grant from Fondazione CARIPARO.
including both KAL1 and the locus encoding the steroid sulphatase that is about 1.2 Mb apart [3,4]. Here we report a boy with this peculiar phenotype who did not present with the classical deletion but instead harboured two distinct mutations in KAL1 and STS. The patient was referred to our clinic at 9 years of age because of ichthyosis, left kidney agenesis and hypogonadotropic hypogonadism. Close examination of the patient’s family history revealed an apparently X-linked pattern of ichthyosis with three affected male relatives of the mother (her father, her paternal uncle and a first cousin once-removed) (Fig. 1). At birth generalized ichthyosis
Fig. 1. Pedigree of the three-generation family, showing the propositus (indicated by the arrow) affected by ichthyosis and Kallmann syndrome and the three male relatives affected by ichthyosis. The patient was born to non-consanguineous parents.
