Letters to the Editor
afflicted by recurrent staphylococcal skin and abdominal infection. Physical examination revealed normal vital signs. Refractory chronic eczema accompanied by pustular and anabrosis with cicatrization occurred on his scalp and limbs (Fig. 1a,b). Laboratory examination revealed high levels of total eosinophil count ratio (0.159; normal, 40 points) and the newly found STAT3 mutation. To our knowledge, this mutation is first reported herein; to date, two other variations at this locus of STAT3 (p.F384S, p.F384L) in HIES patients have been reported.4,5 Moreover, our patient is unusual as from birth he never developed bacterial pneumonia, which is a distinguishing feature of AD-HIES, but had HSV and serious staphylococcal infection simultaneously, which has seldom been reported in AD-HIES patients.4
ACKNOWLEDGMENTS: We thank the patient and his parents for their cooperation. This work was supported by the Nature Science Foundation of China (nos. 81000026, 81072706 and 81202451) and The Science and Technology Project of Hunan Province of China (2014FJ3023). CONFLICT OF INTEREST:
None declared.
AUTHOR CONTRIBUTION:
Qi Lu and Lijuan
Cheng
contributed equally to this work.
Qi LU,1 Lijuan CHENG,2 Lingli CHEN,2 Lan SONG,2 Zhenghui XIAO,3 Guo WANG4 1
Departments of General Surgery, 3Critical Care Medicine, Hunan Children’s Hospital, University of South China, 2Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine and 4 Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, China doi: 10.1111/1346-8138.12466
REFERENCES 1 Minegishi Y. Hyper-IgE syndrome. Curr Opin Immunol 2009; 21: 487– 492. 2 Grimbacher B, Scha¨ffer AA, Holland SM et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet 1999; 65: 735–744. 3 Minegishi Y, Saito M, Tsuchiya S et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 2007; 448: 1058–1062. 4 Chandesris MO, Melki I, Natividad A et al. Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine (Baltimore) 2012; 91: e1–e19. 5 Holland SM, DeLeo FR, Elloumi HZ et al. STAT3 mutations in the hyper-lgE syndrome. N Engl J Med 2007; 357: 1608–1619.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. National Institutes of Health (NIH) hyper-immunoglobulin E syndrome (HIES) score for the patient.
A novel 1-bp deletion mutation of the EDA gene in a Chinese Han family with X-linked hypohidrotic ectodermal dysplasia Dear Editor, Hypohidrotic ectodermal dysplasia (HED) is a rare skin disease characterized by hypotrichosis, hypodontia and hypohidrosis.1,2 HED can be autosomal dominant, autosomal recessive,
or X-linked, with X-linked HED (XLHED) being the most common form. Mutations within the ectodysplasin-A 1 (EDA) gene are responsible for XLHED.1–3 More than 200 XLHEDassociated mutations in EDA have been identified. In this
Correspondence: Yu-Xia Yang, M.D., Department of Emergency, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China. Email: [email protected]
© 2014 Japanese Dermatological Association
659
Letters to the Editor
(a)
(c)
(b)
Figure 1. (a) Pedigree of a Chinese family with X-linked hypohidrotic ectodermal dysplasia (XLHED). Squares and circles indicate males and females, respectively. Blackened squares indicate the affected males and circles with a central black dot represent carrier females. Circles with question marks indicate that at the time of the pedigree analysis the carrier state of these individuals was not known. The arrow indicates the proband. (b) Typical XLHED facial appearance in the proband (individual III:4) including a prominent forehead, high and wide cheekbones, a depressed nasal bridge, large and conspicuous nostrils, thick lips and a pointed chin. (c) Sequence analysis of the EDA gene mutation. (Top) Sequence chromatograms of exon 1 of the EDA gene for the proband individual III:4 showed a 1-bp deletion (c.88delG) in EDA but (middle) no mutation was detected in non-affected male family member I:1. (Bottom) DNA sequence analysis indicated that the mother of III:4 was heterozygous for c.88delG. The arrow indicates the c.88delG. study, we assessed the mutational status of the EDA gene in a Chinese Han family that had inherited XLHED. This study was preformed in accordance with the Declaration of Helsinki and all subjects gave their written informed consent. The family comprised 31 members spanning three generations. (Fig. 1a). Subject III:4, the proband, was a 21-year-old man who had the typical triad of hypohidrosis, hypotrichosis and hypodontia (Fig. 1a,b). His scalp hair and eyelashes were sparse, thin and dry, and his eyebrows were scanty to absent. Sparse hair distributions were also noted in the beard and pubic areas, axillae and trunk. He had a characteristic XLHED facial appearance, including a prominent forehead, high and wide cheekbones and narrow lower half of the face, a depressed nasal bridge, large and conspicuous nostrils, thickened lips and a large chin. Yellow-brown hyperpigmentation was observed around the periorbital area, nose and mouth. His skin was dry and did not sweat, except axillae were able to secrete small amounts of sweat. According to the proband self-report, until adolescence, he had only six teeth, including two permanent mandibular central incisors, two maxillary primary molars and two secondary molars. His physical development was normal. He had no abnormalities in his finger and toe nails. His younger male cousin (III:5) had similar symptoms and clinical onset of the disease. Except for the proband’s mother (II:4) who showed thinning hair, all female carriers were normal.
660
We sequenced the entire EDA coding regions and exon– intron boundaries using polymerase chain reaction (PCR) amplified DNA in patients (III:4 and III:5) affected with XLHED and identified a novel 1-bp deletion mutation (c.88delG) in exon 1 (see Table S1 for PCR primer sequences). This mutation was also present in female carriers, but not in unaffected males or females of this family or 200 healthy Han Chinese individuals (Fig. 1c). The mutation causes a frame-shift and premature termination codon (p.Ala30Profs*27) that deletes 289 amino acids at the C-terminal end of EDA and replaces it with a short unrelated 56 amino acid polypeptide. These results suggest that the c.88delG mutation is likely to be the disease-causing mutation for XLHED in this family. How this mutation affects the function of the gene is not clear. The premature stop codon could result in degradation of the mRNA,4 the abnormal protein may itself be unstable,5 and/ or it does not have the ability to be processed and bind the ectodysplasin-A receptor (EDAR). In summary, we have identified a novel deletion mutation located in exon 1 which if expressed would produce a highly truncated protein. Our findings broaden the spectrum of EDA mutations and may give insight into the molecular basis of XLHED and aid in genetic counseling.
CONFLICT OF INTEREST:
None.
© 2014 Japanese Dermatological Association
Letters to the Editor
Xiang-Dong KONG,1 Ning LIU,1 Hui-Rong SHI,1 Yu-Xia YANG2 1
Center of Prenatal Diagnosis and 2Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China doi: 10.1111/1346-8138.12431
REFERENCES 1 Kere J, Srivastava AK, Montonen O et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 1996; 13: 409–416. 2 Monreal AW, Zonana J, Ferguson B. Identification of a new splice form of the eda1 gene permits detection of nearly all x-linked hypohidrotic ectodermal dysplasia mutations. Am J Hum Genet 1998; 63: 380–389.
3 Monreal AW, Ferguson BM, Headon DJ, Street SL, Overbeek PA, Zonana J. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 1999; 22: 366–369. 4 Kervestin S, Jacobson A. Nmd: a multifaceted response to premature translational termination. Nat Rev Mol Cell Biol 2012; 13: 700–712. 5 Fredrickson EK, Gardner RG. Selective destruction of abnormal proteins by ubiquitin-mediated protein quality control degradation. Semin Cell Dev Biol 2012; 23: 530–537.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. Summary of PCR primer sequences.
Unusual presentation of relapsing neutrophilic dermatosis limited to the face Dear Editor, Neutrophilic dermatosis (ND) is a disorder characterized by neutrophilic hyperfunction and is the generic term for abacterial inflammatory disease. Sweet’s syndrome (SS), pyoderma gangrenosum (PG) and a few other conditions are included in this category.1,2 A 50-year-old man presented with papules on erythematous plaque without ulceration and no subjective symptom on the left cheek (Fig. 1a). The lesions were only limited to the left cheek, and the patient had no fever and no general fatigue. Laboratory tests revealed no abnormal findings including antinuclear antibody. The lesions were ameliorated by topical application of a corticosteroid; however, discontinuation of the corticosteroid resulted in rapid recurrence at the same area, and the lesions in fact had gradually increased in size. A skin biopsy taken from the lesions revealed diffuse and nodular dermatitis, predominantly with neutrophils in the dermis and remnants of ruptured follicles, with the absence of vasculitis, granuloma and Demodex folliculorum (Fig. 1c–f). Direct immunofluorescence studies did not show anything. No bacteria, fungus or acid-fast bacillus were detected by a cultivation survey. Because it did not fulfill the criteria of SS,3 rosacea and discoid lupus erythematosus, a comprehensive diagnosis of
Figure 1. (a) Clinical appearance of erythematous plaque with papules on the left cheek. (b) Clinical appearance after treatment. The lesions improved without scaring and dilation of capillary was showed. Relapsing papules are observed in the lesions (arrowhead). (c) Low-power view of the skin lesions showing diffuse inflammatory cell infiltrates of the superficial to mid-dermis (hematoxylin–eosin [HE], original magnification 940). (d) Remnants of ruptured follicles are observed (HE, 9100). (e) Vasculitis is not observed (HE, 9200). (f) Inflammatory cells are mainly composed of neutrophils (HE, 9400).
ND was made. Diaminodiphenylsulfone (75 mg daily) was administrated p.o. for 2 months, but it was not particularly effective. Consequently, oral prednisolone (15 mg daily) was additionally administrated. Although slight recurrence appeared, the eruptions significantly improved (Fig. 1b).
(a)
(b)
(c)
(d)
(e)
(f)
Correspondence: Tomoko Nomiyama, M.D., Ph.D., Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Email: [email protected]
© 2014 Japanese Dermatological Association
661
afflicted by recurrent staphylococcal skin and abdominal infection. Physical examination revealed normal vital signs. Refractory chronic eczema accompanied by pustular and anabrosis with cicatrization occurred on his scalp and limbs (Fig. 1a,b). Laboratory examination revealed high levels of total eosinophil count ratio (0.159; normal, 40 points) and the newly found STAT3 mutation. To our knowledge, this mutation is first reported herein; to date, two other variations at this locus of STAT3 (p.F384S, p.F384L) in HIES patients have been reported.4,5 Moreover, our patient is unusual as from birth he never developed bacterial pneumonia, which is a distinguishing feature of AD-HIES, but had HSV and serious staphylococcal infection simultaneously, which has seldom been reported in AD-HIES patients.4
ACKNOWLEDGMENTS: We thank the patient and his parents for their cooperation. This work was supported by the Nature Science Foundation of China (nos. 81000026, 81072706 and 81202451) and The Science and Technology Project of Hunan Province of China (2014FJ3023). CONFLICT OF INTEREST:
None declared.
AUTHOR CONTRIBUTION:
Qi Lu and Lijuan
Cheng
contributed equally to this work.
Qi LU,1 Lijuan CHENG,2 Lingli CHEN,2 Lan SONG,2 Zhenghui XIAO,3 Guo WANG4 1
Departments of General Surgery, 3Critical Care Medicine, Hunan Children’s Hospital, University of South China, 2Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine and 4 Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, China doi: 10.1111/1346-8138.12466
REFERENCES 1 Minegishi Y. Hyper-IgE syndrome. Curr Opin Immunol 2009; 21: 487– 492. 2 Grimbacher B, Scha¨ffer AA, Holland SM et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet 1999; 65: 735–744. 3 Minegishi Y, Saito M, Tsuchiya S et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 2007; 448: 1058–1062. 4 Chandesris MO, Melki I, Natividad A et al. Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine (Baltimore) 2012; 91: e1–e19. 5 Holland SM, DeLeo FR, Elloumi HZ et al. STAT3 mutations in the hyper-lgE syndrome. N Engl J Med 2007; 357: 1608–1619.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. National Institutes of Health (NIH) hyper-immunoglobulin E syndrome (HIES) score for the patient.
A novel 1-bp deletion mutation of the EDA gene in a Chinese Han family with X-linked hypohidrotic ectodermal dysplasia Dear Editor, Hypohidrotic ectodermal dysplasia (HED) is a rare skin disease characterized by hypotrichosis, hypodontia and hypohidrosis.1,2 HED can be autosomal dominant, autosomal recessive,
or X-linked, with X-linked HED (XLHED) being the most common form. Mutations within the ectodysplasin-A 1 (EDA) gene are responsible for XLHED.1–3 More than 200 XLHEDassociated mutations in EDA have been identified. In this
Correspondence: Yu-Xia Yang, M.D., Department of Emergency, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China. Email: [email protected]
© 2014 Japanese Dermatological Association
659
Letters to the Editor
(a)
(c)
(b)
Figure 1. (a) Pedigree of a Chinese family with X-linked hypohidrotic ectodermal dysplasia (XLHED). Squares and circles indicate males and females, respectively. Blackened squares indicate the affected males and circles with a central black dot represent carrier females. Circles with question marks indicate that at the time of the pedigree analysis the carrier state of these individuals was not known. The arrow indicates the proband. (b) Typical XLHED facial appearance in the proband (individual III:4) including a prominent forehead, high and wide cheekbones, a depressed nasal bridge, large and conspicuous nostrils, thick lips and a pointed chin. (c) Sequence analysis of the EDA gene mutation. (Top) Sequence chromatograms of exon 1 of the EDA gene for the proband individual III:4 showed a 1-bp deletion (c.88delG) in EDA but (middle) no mutation was detected in non-affected male family member I:1. (Bottom) DNA sequence analysis indicated that the mother of III:4 was heterozygous for c.88delG. The arrow indicates the c.88delG. study, we assessed the mutational status of the EDA gene in a Chinese Han family that had inherited XLHED. This study was preformed in accordance with the Declaration of Helsinki and all subjects gave their written informed consent. The family comprised 31 members spanning three generations. (Fig. 1a). Subject III:4, the proband, was a 21-year-old man who had the typical triad of hypohidrosis, hypotrichosis and hypodontia (Fig. 1a,b). His scalp hair and eyelashes were sparse, thin and dry, and his eyebrows were scanty to absent. Sparse hair distributions were also noted in the beard and pubic areas, axillae and trunk. He had a characteristic XLHED facial appearance, including a prominent forehead, high and wide cheekbones and narrow lower half of the face, a depressed nasal bridge, large and conspicuous nostrils, thickened lips and a large chin. Yellow-brown hyperpigmentation was observed around the periorbital area, nose and mouth. His skin was dry and did not sweat, except axillae were able to secrete small amounts of sweat. According to the proband self-report, until adolescence, he had only six teeth, including two permanent mandibular central incisors, two maxillary primary molars and two secondary molars. His physical development was normal. He had no abnormalities in his finger and toe nails. His younger male cousin (III:5) had similar symptoms and clinical onset of the disease. Except for the proband’s mother (II:4) who showed thinning hair, all female carriers were normal.
660
We sequenced the entire EDA coding regions and exon– intron boundaries using polymerase chain reaction (PCR) amplified DNA in patients (III:4 and III:5) affected with XLHED and identified a novel 1-bp deletion mutation (c.88delG) in exon 1 (see Table S1 for PCR primer sequences). This mutation was also present in female carriers, but not in unaffected males or females of this family or 200 healthy Han Chinese individuals (Fig. 1c). The mutation causes a frame-shift and premature termination codon (p.Ala30Profs*27) that deletes 289 amino acids at the C-terminal end of EDA and replaces it with a short unrelated 56 amino acid polypeptide. These results suggest that the c.88delG mutation is likely to be the disease-causing mutation for XLHED in this family. How this mutation affects the function of the gene is not clear. The premature stop codon could result in degradation of the mRNA,4 the abnormal protein may itself be unstable,5 and/ or it does not have the ability to be processed and bind the ectodysplasin-A receptor (EDAR). In summary, we have identified a novel deletion mutation located in exon 1 which if expressed would produce a highly truncated protein. Our findings broaden the spectrum of EDA mutations and may give insight into the molecular basis of XLHED and aid in genetic counseling.
CONFLICT OF INTEREST:
None.
© 2014 Japanese Dermatological Association
Letters to the Editor
Xiang-Dong KONG,1 Ning LIU,1 Hui-Rong SHI,1 Yu-Xia YANG2 1
Center of Prenatal Diagnosis and 2Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China doi: 10.1111/1346-8138.12431
REFERENCES 1 Kere J, Srivastava AK, Montonen O et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 1996; 13: 409–416. 2 Monreal AW, Zonana J, Ferguson B. Identification of a new splice form of the eda1 gene permits detection of nearly all x-linked hypohidrotic ectodermal dysplasia mutations. Am J Hum Genet 1998; 63: 380–389.
3 Monreal AW, Ferguson BM, Headon DJ, Street SL, Overbeek PA, Zonana J. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 1999; 22: 366–369. 4 Kervestin S, Jacobson A. Nmd: a multifaceted response to premature translational termination. Nat Rev Mol Cell Biol 2012; 13: 700–712. 5 Fredrickson EK, Gardner RG. Selective destruction of abnormal proteins by ubiquitin-mediated protein quality control degradation. Semin Cell Dev Biol 2012; 23: 530–537.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. Summary of PCR primer sequences.
Unusual presentation of relapsing neutrophilic dermatosis limited to the face Dear Editor, Neutrophilic dermatosis (ND) is a disorder characterized by neutrophilic hyperfunction and is the generic term for abacterial inflammatory disease. Sweet’s syndrome (SS), pyoderma gangrenosum (PG) and a few other conditions are included in this category.1,2 A 50-year-old man presented with papules on erythematous plaque without ulceration and no subjective symptom on the left cheek (Fig. 1a). The lesions were only limited to the left cheek, and the patient had no fever and no general fatigue. Laboratory tests revealed no abnormal findings including antinuclear antibody. The lesions were ameliorated by topical application of a corticosteroid; however, discontinuation of the corticosteroid resulted in rapid recurrence at the same area, and the lesions in fact had gradually increased in size. A skin biopsy taken from the lesions revealed diffuse and nodular dermatitis, predominantly with neutrophils in the dermis and remnants of ruptured follicles, with the absence of vasculitis, granuloma and Demodex folliculorum (Fig. 1c–f). Direct immunofluorescence studies did not show anything. No bacteria, fungus or acid-fast bacillus were detected by a cultivation survey. Because it did not fulfill the criteria of SS,3 rosacea and discoid lupus erythematosus, a comprehensive diagnosis of
Figure 1. (a) Clinical appearance of erythematous plaque with papules on the left cheek. (b) Clinical appearance after treatment. The lesions improved without scaring and dilation of capillary was showed. Relapsing papules are observed in the lesions (arrowhead). (c) Low-power view of the skin lesions showing diffuse inflammatory cell infiltrates of the superficial to mid-dermis (hematoxylin–eosin [HE], original magnification 940). (d) Remnants of ruptured follicles are observed (HE, 9100). (e) Vasculitis is not observed (HE, 9200). (f) Inflammatory cells are mainly composed of neutrophils (HE, 9400).
ND was made. Diaminodiphenylsulfone (75 mg daily) was administrated p.o. for 2 months, but it was not particularly effective. Consequently, oral prednisolone (15 mg daily) was additionally administrated. Although slight recurrence appeared, the eruptions significantly improved (Fig. 1b).
(a)
(b)
(c)
(d)
(e)
(f)
Correspondence: Tomoko Nomiyama, M.D., Ph.D., Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Email: [email protected]
© 2014 Japanese Dermatological Association
661
