Detection of ATP2C1 gene mutations in a family with generalized familial benign chronic pemphigus / 中华皮肤科杂志

A 60-year-old female proband presented with recurrent erythema, blisters and erosions all over the body for 30 years, which had been aggravated 10 days prior to the presentation. Skin examination showed erythematous swelling of the bilateral eyelids with scattered dark red crusts, scattered erythema and erosions on the nasolabial folds and chin, large areas of erythema and erosions on the neck, bilateral axillae, left cubital fossa, perineum and perianal area, accompanied by bright red granulation tissues and positive Nikolsky′s sign. The proband had two sons, both of whom occasionally presented with erythema and erosions on the axillae and groin, and had not been diagnosed or treated. Blood samples were collected from the proband and her two sons, and genomic DNA was extracted and subjected to whole-exome sequencing. A heterozygous deletion mutation c.955_957del (p.A319del) was identified in the ATP2C1 gene in the proband and her two sons, which had not been previously reported. The patient was finally diagnosed with generalized familial benign chronic pemphigus.

Enfermedad de Hailey-Hailey, una familia diagnosticada a partir de un caso propositus / Hailey-Hailey diseases, a family diagnosed starting from a case propositus

RESUMEN Introducción: La enfermedad de Hailey-Hailey, también conocida como pénfigo benigno familiar, es una enfermedad de muy baja frecuencia de aparición, aunque es una genodermatosis,las manifestaciones clínicas se manifiestan en la adolescencia o adultez temprana. Objetivo: Profundizar en los elementos que permiten el diagnóstico temprano de la enfermedad de Hailey-Hailey. Presentación del caso: En Las Tunas, provincia oriental de Cuba, es atendida en consulta especializada multidisciplinaria de genodermatosis, una mujer de 50 años de edad, quien presentabalesiones eritematosas, vesiculosas y erosivas, localizadas en zonas de pliegues, que habían aparecido desde la adolescencia, siendo tratadas en varias ocasiones como una micosis superficialo dermatitis. Se lerealiza estudio histopatológico que constató el diagnósticode enfermedad de Hailey-Hailey. Se estudiaron los demás miembros de la familia afectados con similareslesiones dermatológicasy se corrobora el diagnóstico familiar. La paciente fue tratada con esteroides en dosis antinflamatorias, vitaminoterapia y terapéutica tópica consistente en uso de fomentos antisépticos naturales y crema antinflamatoria de aloe, con buena respuesta a la terapéutica. Conclusiones: Se presenta el caso porque la enfermedad de Hailey Hailey es infrecuente, las manifestaciones comienzan en la adolescencia, pudiendo confundirse con otras dermatosis. En la investigación se determinó el diagnóstico de los demás miembros de la familia afectados a partir del caso propositus.

ABSTRACT Introduction: The Hailey-Hailey diseases,also known asbenign familial pemphigus, is an disease of very low appearance frequency,although it is a genodermatoses, the clinical manifestations are manifested in the adolescence or early adulthood. Objective: To deepen in the elements that allows the early diagnosis of Hailey-Hailey diseases. Case presentation: In Las Tunas, oriental county of Cuba, is assisted in multidisciplinary specialized consultation of genodermatoses, a 50-year-old woman who presented lesions erytmematous, vesiculous and erosive, located in areas of pleats that had appeared from the adolescence, being treated in several occasions like a superficial mycosis or dermatitis. She is carried out study histopathologyc that verified the diagnosis of Hailey-Hailey diseases. The other members of the family were studied affected with similar injure dermatological and the family diagnosis is corroborated. The patient was treated with steroids in dose antinflammatory, vitamintherapy and topical therapeutic consistentin use of antiseptic natural foments and cream antinflammatory of aloe, with good answer to the therapy. Conclusions: The case is presented because the Hailey-Hailey diseases areuncommon; the manifestations begin in the adolescence, being able to make a mistake with other dermatomes.In the investigation the diagnosis of the other members of the family was determined affected starting from the case propositus.

Familial "benign" pemphigus? Erythroderma and fatal outcome

Abstract Hailey-Hailey disease, or familial benign pemphigus, is a rare bullous genodermatosis that usually presents with flaccid blisters, erosions, and maceration limited to flexural areas, resulting in increased morbidity and reduced quality of life for affected patients. The authors report an unusual case of generalized Hailey-Hailey disease with erythroderma and fatal outcome.

Study on gene mutation in benign familial neonatal epilepsy / 中华实用儿科临床杂志

Objective To investigate the gene mutations in benign familial neonatal epilepsy(BFNE) in China.Methods Data of all BFNE probands and their family members were collected from Peking University First Hospital from January 2012 to December 2013.Clinical phenotypes of affected members were analyzed.Genomic DNA was extracted from peripheral blood samples with standard protocol.Mutations in candidate genes mutations were further screened by next-generation sequencing.Results A total of 4 families were collected,from which there were 10 affected members,6 males and 4 females.The age of epilepsy onset was from 1 day to 4 days after birth.The age of last seizure was from 3 days to 3 years and 10 months old.The age of last follow-up was from 4 years and 3 months old to 37 years old.All affected members had normal development.Genetic testing identified KCNQ2 mutations in 3 families (75％,3/4 cases).Two families had missense KCNQ2 mutations (c.1048A ＞ C/p.N350H and c.242T ＞ C/ p.L81P).One family had nonsense KCNQ2 mutation(c.2506G ＞ T/p.E836X).The other 3 KCNQ2 mutations were novel.The remaining BFNE family was not detected with any pathogenic mutation.The age of inital seizure onset of the proband was 1 day after birth.The seizures got controlled at 3 months old.However,this proband had another 2 afebrile seizures during sleep at 3 years and 10 months old.Electroenlephalography monitoring showed focal central temporal spikes.It is speculated that the seizures had evolved into benign epilepsy of childhood with central temporal spikes.Conclusions Mutations in KCNQ2 are major genetic causes in Chinese families with BFNE.KCNQ2 mutation c.1048A ＞ C/p.N350H,c.242T ＞ C/p.L81P,and c.2506G ＞ T/p.E836X are novel mutations.Identification of underlying gene mutation can be helpful for clinical diagnosis and judgment of the prognosis.

Dermatosis intertriginosa crónica de aparición tardía: pénfigo de Hailey-Hailey / Chronic late-onset intertriginous dermatitis: Hailey-Hailey's pemphigus

El pénfigo familiar benigno o enfermedad de Hailey Hailey, es una genodermatosis vesico-ampollar autosómica dominante, con penetrancia incompleta y expresividad variable de presentación infrecuente. Se presenta el caso de un paciente con un cuadro de cinco años de evolución, caracterizado por lesiones vesiculares intertriginosas, de olor desagradable, con mala respuesta al tratamiento tópico con antifúngicos y corticoides. Se realiza biopsia de piel compatible con pénfigo de Hailey Hailey, el que fue manejado con antibióticoterapia y corticoides sistémicos, evolucionando favorablemente.

The benign familial pemphigus or Hailey Hailey´s disease is a rare autosomal dominant disorder. We present the clinical case of a patient with a five years history, characterized by vesicular intertriginous malodorous lesions with poor response to topical antifungal therapy. Skin biopsy it was compatible with Hailey Hailey´s disease which was managed with antibiotic therapy and systemic corticosteroids. The patient evolved favorably.

Tratamento da doença de Hailey-Hailey com laser de CO2 fracionado: uma série de três casos / Treatment of the Hailey-Hailey disease with fractional CO2 laser: a three-case series

A doença de Hailey-Hailey ou pênfigo familiar benigno é condição rara, que se caracteriza por lesões vesiculares e erosões, associadas a dor e queimação, que comprometem a qualidade de vida dos pacientes. Existem vários tratamentos tópicos e sistêmicos que podem promover temporariamente a remissão das lesões, não existindo tratamento curativo. Algumas opções de tratamento com resultados duradouros abrangem a dermoabrasão e a vaporização com laser de Erbium YAG ou CO2. Relatamos três casos de pacientes com lesões recorrentes e respostas limitadas aos tratamentos clássicos, que apresentaram melhora clínica importante e alívio sintomático após terapia com laser de CO2 fracionado.

The Hailey-Hailey disease or familial benign pemphigus is a rare condition, characterized by vesicular lesions and erosions with a predilection for intertriginous areas associated with pain and burning sensation that affect the quality of life of patients. There are many topical and systemic treatments for the injuries that can temporarily promote partial or complete remission, but there is no curative treatment. Some treatment options with lasting results include dermabrasion and Erbium laser resurfacing (YAG or CO2). We report three cases of patients with recurrent lesions and limited responses to classical treatments, which showed significant clinical improvement after fractional CO2 laser therapy.

Research progress of benign familial hematuria / 中华实用儿科临床杂志

Benign familial hematuria,also called thin basement membrane nephropathy,is caused by a heterozygous mutation in the COL4A3 or COL4A4 gene.The prognosis of the patients with benign familial hematuria,who present isolated hematuria without associated with proteinuria and normal renal function,is good in childhood.However,the prognosis of part of the patients with benign familial hematuria,who appear proteinuria,hypertension,chronic renal failure and end-stage kidney disease,is poor in adulthood.Therefore,the patients with benign familial hematuria should be carried on the long-term follow-up,and may be reviewed every 1-2 years for hypertension,proteinuria,and renal impairment.Treatment for benign familial hematuria should include an angiotensin converting enzyme inhibitor to delay the onset of renal failure.

Study of Pathogenic gene spectrum in benign familial infantile epilepsy / 中华实用儿科临床杂志

Objective To investigate the gene mutations in benign familial infantile epilepsy(BFIE)in Chi-na. Methods Data of all BFIE probands and their family members were collected from Peking University First Hospital and other three hospitals between October 2006 and June 2017. Clinical phenotypes of affected members were analyzed. Genomic DNA was extracted from peripheral blood samples with standard protocol. Mutations in PRRT2 were screened using Sanger sequencing. For families that PRRT2 mutations were not detected by Sanger sequencing,candidate gene mutations were further screened by next - generation sequencing. Results A total of 71 families including 227 affected members were collected. Genetic testing led to the identification of gene mutations in 52 families (52 / 71,73. 2％). Forty - three families had PRRT2 mutations (43 / 71,60. 6％),including 40 families with frameshift mutations(hotspot mutations c. 649_650insC and c. 649delC were detected in 29 families and 6 families,respectively),one family with nonsense mutation,one family with a loss of a stop codon,and one family with a microdeletion of the gene. C. 560_561insT and c. 679C > T were novel PRRT2 mutations. Five families had SCN2A mutations. All SCN2A mutations were missense mutations(c. 668G > A,c. 752T > C,c. 1307T > C,c. 4835C > G,c. 1737C > G). Mutation c. 752T > C, c. 1307T > C,c. 4835C > G,and c. 1737C > G were novel mutations. Three families had KCNQ2 mutations. All KCNQ2 mutations were missense mutations(c. 775G > A,c. 237T > G,c. 1510C > T). Mutation c. 237T > G and c. 1510C > T were novel mutations. One family had a novel GABRA6 mutation c. 523G > T. In 71 BFIE families,16 families had mem-bers who showed paroxysmal kinesigenic dyskinesias(PKD)and subclassified as infantile convulsions with paroxysmal choreoathetosis syndrome(ICCA). Fifteen ICCA families were found having PRRT2 mutations (15 / 16,93. 8％). The remaining ICCA family was not detected with any pathogenic mutation. Conclusion There is high frequency of gene mutations in BFIE families. Mutations in KCNQ2,SCN2A,and PRRT2 are genetic causes of BFIE. PRRT2 is the main gene responsible for BFIE. GABRA6 mutation might be a new cause of BFIE.

Enfermedad de Hailey-Hailey en varias generaciones de una familia / Hailey - Hailey disease in several generations of a family

Se describen 2 casos clínicos de hermanos adultos que presentaban pénfigo benigno familiar o enfermedad de Hailey-Hailey, tipo de genodermatosis por alteración en la cohesión epidérmica, atendidos en el Hospital General Docente Dr Juan Bruno Zayas Alfonso de Santiago de Cuba. Los pacientes fueron tratados con esteroides en dosis antiinflamatorias, antibióticos y, de forma tópica, linimento vegetal y crema de aloe, además de recibir terapia floral. De manera general, ambos mejoraron su cuadro clínico durante la estadía en dicha institución hospitalaria

Two case reports of adult siblings are described, who presented with benign familial pemphigus or Hailey-Hailey disease --type of genodermatosis by altered epidermal cohesion-- attended in Dr Juan Bruno Zayas Alfonso Teaching General Hospital of Santiago de Cuba. Patients were treated with steroids at anti-inflammatory doses, antibiotics, and topical plant liniment and aloe cream, besides receiving flower therapy. In general, both of them improved the clinical picture during their stay in this institution

Mutation analysis of ATP2C1 gene in Chinese families with Hailey-Hailey disease / 中华皮肤科杂志

Objective To detect the mutations in ATP2C1 gene in 3 Chinese Hailey-Hailey-disease (HHD) families and 1 sporadic HHD patient.Methods Three Chinese HHD families and 1 sporadic HHD patient were recruited into this study with informed consent.Blood samples were taken from the patients with HHD,unaffected individuals in the HHD families and 100 unrelated normal human controls.Genomic DNA was extracted from these blood samples.All the exons and exon-intron boundaries of the ATP2C1 gene were amplified by PCR followed by direct sequencing via dye-termination chemistry.Results Three novel missense mutations in ATP2C1 gene were identified,including a 2048 G→A mutation in exon 20 causing the substitution of arginine by lysine at position 619 in the patients from HHD family 1,853A→C mutation in exon 8 causing the substitution of threonine by proline at position 221 in the patients from family 2,and 2323T→C mutation in exon 23 causing the substitution of tyrosine by histidine at position 711.None of these mutations were found in patients from the HHD family 3,unaffected individuals from the HHD family 1 and 2,or the unrelated normal human controls.Conclusion Three novel missense mutations are identified in the ATP2C 1 gene of patients with HHD.

Tratamento da doença de Hailey-Hailey com toxina botulínica tipo A / Hailey-Hailey disease treatment with Botulinum toxin type A

Duas irmãs com doença de Hailey-Hailey, com lesões recorrentes - uma em axilas e outra em região inguinal -, e resposta limitada aos tratamentos clássicos. Elas foram tratadas com aplicação de toxina botulínica tipo A. Observamos que houve importante melhora na paciente tratada na região inguinal e remissão completa na paciente em cujas axilas sofreram tratamento. Além disso, foi possível poupar uso de antibióticos sistêmicos e corticoides tópicos. O alto custo é um fator restritivo para uso rotineiro e estudos maiores são necessários para definir eficácia e relação custo-benefício dessa intervenção.

Two sisters with recurrent lesions, one on axillae and other on the groin, and with limited response to classical treatments were treated with injections botulinum toxin type A. We observed marked improvement in the patient treated in the groin and complete remission in the patient treated in the axillae. It was possible to spare the use of systemic antibiotics and topical corticosteroids. The high cost is a restrictive factor to routine use and large studies are necessary to access efficacy and cost benefit profile.

Mutation analysis of ATP2C1 gene in patients with Hailey-Hailey disease / 中华皮肤科杂志

Objective To detect the mutations in ATP2C1 gene of 5 sporadic patients with Hailey-Hailey disease (HHD).Methods Five sporadic patients with HHD collected from the outpatient clinic setting were recruited into this study with informed consent.Blood samples were taken from all patients and 100 unrelated human controls.and DNA was extracted from these samples.Mutation scanning was carried out for ATP2C1 gene by polymerase chain reaction (PCR) and direct sequencing.Results The diagnosis of all cases was confirmed by typical clinical manifestation,cutaneous pathology and immunofluorescence pathology.Five novel mutations.including a deletion mutation (2025delG),three missence mutations (L269R,C348R,A651D) and a non-sense mutation (Q259X) were identified in these cases.No mutations were detected in any of the 100 controls.Conclusion Five novel mutations in ATP2C1 gene have been identified for Hailey-Hailey disease.

A novel mutation of ATP2C1 gene in a Chinese pedigree with Hailey-Hailey disease / 中华皮肤科杂志

ed in a Chinese pedigree with HHD.

Gene Mutations in a Chinese Family with Hailey-Hailey Disease / 中华皮肤科杂志

Objective To analyse gene mutation in members of a Chinese family with Hailey-Hailey disease(HHD)and study the relationship between the genotype and clinical features of the disease.Meth-ods Genomic DNA of leucocytes were obtained from members of the Chinese family with HHD including4patients and6normal persons.Ten exons of ATP2C1gene were amplified by polymerase chain reaction(PCR)and the products were analysed by single-strand conformation polymorphism(SSCP)and direct DNA sequencing.Results A novel mutation was identified in this family.The sequence of"TGTAGCCAT"(2068→2076)was substituded by"AGATGGAACA",which caused a frame shift of open reading frame and premature termination codon(PTC)in gene ATP2C1.There was no relationship between the genotypes and the phenotypes.Conclusion Gene mutation of ATP2C1gene at exon21is the cause for HHD in this fami-ly.

Study on gene mapping of one Chinese benign familial infantile convulsions pedigree / 中华神经科杂志

Objective To make the gene mapping of one Chinese benign familial infantile convulsion (BFIC )pedigree on chromosome 19q12 13 1 Methods Five microsatellite DNA markers (D19S49, D19S250, D19S414, D19S416, D19S245) were chosen to make haplotype and linkage analysis of this BFIC family Results Among the 3 markers D19S49,D19S416,D19S245, the maximum LODs was located on D19S416 When the recombinant rate was 0 3, the maximum LOD score was 0 52; when the recombinant rate was 0, the LOD score was ∞; when the recombinant rate was 0 1, the LOD score was less than 0 The D19S414 and D19S250 could not provide information Conclusion BFIC gene of the family was not linked between D19S49 and D19S245, which suggested that there was heterogeneity in BFIC

Benign familial elevated AFP / 中华消化杂志

Objective To evaluate the nature of a family with elevated AFP, and the importance of recognition and diagnosis of familial AFP elevation. Methods In 1984 and 1997, a series of AFP radioimmunoassay in two families with persistent high AFP have been investigated and their family pedigree analyzed. Results Among 29 members in these two families 15 were examined. The AFP level was persistently elevated in 10. Two of them have been misdiagnosed as primary hepatocellular carcinoma. Conclusion Familial elevated AFP is benign in nature. Therefore it should be keep in mind in AFP mass survey.

Study on the mutations of ATP2C1 gene in patients with Harley-Harley disease / 中华皮肤科杂志

Objective To detect the mutations of ATP2C1 gene in patients with Hailey-Hailey dis- ease (HHD).Methods PCR and direct sequencing were performed in 17 patients and 120 healthy controls to screen the mutations in the exons of ATP2C1 gene.Results Eight mutations were identified in nine probands, including three deletion mutations (nt1464-1487 del/nt1462-1485del,1523delAT,2375delTTGT),three splice site mutations (360—2A→G,1415—2A→T,2243+2T→C) and two missence mutations (C920T and G1942T).None of the above mutations was found in the controls.Conclusion Eight specific novel mutations were identified in nine probands of HHD,which could be causative factors of the disease.