Genetic study of a Chinese pedigree affected with pachyonychia congenita / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with pachyonychia congenita (PC).@*METHODS@#With informed consent obtained, peripheral blood samples were taken from the pedigree. Genomic DNA was extracted with a phenol/chloroform method. Based on the clinical manifestation of the patients, candidate genes for PC were selected. Potential mutation was screened by PCR and Sanger sequencing. Suspected mutation was verified in other family members by PCR-high resolution melting (HRM) analysis. Haplotype analysis using microsatellite markers was also carried out to determine the founder of the mutation.@*RESULTS@#A heterozygous c.275A>G (Asn92Ser) mutation was discovered in exon 1 of the KRT17 gene in the proband. PCR-HRM analysis showed that all affected members were heterozygous carriers of the mutation. The same mutation was found in none of the unaffected members. Haplotype analysis and sequencing indicated the mother of the proband to be the founder.@*CONCLUSION@#The c.275A>G (Asn92Ser) mutation of the KRT17 gene probably underlies the disease in this pedigree. Above finding has facilitated genetic counseling and prenatal diagnosis for this pedigree.

Diagnóstico molecular de paquioniquia congénita / Molecular diagnosis of congenital pachyonychia

La paquioniquia congenital (PC) es una genodermatosis poco frecuente, caracterizada por presentar queratodermia palmoplantar dolorosa y debilitante, uñas hipertróficas, hiperqueratosis folicular, quistes epidérmicos, leucoqueratosis oral y ocasionalmente hiperhidrosis, ronquera y dientes natales. Está asociada a mutaciones heterocigotas en los genes que codifican queratinas 6a, 6b, 6c, 16 y 17. Se presenta una familia con dos miembros en dos generaciones afectados por PC: un niño de 2 años de edad con alteración de la coloración, hiperqueratosis de las 20 uñas, con dolor periungueal, múltiples pápulas foliculares color piel en tronco y dientes natales y su madre, con alteración del esmalte dentario, distrofia hipertrófica de las 20 uñas, cromoniquia, queratodermia plantar dolorosa y múltiples esteatocistomas de distribución generalizada.En ambos, se realizó el diagnóstico molecular por secuenciación masiva de exoma clínico, el cual confirmó el diagnóstico clínico y permitió determinar inequívocamente el tipo de PC en el niño, motivo de ésta presentación.

Pachyonychia congenital (PC) is a rare genodermatosis characterized by painful palmoplantar keratoderma, hypertrophic nail dystrophy, follicular hyperkeratosis, epidermal cysts, oral leukokeratosis and, less commonly, palmoplantar hyperhidrosis, hoarseness and natal teeth. PC is caused by mutations in keratin 6a, 6b, 6c, 16 and 17 genes. We report a family with two members in two generations affected by PC: a two-year old boy, presenting abnormal pigmentation and hyperkeratosis of the 20 nails, perionychium pain, multiple skin-colored follicular papules on the trunk and natal teeth. His mother has dental enamel defects, hypertrophic dystrophy of the fingernails and toenails, chromonychia, painful plantar keratoderma and generalized steatocystoma multiplex. We performed the molecular diagnosis by clinical exome massive sequencing which allowed us to confirm the clinical diagnosis and to determine the specific type of PC in our patient.

A novel H1 mutation in keratin 6a in an infant with pachyonychia congenita.

Pachyonychia congenita (PC) is a rare genetic disorder which is inherited in an autosomal dominant pattern. We report a sporadic novel H1 mutation in the KRT6A gene (c. 428G>A/p. Ser143Asn) in a Chinese infant patient. The mutation is concurrent with a single-nucleotide polymorphism and resulted in a serine for asparagine substitution in H1 subdomain of KRT6A chain next to the rod domain. The infant showed the classic symptoms of pachyonychia congenita. Conclusion: The heterozygous missense mutation c. 428G > A/p.Ser143Asn in KRT6A exon 1 may cause severe disease

familial case of pachyonychia congenital

Pachyonychia congenita [PC] comprises a group of rare autosomal genodermatosis caused by mutation in any of the four genes KRT6A, KRT6B, KRT16 or KRT17. Classically, it is subdivided into two major variant types, PC-1 [Jadassohn-Lewandowski syndrome] and PC-2 [Jackson-Lawler syndrome]. We hereby report a case of 22-year-old, married woman with progressive thickening and discoloration of all 20 nails, multiple, hyperkeratotic lesions present all over the body with oral lesions since childhood. She had a 2-month-old male baby [the only child] who presented with similar lesions of yellowish discoloration and nail thickening of both nails and foot since birth. She was diagnosed as PC type 1

Paquioniquia congénita tipo 1 / Pachyonycha congenita type 1

La paquioniquia cong‚nita (PC) es una rara genodermatosis de inicio en la infancia temprana caracterizada por una hiperqueratosis ungueal y frecuentes alteraciones asociadas. Se presenta el caso de una mujer de 28 a¤os con lesiones cl¡nicas compatibles con paquioniquia cong‚nita tipo 1.

The pachyonychia congenita (PC) is a rare genodermatosis of onset in early infancy characterized by hyperkeratosis nail and frequent partner changes. The case of a 28 year old woman with clinical lesions compatible with pachyonychia congenita type 1 is presented.

Síndrome de Jackson-Lawler / Jackson-Lawler sydrome: a case report

El síndrome de Jackson-Lawler (paquioniquia congénita tipo 2) es una rara genodermatosis, de carácter autosómico dominante, se debe a mutación de genes de citoqueratinas. Clinicamente se caracteriza por onicodistrofia congénita de las veinte uñas asociada al desarrollo de queratodermia palmoplantar, esteatocistomas múltiples, queratosis folicular, hiperhidrosis palmo-plantar, leucoqueratosis oral. Se presenta caso de mujer de 23 años de edad, sin antecedentes personales y familiares, que acude por alteraciones morfológicas en uñas de manos y pies, asociado a sudoración excesiva en palmas y plantas, aparición de lesiones en axilas, para lo cual se le realiza biopsia infromada como esteatocistomas. Se le diagnóstica sindrome de Jackson-Lawler.

Jackson-Lawler syndrome (pachyoncychia congenital type 2) is a rare genodermatosis of autosomal dominant mutation is due to genes of citokeratins. Clinically it is characterized by congenital onychodystrophy associated with the development of: palmoplantar keratderma, steatocystomas multiplex, follicular leratosis, palmoplantar hyperhidrosis, oral leucoqueratosis. We report a 23 year-old girl, without personal and family history, presented with morphological changes in fingers and feet nails, associated with excessive sweating in palms and soles and axilar lesions informed as steatocystoma after the histopathological study. We diagnose a Jackson-Lawler syndrome.

Keratinization and its disorders

Keratins are a diverse group of structural proteins that form the intermediate filament network responsible for maintaining the structural integrity of keratinocytes. In humans, there are around 30 keratin families divided into two groups, namely, acidic and basic keratins, which are arranged in pairs. They are expressed in a highly specific pattern related to the epithelial type and stage of cellular differentiation. A total of 54 functional genes exist which codes for these keratin families. The expression of specific keratin genes is regulated by the differentiation of epithelial cells within the stratifying squamous epithelium. Mutations in most of these genes are now associated with specific tissue fragility disorders which may manifest both in skin and mucosa depending on the expression pattern. The keratins and keratin-associated proteins are useful as differentiation markers because their expression is both region specific and differentiation specific. Antibodies to keratin are considered as important tissue differentiation markers and therefore are an integral aid in diagnostic pathology. The present review discusses the structure of keratin, the various types of keratin and their distribution and the disorders associated with keratinization with special emphasis on the disorders of the oral cavity. A brief note on the clinical significance of keratin is also mentioned

Pachyonychia Congenita Affecting the Nails Only in the Mother and Son / 대한피부과학회지

Pachyonychia congenita (PC) is a rare autosomal-dominant ectodermal dysplasia, which is characterized by hypertrophic nail dystrophy, diffuse or focal symmetrical hyperkeratosis of the palms and soles, oral leukokeratosis, follicular keratosis on the extensor surfaces of the extremities, and other ectodermal defects. However, the variable degree of gene mutation may result in nail abnormalities alone. The nail changes presented in our patient are the only clinical manifestation. Hypertrophic nail dystrophy and yellowish discoloration, without involving any other organs, were shown in both mother and baby since birth. To the best of our knowledge, the case of PC affecting only the nails has never been reported in Korea before. Herein, we report monosymptomatic form of PC, which is notable for its rareness and unique pattern, distinct from previously reported cases.

Caso para diagnóstico / Case for diagnosis

Esteatocistoma múltiplo é um raro transtorno genético autossômico dominante que se caracteriza por múltiplos cistos dérmicos de tamanho variável e assintomáticos. Descreve-se o caso de um paciente do sexo masculino, de 23 anos, com quadro clínico e evolutivo típicos dessa desordem.

Steatocystoma multiplex is a rare genetic disorder, autosomal dominant, that is characterized by multiple asymptomatic dermal cysts which vary in size. It is described here the case of a 23 year-old male patient with a typical clinical and evolutional progression of this disease.

A Case of Type 1 Pachyonychia Congenita (Jadassohn-Lewandowsky Syndrome) / 대한피부과학회지

Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, focal palmoplantar keratoderma and blistering, oral leukokeratosis, cyst formation, palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities. PC is diagnosed by clinical findings and molecular genetic studies. A 26-year-old man presented with hypertrophic nail dystrophy and subungual debris of all 20 nails, hyperkeratotic plaques on the heels of both soles, and oral leukokeratosis. He had no family history of similar clinical findings. The patient's clinical presentation and history were consistent with PC. Herein we report on a rare case of pachyonychia congenita with a review of literature.

Keratin 17 mutation in pachyonychia congenita type 2 in a Chinese Han family / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the keratin 17 gene (KRT17) mutation in a pedigree with pachyonychia congenita type 2 (PC-II).</p><p><b>METHODS</b>DNA was extracted from the blood samples of the patients, unaffected members of the pedigree, and 100 unrelated healthy controls. PCR was performed to amplify the hot spots in KRT17 gene. PCR products were directly sequenced to detect mutation.</p><p><b>RESULTS</b>A heterozygous 296T-->C mutation was found in all the affected members of this family, which resulted in the substitution of leucine by proline in codon 99 (L99P) in the 1A domain of the KRT17, but not in the healthy individuals from the family and the 100 unrelated controls.</p><p><b>CONCLUSION</b>The mutation of KRT17 may play a major role in the pathogenesis of this pedigree with pachyonychia congenita type 2.</p>

The 521 T--> C mutation in the keratin 6A gene in a pedigree with pachyonychia congenita type I / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To identify the mutation in the keratin 6A(K6A) gene in a pedigree with pachyonychia congenita type I (PC-I).</p><p><b>METHODS</b>Blood samples were obtained from 2 affected, 3 unaffected members in this family, and 100 unrelated healthy individuals. Mutation detection was carried out by PCR amplification of the K6A gene and direct DNA sequencing.</p><p><b>RESULTS</b>A heterozygous mutation of T--> C transition at position 521 in exon 1 of the K6A gene was found in the 2 affected, but not in the unaffected members and 100 unrelated healthy individuals.</p><p><b>CONCLUSION</b>The mutation of 521T--> C in the K6A gene is the disease causing mutation in this PC-I family.</p>

Nuevos horizontes en el tratamiento de las callosidades plantares de la paquioniquia congénita / New horizons in the treatment of plantar callosities congenital pachyonychia

Los avances recientes en el campo de la terapia génica, tales como el desarrollo de ARN de cadena corta inhibitorios (ARNsi) capaces de silenciar la expresión de alelos mutados dominantes, ofrecen nuevas expectativas para el tratamiento de la queratodermia plantar en pacientes con paquioniquia congénita. Revisamos brevemente las características clínicas de esta entidad y describimos un estudio de fase 1 que arrojó resultados prometedores. Los mismos serían aplicables a todo el campo de las enfermedades monogénicas.

Recent advances in the genetic therapy field like development of short inhibitory RNA (RNAsi) capable of silencing mutant dominant alleles, offer new expectations for treatment of plantar keratoderma in patients with pachyonichya congenita. We briefly review clinical features of this entity and describe a fase 1 study that showed promising results that may be usefull for the whole monogenic diseases field.

Paquioniquia congénita: a propósito de un caso / Pachyonichia congenita: a case report

Niña de 08 años de edad, sin antecedentes familiares que desde el nacimiento presenta distrofiaungueal hipertrófica, a los 2 años de edad se agrega hiperqueratosis plantar, cuadro compatible con paquioniquia congénita tipo 1 o de Jadassohn Lewandowsky. No hay tratamiento curativo exitoso. Se reportan terapéuticas desde amputación de las falanges distales, electrocoagulación de la matriz ungueal, medidas ortopédicas, uso de queratolíticos, etc. Según últimas experiencias, la isotretinoina oral seria una buena opción tanto para la distrofia ungueal como para la queratodermiapalmo plantar.

Girl of 08 years of age, unique in her family who from the birth presents/displays hypertrophic ungueal dystrophy, to the 2 years of age adds plantar hiperqueratosis, compatible picture with paquioniquia congenital type 1 or of Jadassohn Lewandowsky. There is no successful curative treatment. They are reported therapeutic from amputation of distales phalanges, orthopaedic electrocoagulaciónof the ungueal matrix, measures, use of queratolíticos, etc. According to you complete experiences, the serious oralisotretinoina a good option as much for the ungueal dystrophy as for queratodermiaplantar.

Pachyonychia congenita with unusual features.

Pachyonychia congenita is a rare hereditary disorder characterized by gross thickening of all finger and toenails. We report an infant who had clinical features consistent with pachyonychia congenita type II, with unusual features of microcephaly, seizures, electroencephalogram abnormalities, failure to thrive, and heterochromia iridis.

Two mutations of the KRT6A gene in Chinese patients with pachyonychia congenita type I / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the gene mutation in a Chinese pedigree and one sporadic case with pachyonychia congenita type I(PC-1), as well as to explore the relationship between the genotype and phenotype.</p><p><b>METHODS</b>The whole coding region of the KRT16 and KRT6A genes were amplified by long-range polymerase chain reaction (PCR). Six patients with PC-1 were studied, five of them were from a pedigree and the other one was sporadic. One unaffected member in the pedigree and 100 unrelated healthy individuals were also studied in order to exclude polymorphism. PCR products were directly sequenced to detect the mutation.</p><p><b>RESULTS</b>No mutations in the KRT16 gene were observed. All patients harbored a mutation in the KRT6A gene. All five patients in the pedigree had a mutation at codon 465 (TAC to CAC) which substitutes tyrosine (Y) by histidine (H). In the sporadic patient, codon 171 (AAC) was mutated to GAC, which changes the asparagines (N) to aspartic acid (D). No such mutations were found in the unaffected member of the pedigree and the 100 unrelated controls. The mutation of Y465H is located at the end of 2B and N171D at the beginning of 1A domain of KRT6A, both are hotspots for pathogenic keratin mutations.</p><p><b>CONCLUSION</b>The mutations Y465H and N171D of the KRT16A gene were detected in the pedigree and the sporadic case respectively. The Y465H mutation was a novel mutation, and the N171D mutation was reported recently.</p>

Dermatology case diagnosis, Steatocystoma multiplex

A patient with multiple subcutaneous mobile lesions limited to forearms is presented. Pathologic review of the biopsy confirmed the diagnosis

A Case of Pachyonychia Congenita / 대한피부과학회지

Pachyonychia congenita is an uncommon genodermatosis of abnormal keratinization characterized by dystrophic nails and hyperkeratosis of the palms, soles, oral mucosa, and hair follicles. Mutations in keratin 6, 16, and 17 have been identified in a number of families. The 4 major features of the syndrome are onychogryphosis, palmoplantar keratoderma, follicular hyperkeratosis, and oral leukokeratosis. Treatment is only palliative, however, with attempts directed at improving symptoms that cause significant disability. We report a case of pachyonychia congenita in a 5-day-newborn with characteristic changes of nail, palms, soles, and oral mucosa.