Pathogenic variants in the SPTLC1 gene cause hyperkeratosis lenticularis perstans (original) (raw)
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Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis
Haematologica, 2016
Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically these were homozygous variants in USB1 (eight families), homozygous missense variants in GRHL2 (two families) and identical compound heterozygous variants in LIG4 (two families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Du...
Impact of next generation sequencing on diagnostics in a genetic skin disease clinic
Abstract: Individuals with inherited skin diseases often pose one of the most difficult diagnostic challenges in dermatology. The hunt for the underlying molecular pathology may involve candidate gene screening or linkage analysis, which is usually determined by the initial history, the physical findings and laboratory tests. Recent technical advances in DNA sequencing, however, are shifting the diagnostic paradigm. Notably, nextgeneration sequencing allows a more comprehensive approach to diagnosing inherited diseases, with potential savings of both time and money. In the setting of a paediatric dermatology genetics clinic in Kuwait, we therefore performed whole-exome sequencing on seven individuals without a priori detailed knowledge of the patients’ disorders: from these sequencing data, we diagnosed X-linked hypohidrotic ectodermal dysplasia (two cases), acrodermatitis enteropathica, recessive erythropoietic protoporphyria (two siblings) and localized recessive dystrophic epidermolysis bullosa (two siblings). All these groups of disorders are clinically and genetically heterogeneous, but the sequencing data proved inherently useful in improving patient care and avoiding unnecessary investigations. Our observations highlight the value of whole-exome sequencing, in combination with robust bioinformatics analysis, in determining the precise molecular pathology and clinical diagnosis in patients with genetic skin disorders, notably at an early stage in the clinical evaluation of these often complex disorders and thereby support a new paradigm for future diagnostics. Abbreviations: NGSnext, generation sequencing; WGS, whole, genome sequencing; WES, whole, exome sequencing; PolyPhen-2, polymorphism phenotyping version-2; SIFT, sorting intolerant from tolerant; HED, hypohidrotic ectodermal dysplasia; AE, acrodermatitis enteropathica; EPP, erythropoietic protoporphyria; EB, epidermolysis bullosa; RDEB, recessive dystrophic epidermolysis bullosa.
Clinico-Pathological Correlation of Acquired Palmoplantar Hyperkeratotic Disorders
Journal of Evidence Based Medicine and Healthcare
BACKGROUND Acquired hyperkeratotic disorders of the palms and soles constitute a large majority of outdoor visits in Dermatology practice. Even though they can easily be identified from their morphological appearance, treating them properly needs accurate clinical diagnosis corroborated by histopathological examination. The objectives of the present study were to find out the clinical features of patients presenting with acquired hyperkeratosis over palms and soles and to correlate the findings with that of histopathological examination. MATERIALS AND METHODS It was a hospital based study where 100 patients presenting with acquired hyperkeratosis over palms and soles were included. Clinical examination was done followed by biopsy in all cases. RESULTS Male agricultural workers in their 4 th and 5 th decade were the most common group of patients. Eczema comprised the maximum number of cases (45%), followed by psoriasis (37%). Hyperkeratosis, parakeratosis, and acanthosis were present in all cases of psoriasis while Munro's microabscess, pustule of Kogoj and suprapapillary thinning were found specific in 13%, 13% and 64.8% case of psoriasis respectively. Hyperkeratosis and acanthosis were seen in all cases of eczema whereas elongation of rete ridges and spongiosis were seen in 93.3% and 84.4% of cases respectively. The clinical findings matched with the histopathological findings in 75.6 % cases of psoriasis and 73.6% cases of eczema whereas the concordance was 100% in warts and callosity. CONCLUSION Hyperkeratotic lesions of palm and sole often present with typical clinical features and in cases in which they are absent, skin biopsy and special tests has to be done to aid diagnosis.
Dyskeratosis congenita with a novel genetic variant in the DKC1 gene: a case report
BMC medical genetics, 2018
Dyskeratosis congenita (DC) is a rare genetic disorder of bone marrow failure inherited in an X-linked, autosomal dominant or autosomal recessive pattern. It has a wide array of clinical features and patients may be cared for by many medical sub specialties. The typical clinical features consist of lacy reticular skin pigmentation, nail dystrophy and oral leukoplakia. As the disease advances, patients may develop progressive bone marrow failure, pulmonary fibrosis, oesophageal stenosis, urethral stenosis, liver cirrhosis as well as haematological and solid malignancies. Several genes have been implicated in the pathogenesis of dyskeratosis congenita, with the dyskerin pseudouridine synthase 1 (DKC1) gene mutations being the X-linked recessive gene. Herein, we report a 31-year-old male with history of recurrent febrile episodes who was found to have reticulate skin pigmentation interspersed with hypopigmented macules involving the face, neck and extremities, hyperkeratosis of palms a...
Abstract Booklet SCUR-37th Ann. Meeting. published on Behalf of ESDR-Conference Helsinki 2010, 2010
A MEMORABLE PATIENT: PAINFUL, SPIKY AND STACK-LIKE HYPERKERATOSES ON THE LEGS: HISTOLOGICAL, IMMUNOHISTO-CHEMICAL, ULTRASTRUCTURAL AND MUTATION ANALYSIS FINDINGS MUSS WH 1, Klausegger A 3, Laimer M 4,5, Haufe H 2, Hintner H 4, Bauer JW 4,5, Koller J 4 1 EM-Lab, Univ.-Inst. Pathol, 2 Univ.-Inst. Pathol, 3 Lab for Molecular Therapy/EB-House, 4 Dept. of Dermatology - 5 Div.of Molecular Dermatology and EB-House, Salzburger Landeskliniken - SALK-LKH & Paracelsus Medical University Salzburg, Austria. A 45-year-old male patient underwent mechanical ablation of painful „spiky“ and thick, stack-like hyperkeratotic plaques involving most of his both lower extremities. Pre- and postinterventional biopsies of lesional skin were processed for histology, ultrastructural evaluation and mutation analysis. Histologically, the epidermis showed a partially compact or basket-weave orthohyperkeratosis, an irregular acanthosis with discrete papillomatosis as well as scattered dyskeratotic keratinocytes. .. (unfortunately no DOI). Edit 2023-04-27: The PDF / PPT-file of the Oral Presentation (unfortunately no DOI) will be uploaded into this Academia.edu -compilation by Thursday, 2023-04-27. Regards W.H.M.
Discovery in Genetic Skin Disease: The Impact of High Throughput Genetic Technologies
Genes, 2014
The last decade has seen considerable advances in our understanding of the genetic basis of skin disease, as a consequence of high throughput sequencing technologies including next generation sequencing and whole exome sequencing. We have now determined the genes underlying several monogenic diseases, such as harlequin ichthyosis, Olmsted syndrome, and exfoliative ichthyosis, which have provided unique insights into the structure and function of the skin. In addition, through genome wide association studies we now have an understanding of how low penetrance variants contribute to inflammatory skin diseases such as psoriasis vulgaris and atopic dermatitis, and how they contribute to underlying pathophysiological disease processes. In this review we discuss strategies used to unravel the genes underlying both monogenic and complex trait skin diseases in the last 10 years and the implications on mechanistic studies, diagnostics, and therapeutics.
The genetic basis for most patients with pustular skin disease remains elusive
British Journal of Dermatology, 2017
Background Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). Objectives To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. Methods Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients-61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. Results The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset.