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Blood Science (Baltimore, Md.) Apr 2023Rothmund-Thomson syndrome (RTS) is a rare autosomal-recessive disorder with clinical features consisting of rash, poikiloderma, sparse hair, short stature, juvenile...
Rothmund-Thomson syndrome (RTS) is a rare autosomal-recessive disorder with clinical features consisting of rash, poikiloderma, sparse hair, short stature, juvenile cataracts, skeletal abnormalities, and cancer predisposition. Genetic studies involving detection of pathogenic variants provide the diagnostic certitude. Osteosarcoma was found in two-thirds -mutated RTS patients, while hematological malignancies were rarely reported. The variant diversity of gene has not been fully identified and mutations associated with hematologic malignancies are not well described. In this study, we presented a pedigree of RTS from a Chinese family, among which the proband was diagnosed with de novo myelodysplastic syndrome (MDS). Comprehensive medical examination and chromosome karyotyping were performed on the proband. Whole exome sequencing (WES) was performed on the proband, his sister and his mother. The familial cosegregation of sequence variants derived from WES was conducted by polymerase chain reaction-based Sanger sequencing. Structures of candidate RECQL4 mutants were done by in silico analysis to assess pathogenicity. Three novel germline variants, including c.T274C, c.G3014A, and c.G801C, were identified by WES and validated by Sanger sequencing. Prediction of conformation indicated that the structural stability of human RECQL4 protein was largely affected with these variants. The co-occurring p.S34F and p.Y220C mutations might contribute to the development of MDS. Our study expands the mutational spectrum of and provides underlying molecular mechanism for the development of MDS in RTS patients.
PubMed: 37228773
DOI: 10.1097/BS9.0000000000000152 -
Contemporary Clinical Dentistry Apr 2014Kindler syndrome is a rare hereditary disorder, associated with skin fragility. The syndrome involves the skin and mucous membrane with radiological changes. The genetic...
Kindler syndrome is a rare hereditary disorder, associated with skin fragility. The syndrome involves the skin and mucous membrane with radiological changes. The genetic defect has been identified on the short arm of chromosome 20. This report describes a 16-year-old patient with classical features like blistering and photosensitivity in childhood and the subsequent development of poikiloderma.
PubMed: 24963250
DOI: 10.4103/0976-237X.132342 -
Dermatology Practical & Conceptual Jan 2021
PubMed: 33614208
DOI: 10.5826/dpc.1101a111 -
American Journal of Medical Genetics.... Oct 2022POIKiloderma, tendon contractures, myopathy, pulmonary fibrosis is a congenital multisystem disorder due to FAM111B dominant variants. We present a literature review... (Review)
Review
Expanding phenotype of FAM111B-related disease focusing on liver involvement: Literature review, report of a case with end-stage liver disease and proposal for a new acronym.
POIKiloderma, tendon contractures, myopathy, pulmonary fibrosis is a congenital multisystem disorder due to FAM111B dominant variants. We present a literature review focusing on the frequency and the impact of hepatic involvement and a case report of a patient with severe end-stage liver disease. Whole exome sequencing (WES) was conducted on the proband and his parents. A de novo FAM111B: c.1879A > G; (p.Arg627Gly) variant was identified. Hepatic involvement is present in 11 out of the 30 patients described in the literature, with different levels of dysfunction ranging from mild transaminitis to liver fibrosis found in three different cases by liver biopsies. Liver involvement seems to be a significant cause of morbidity. We propose to modify the previous acronym in POIK-TMPL: including POIKiloderma, tendon contractures, myopathy, pulmonary fibrosis/pancreas insufficiency and cancer, liver involvement/lymphedema. Moreover, we suggest screening patients with FAM111B variants for liver involvement from the first month of life and continue with an appropriate follow-up. Further studies are needed to better understand this frequent complication.
Topics: Atrophy; Cell Cycle Proteins; Contracture; End Stage Liver Disease; Humans; Muscular Diseases; Pancreatic Diseases; Phenotype; Pulmonary Fibrosis; Skin Abnormalities
PubMed: 35869874
DOI: 10.1002/ajmg.a.62906 -
Frontiers in Cell and Developmental... 2023Hereditary fibrosing poikiloderma (HFP) is a rare human dominant negative disorder caused by mutations in the gene that encodes a nuclear trypsin-like serine protease....
Hereditary fibrosing poikiloderma (HFP) is a rare human dominant negative disorder caused by mutations in the gene that encodes a nuclear trypsin-like serine protease. HFP patients present with symptoms including skin abnormalities, tendon contractures, myopathy and lung fibrosis. We characterized the cellular roles of human FAM111B using U2OS and MCF7 cell lines and report here that the protease interacts with components of the nuclear pore complex. Loss of expression resulted in abnormal nuclear shape and reduced telomeric DNA content suggesting that FAM111B protease is required for normal telomere length; we show that this function is independent of telomerase or recombination driven telomere extension. Even though -deficient cells were proficient in DNA repair, they showed hallmarks of genomic instability such as increased levels of micronuclei and ultra-fine DNA bridges. When mutated as in HFP, FAM111B was more frequently localized to the nuclear envelope, suggesting that accumulation of the mutated protease at the nuclear periphery may drive the disease pathology.
PubMed: 37342232
DOI: 10.3389/fcell.2023.1175069 -
Orphanet Journal of Rare Diseases Oct 2015Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic...
BACKGROUND
Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients.
METHODS
Clinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected.
RESULTS
Key features consist of: (i) early-onset poikiloderma, hypotrichosis and hypohidrosis; (ii) multiple contractures, in particular triceps surae muscle contractures; (iii) diffuse progressive muscular weakness; (iv) pulmonary fibrosis in adulthood and (v) other features including exocrine pancreatic insufficiency, liver impairment and growth retardation. Muscle magnetic resonance imaging was informative and showed muscle atrophy and fatty infiltration. Histological examination of skeletal muscle revealed extensive fibroadipose tissue infiltration. Microscopy of the skin showed a scleroderma-like aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two recurrent mutations were found respectively in three and four independent families). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain-of-function or dominant-negative mutations resulting in FAM111B enzymatic activity changes.
CONCLUSIONS
HFP with tendon contractures, myopathy and pulmonary fibrosis, is a multisystemic disorder due to autosomal dominant FAM111B mutations. Future functional studies will help in understanding the specific pathological process of this fibrosing disorder.
Topics: Adolescent; Adult; Amino Acid Sequence; Cell Cycle Proteins; Child; Child, Preschool; Contracture; Female; Humans; Infant; Male; Middle Aged; Molecular Sequence Data; Muscular Diseases; Mutation; Pulmonary Fibrosis; Sclerosis; Skin Abnormalities; Skin Diseases, Genetic; Tendons
PubMed: 26471370
DOI: 10.1186/s13023-015-0352-4 -
Indian Journal of Dermatology 2016Kindler's syndrome (KS) is a rare inherited skin disease characterized by acral blistering, photosensitivity, progressive poikiloderma, and cutaneous atrophy along with...
Kindler's syndrome (KS) is a rare inherited skin disease characterized by acral blistering, photosensitivity, progressive poikiloderma, and cutaneous atrophy along with different types of mucosal involvement. We hereby report KS in two siblings. The case is being reported for its rarity and for emphasizing the importance of considering this condition in the differential diagnosis of disorders that may cause blistering, cutaneous atrophy, and/or poikilodermatous skin changes. Besides, the presentation of the disease in two of the members of the same family makes the case even more interesting.
PubMed: 27512212
DOI: 10.4103/0019-5154.185767 -
Haematologica Oct 2016Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate...
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 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 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/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements.
Topics: DNA Ligase ATP; DNA-Binding Proteins; Dyskeratosis Congenita; Exome; Genetic Variation; Humans; Pedigree; Phosphoric Diester Hydrolases; Sequence Analysis, DNA; Syndrome; Transcription Factors
PubMed: 27612988
DOI: 10.3324/haematol.2016.147769 -
Journal of Pharmacological Sciences Jan 2021In the present study, we investigated the renoprotective effects of long-term treatment with yohimbine, an α-adrenoceptor inhibitor, in a 5/6 nephrectomy-induced...
In the present study, we investigated the renoprotective effects of long-term treatment with yohimbine, an α-adrenoceptor inhibitor, in a 5/6 nephrectomy-induced chronic kidney disease (CKD) rat model. Male Sprague-Dawley rats were randomly allocated into the following groups: sham-operated, 5/6-nephrectomized (5/6 Nx), 5/6 Nx + low or high dose of yohimbine (0.3 or 3.0 mg/L in drinking water, respectively), and 5/6 Nx + hydralazine (250 mg/L in drinking water). The 5/6 Nx group presented with renal dysfunction, hypertension, noradrenaline overproduction, and histopathological injuries. Blood pressure decreased in both the yohimbine- and hydralazine-treated groups. Treatment with high dose of yohimbine, but not hydralazine, apparently attenuated urinary protein excretion and noradrenaline concentration of renal venous plasma. Renal fibrosis and upregulated fibrosis-related gene expression were suppressed by high dose of yohimbine. Furthermore, yohimbine, but not hydralazine, treatment ameliorated the urinary concentration ability. These findings suggest that long-term yohimbine treatment can be a useful therapeutic option to prevent the progression of CKD.
Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Blister; Disease Models, Animal; Disease Progression; Epidermolysis Bullosa; Fibrosis; Hydralazine; Male; Nephrectomy; Norepinephrine; Periodontal Diseases; Photosensitivity Disorders; Proteinuria; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Yohimbine; Rats
PubMed: 33357783
DOI: 10.1016/j.jphs.2020.11.001 -
The Journal of Investigative Dermatology Mar 2012In this issue, Lai-Cheong et al. report a patient with Kindler syndrome who showed revertant mosaicism: a patch of normal-looking skin attributable to a reverse...
In this issue, Lai-Cheong et al. report a patient with Kindler syndrome who showed revertant mosaicism: a patch of normal-looking skin attributable to a reverse mutation. The molecular basis of the reverted patch appeared to be the deletion of a duplicated cytosine, thus restoring the reading frame of FERMT1 transcripts. This finding further pushes the frontier of revertant mosaicism, a phenomenon of spontaneous gene repair, which can be seen with the naked eye in skin.
Topics: Blister; Epidermolysis Bullosa; Humans; Male; Mosaicism; Periodontal Diseases; Photosensitivity Disorders
PubMed: 22327264
DOI: 10.1038/jid.2011.445