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Clinical Case Reports Oct 2021There are various causes of childhood poikiloderma. A proper history and clinical examination may help to get conclusion and narrow down the differentials for the causes...
There are various causes of childhood poikiloderma. A proper history and clinical examination may help to get conclusion and narrow down the differentials for the causes of poikiloderma.
PubMed: 34703608
DOI: 10.1002/ccr3.4977 -
Skin Health and Disease Mar 2021Rare syndromic skin disorders may represent a diagnostic challenge.
BACKGROUND
Rare syndromic skin disorders may represent a diagnostic challenge.
AIMS
We report a unique case associating cutaneous manifestations and developmental delay.
MATERIALS & METHODS
The affected 14 months old boy had poikiloderma, facial dysmorphism with deep-set eyes, atrichia, as well as nail dysplasia and non-descended testes. In addition, his psychomotor development was delayed. Exome sequencing and molecular karyotyping via array-CGH (oligo-array, 180k Agilent, design 22060) were performed.
RESULTS
Mutations in RECQL4 (found in patients with RTS2) were first excluded. In the ANAPC1 gene, a novel combination of a recurrent intronic mutation (c.2705-198C>T) and a deletion of the second ANAPC1 allele was detected, thus confirming the clinical diagnosis of RTS1. The deletion on chromosome 2q13 comprised further genes and spanned 1,7 megabases. Heterozygous deletions in this region are known as 2q13 microdeletion syndrome and are associated with developmental delay, autism and facial dysmorphism.
DISCUSSION
The genetic findings most probably explain both, the RTS1 features and the developmental delay. Genetic diagnosis in RTS is indispensable to confirm the specific subtype and its associated risks: juvenile cataracts are features of RTS1 (ANAPC1 gene), whereas a high risk of osteosarcoma is part of RTS2 (RECQL4 gene). Thus, the patient described here is at high risk for the development of juvenile cataracts and requires regular ophthalmologic examination.
CONCLUSION
This case report underlines the necessity of thorough clinical diagnosis prior to genetic diagnosis of RTS1, since the recurrent intronic ANAPC1 mutation is otherwise missed.
PubMed: 35664819
DOI: 10.1002/ski2.12 -
PLoS Genetics Dec 2021Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes,...
Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.
Topics: Adenosine Triphosphate; Cell Proliferation; Cell Respiration; Cellular Senescence; Electron Transport Complex I; Gene Expression Regulation, Developmental; Humans; Induced Pluripotent Stem Cells; Mitogen-Activated Protein Kinase Kinases; Mutation; Osteoblasts; Osteogenesis; Osteosarcoma; Oxadiazoles; Oxidative Phosphorylation; Piperidines; RNA, Long Noncoding; RecQ Helicases; Rothmund-Thomson Syndrome
PubMed: 34965247
DOI: 10.1371/journal.pgen.1009971 -
Experimental and Therapeutic Medicine Nov 2020Kindler syndrome (KS) is a rare subtype of epidermolysis bullosa that is inherited in an autosomal recessive manner with mutations in . A number of mutations in have...
Kindler syndrome (KS) is a rare subtype of epidermolysis bullosa that is inherited in an autosomal recessive manner with mutations in . A number of mutations in have been identified in KS. The current study reported a 33-year-old Chinese man who exhibited a wide variety of clinical features, including formation of blisters, photosensitivity, cutaneous atrophy and poikiloderma, telangiectasia of the face and neck, contracture of the end limbs, nail dystrophy, muscle, eye and oral damage, tympanitis, esophagus narrowing, pneumothorax and palmoplantar keratoderma. The patient's parents were healthy and the patient had no siblings or children. Peripheral blood was obtained from the patient, his parents and 100 controls, who were admitted to the Dermatology Clinic of Shanghai Skin Disease Hospital, Shanghai, China. A multi-gene panel test consisting of 541 genetic loci of monogenic hereditary diseases was performed. The results identified one novel homogenous mutation in the patient: c.1885_1901del (p.Val629fs) on exon 15 in . The patient's parents exhibited heterogeneous identical mutations. This mutation was absent in the control group. The results of the multi-gene panel test were further verified by Sanger sequencing. Based on the clinical manifestations and genetic analysis, KS was diagnosed in the patient. The current study reported a Chinese case of KS with one novel mutation c.1885_1901del in and presented a brief summary of all pathogenic mutations in that have been reported in KS between 1984 and May 2020 via a PubMed literature search.
PubMed: 32973952
DOI: 10.3892/etm.2020.9233 -
European Journal of Dermatology : EJD Aug 2020
Topics: Amyloidosis; Chronic Disease; Female; Humans; Hyperpigmentation; Hypopigmentation; Middle Aged; Skin Diseases
PubMed: 32969819
DOI: 10.1684/ejd.2020.3827 -
Journal of Pediatric Genetics Mar 2023Kindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood,...
Kindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.
PubMed: 36684545
DOI: 10.1055/s-0040-1721077 -
Familial Cancer Jan 2023Rothmund-Thomson syndrome, a heterogeneous genodermatosis with autosomal recessive hereditary pattern, is an uncommon cancer susceptibility genetic syndrome. To date,...
Rothmund-Thomson syndrome, a heterogeneous genodermatosis with autosomal recessive hereditary pattern, is an uncommon cancer susceptibility genetic syndrome. To date, only 400 cases have been reported in the literature, and the severity of the features varies among individuals with the condition. Here, we describe a 55-year-old male who had been diagnosed with Bloom Syndrome during childhood due to the suggestive physical features such as short stature, chronic facial erythema, poikiloderma in face and extremities, microtia and microcephaly. However, the genetic test demonstrated that the patient carried two pathogenic variants resulting in compound heterozygous in the RECQL4 gene (c.2269C>T and c.2547_2548delGT). He subsequently developed a calcaneal osteosarcoma, which was successfully treated, and has currently been oncologic disease-free for 3 years.
Topics: Male; Humans; Middle Aged; Rothmund-Thomson Syndrome; RecQ Helicases; Bloom Syndrome
PubMed: 35781852
DOI: 10.1007/s10689-022-00303-2 -
Pediatric Dermatology Jul 2022Two siblings presented with sun sensitivity and progressive dyspigmentation. A diagnosis of xeroderma pigmentosum was initially favored due to XPC mutations, although...
Two siblings presented with sun sensitivity and progressive dyspigmentation. A diagnosis of xeroderma pigmentosum was initially favored due to XPC mutations, although variants were not clearly diagnostic. However, new moderate neutropenia and homozygous suspected pathogenic variants in USB1 led to diagnosis of poikiloderma with neutropenia. This case highlights the importance of reevaluation of diagnosis due to significant phenotypic overlap in congenital disorders of photosensitivity with poikiloderma or dyspigmentation.
Topics: Connective Tissue Diseases; Homozygote; Humans; Mutation; Neutropenia; Phosphoric Diester Hydrolases; Skin Abnormalities
PubMed: 35522049
DOI: 10.1111/pde.15007 -
Pediatric Dermatology Sep 2020FILS syndrome (facial dysmorphism, immunodeficiency, livedo, and short stature) is a rare autosomal recessive disorder caused by pathogenic alterations in the POLE gene... (Review)
Review
FILS syndrome (facial dysmorphism, immunodeficiency, livedo, and short stature) is a rare autosomal recessive disorder caused by pathogenic alterations in the POLE gene leading to multisystemic manifestations, including poorly characterized skin findings. We report a child with a homozygous variant, c.100C > T (p.Arg34Cys), in POLE and features consistent with poikiloderma, expanding the dermatologic signs associated with this rare disorder. Additionally, we review reported cases of FILS syndrome, discuss possible pathomechanisms for our patient's presentation, and consider implications for management.
Topics: Abnormalities, Multiple; Child; Dwarfism; Homozygote; Humans; Musculoskeletal Abnormalities
PubMed: 32705701
DOI: 10.1111/pde.14274 -
Clinical and Experimental Dermatology Jun 2021A 5-year-old boy presented with generalized cutaneous erosions, severe scarring, depigmentation and contractures affecting major joints. The lesions had initially...
A 5-year-old boy presented with generalized cutaneous erosions, severe scarring, depigmentation and contractures affecting major joints. The lesions had initially affected his ears, nose, feet, and the genital and ocular mucosa, leading to significant depigmentation, scarring, contractures and mutilation. The whole of the trunk and limbs were involved at the time of presentation, with the exception of some islands of spared skin on the proximal thighs, legs, nipples and external genitalia. Electron microscopy revealed a split in the sublamina densa with the absence of anchoring fibrils, suggestive of dystrophic epidermolysis bullosa (EB). Immunofluorescence antigen mapping demonstrated a broad reticulate pattern of staining with collagen IV, VII, and laminin 332 in the floor of the blister, suggestive of Kindler syndrome. Next-generation sequencing revealed a de novo heterozygous missense mutation (a variant of unknown significance) in exon 22 of the phospholipase-C gamma 2 gene (PLCG2), which resulted in a substitution of serine by asparagine at codon 798 (p.Asp798Ser), a result that was validated using Sanger sequencing. The child was diagnosed with PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) syndrome. The cutaneous and corneal erosions, inflammation and scarring of this magnitude, and the eventual result of death have not been described previously for the PLAID/APLAID spectrum previously. In conclusion, this was an unusual acquired autoinflammatory severe EB-like disease that may be associated with de novo PLCG2 mutation.
Topics: Blister; Child, Preschool; Epidermolysis Bullosa; High-Throughput Nucleotide Sequencing; Humans; Male; Microscopy, Electron; Mutation, Missense; Periodontal Diseases; Phenotype; Phospholipase C gamma; Photosensitivity Disorders; Skin
PubMed: 33625737
DOI: 10.1111/ced.14557