Expanding spectrum of "spitzoid" lesions: a small series of 4 cases with MAP2K1 mutations.
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ABSTRACT:
SUBMITTER: Kerckhoffs KGP
PROVIDER: S-EPMC8298358 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Melorheostosis is a rare non-hereditary condition characterized by dense hyperostotic lesions with radiographic "dripping candle wax" appearance. Somatic activating mutations in MAP2K1 have recently been identified as a cause of melorheostosis. However, little is known about the development, composition, structure, and mechanical properties of the bone lesions. We performed a multi-method phenotype characterization of material properties in affected and unaffected bone biopsy samples from six melorheostosis patients with MAP2K1 mutations. On standard histology, lesions show a zone with intensively remodeled osteonal-like structure and prominent osteoid accumulation, covered by a shell formed through bone apposition, consisting of compact multi-layered lamellae oriented parallel to the periosteal surface and devoid of osteoid. Compared with unaffected bone, melorheostotic bone has lower average mineralization density measured by quantitative backscattered electron imaging (CaMean: -4.5%, p = 0.04). The lamellar portion of the lesion is even less mineralized, possibly because the newly deposited material has younger tissue age. Affected bone has higher porosity by micro-CT, due to increased tissue vascularity and elevated 2D-microporosity (osteocyte lacunar porosity: +39%, p = 0.01) determined on quantitative backscattered electron images. Furthermore, nano-indentation modulus characterizing material hardness and stiffness was strictly dependent on tissue mineralization (correlation with typical calcium concentration, CaPeak: r = 0.8984, p = 0.0150, and r = 0.9788, p = 0.0007, respectively) in both affected and unaffected bone, indicating that the surgical hardness of melorheostotic lesions results from their lamellar structure. The results suggest a model for pathophysiology of melorheostosis caused by somatic activating mutations in MAP2K1, in which the genetically induced gradual deterioration of bone microarchitecture triggers a periosteal reaction, similar to the process found to occur after bone infection or local trauma, and leads to an overall cortical outgrowth. The micromechanical properties of the lesions reflect their structural heterogeneity and correlate with local variations in mineral content, tissue age, and remodeling rates, in the same way as normal bone. © 2018 American Society for Bone and Mineral Research.
| S-EPMC8302214 | biostudies-literature
Project description:CONTEXT:GLIS3 (GLI-similar 3) is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with 5 C2H2-type zinc finger domains. The protein is expressed early in embryogenesis and plays a critical role as both a repressor and activator of transcription. Human GLIS3 mutations are extremely rare. OBJECTIVE:The purpose of this article was determine the phenotypic presentation of 12 patients with a variety of GLIS3 mutations. METHODS:GLIS3 gene mutations were sought by PCR amplification and sequence analysis of exons 1 to 11. Clinical information was provided by the referring clinicians and subsequently using a questionnaire circulated to gain further information. RESULTS:We report the first case of a patient with a compound heterozygous mutation in GLIS3 who did not present with congenital hypothyroidism. All patients presented with neonatal diabetes with a range of insulin sensitivities. Thyroid disease varied among patients. Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation. We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia and confirm further cases with sensorineural deafness and exocrine pancreatic insufficiency. CONCLUSION:We report new findings within the GLIS3 phenotype, further extending the spectrum of abnormalities associated with GLIS3 mutations and providing novel insights into the role of GLIS3 in human physiological development. All but 2 of the patients within our cohort are still alive, and we describe the first patient to live to adulthood with a GLIS3 mutation, suggesting that even patients with a severe GLIS3 phenotype may have a longer life expectancy than originally described.
| S-EPMC4596041 | biostudies-literature
Project description:Biallelic intronic repeat expansion in the replication factor complex unit 1 (RFC1) gene has recently been described as a cause of late onset ataxia with degeneration of the cerebellum, sensory pathways and the vestibular apparatus. This condition is termed cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Since the identification of this novel gene mutation, the phenotypic spectrum of RFC1 mutations continues to expand and includes not only CANVAS but also slowly progressive cerebellar ataxia, ataxia with chronic cough (ACC), isolated sensory neuropathy and multisystemic diseases. We present a patient with a genetically confirmed intronic repeat expansion in the RFC1 gene with a symptom complex not described previously.
| S-EPMC9171309 | biostudies-literature
Project description:ImportanceSpitzoid lesions are a group of melanocytic tumors characterized by spindle-like or epithelioid cells with variable malignant potential. While some spitzoid lesions are classified as evidently benign or malignant by clinic and histology, others present with unclear clinical and histological characteristics and are categorized as lesions of intermediate biologic potential. These lesions represent a challenge for pathologists and clinicians alike. No consensus on ancillary diagnostics and clinical management exists. Prediction of their clinical course is difficult. The implementation of ancillary diagnostics is currently subject of extensive discussions.ObservationsWe report three cases of spitzoid lesions in three young female patients (3-, 15- and 17 years old) from a single reference center with different clinical and histological manifestations. In each case, uncertain clinical and histological presentation led to the stepwise application of additional diagnostics using immunohistochemistry and a custom next generation sequencing panel optimized for melanocytic lesions (MelArray). Combining ancillary diagnostics helped determine clinical management in all cases by characterizing the biology of these lesions.Conclusions and relevanceWe illustrate how clinical, histological and molecular features contribute to an optimized management plan in these critical situations and present a possible algorithm for the assessment of spitzoid neoplasms.
| S-EPMC7825637 | biostudies-literature
Project description:BackgroundThe association between mutations in the TNFAIP3 gene and a new autoinflammatory disease (called A20 haploinsufficiency, HA20) has recently been recognized. Here, we describe four patients with HA20 from two unrelated Chinese families.Case presentationA total of four patients from two families were included. The average age at onset was 5.9 years. All patients had no signs of eye or skin problems, such as uveitis, rash, folliculitis and dermal abscess. Prior to the recognition of HA20, P1 was diagnosed with SLE, liver fibrosis and hypothyroidism. She also had no oral, genital or perineal ulcers. P2 was diagnosed with Crohn's disease and inflammatory bowel disease-related arthritis (IBD-RA). He had a perianal abscess but no oral or genital ulcers. P3, the father of P1 and P2, only had mild oral ulcers, arthralgia, and archosyrinx. P4 was diagnosed with polyarticular juvenile idiopathic arthritis (JIA), macrophage activation syndrome (MAS) and interstitial lung disease (ILD). Whole exome sequencing (WES) was performed in two families. WES revealed heterozygous c.559C > T in the TNFAIP3 gene in P1, P2 and P3, while the c.259C > T mutation in the TNFAIP3 gene was identified in P4. The c.259C > T mutations is novel.ConclusionHA20 had a different phenotype between families and even between family members with the same mutation. Liver fibrosis, hypothyroidism, ILD and MAS in the patients with HA20 were first reported in this study. Our results expanded the phenotype and genotype spectrum of A20 haploinsufficiency.
| S-EPMC6624950 | biostudies-literature
Project description:Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis. The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative regulatory domain. Affected bone displays a mosaic pattern of increased p-ERK1/2 in osteoblast immunohistochemistry. Osteoblasts cultured from affected bone comprise two populations with distinct p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell proliferation. However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology. Mosaicism is also detected in the skin overlying bone lesions in four of five patients tested. Our data show that the MAP2K1 oncogene is important in human bone formation and implicate MEK1 inhibition as a potential treatment avenue for melorheostosis.
| S-EPMC5895796 | biostudies-literature
Project description:Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different PEX genes. This includes PEX16, an important regulator of peroxisome biogenesis. Using whole genome sequencing, we detected previously unreported, biallelic variants in PEX16 [NM_004813.2:c.658G>A, p.(Ala220Thr) and NM_004813.2:c.830G>A, p.(Arg277Gln)] in an individual with leukodystrophy, spastic paraplegia, cerebellar ataxia, and craniocervical dystonia with normal plasma very long chain fatty acids. Using olfactory-neurosphere derived cells, a population of neural stem cells, we showed patient cells had reduced peroxisome density and increased peroxisome size, replicating previously reported findings in PEX16 cell lines. Along with alterations in peroxisome morphology, patient cells also had impaired peroxisome function with reduced catalase activity. Furthermore, patient cells had reduced oxidative stress levels after exposure to hydrogen-peroxide (H2O2), which may be a result of compensation by H2O2 metabolising enzymes other than catalase to preserve peroxisome-related cell functions. Our findings of impaired catalase activity and altered oxidative stress response are novel. Our study expands the phenotype of PEX16 mutations by including dystonia and provides further insights into the pathological mechanisms underlying PEX16-associated disorders. Additional studies of the full spectrum of peroxisomal dysfunction could improve our understanding of the mechanism underlying PEX16-associated disorders.
| S-EPMC6072801 | biostudies-other
Project description:The aim of the study was to investigate the frequency and types of mutations on the retinoblastoma gene (RB1 gene) in Turkish population. RB1 gene mutation analysis was performed in a total of 219 individuals (122 probands with retinoblastoma, 14 family members with retinoblastoma and 83 clinically healthy family members). All 27 exons and close intronic regions of the RB1 gene were sequenced for small deletions and insertions using both the Sanger sequencing or NGS methods, and the large deletions and duplications were investigated using the MLPA analysis and CNV algorithm. The bilateral/trilateral retinoblastoma rate was 66% in the study population. The general frequency of RB1 gene mutation in the germline of the patients with retinoblastoma was 41.9%. Approximately 51.5% of the patients were diagnosed earlier than 12 months old, and de novo mutation was found in 32.4% of the patients. Germline small genetic rearrangement mutations were detected in 78.9% of patients and LGRs were detected in 21.1% of patients. An association was detected between the eye color of the RB patients and RB1 mutations. 8 of the mutations detected in the RB1 gene were novel in the study.
| S-EPMC10489529 | biostudies-literature
Project description:BackgroundCornelia de Lange Syndrome (CdLS) is a rare genetic disorder characterized by a range of physical, cognitive, and behavioral abnormalities. This study aimed to perform a comprehensive review of the literature on CdLS and investigate two cases of CdLS with distinct phenotypes that underwent WES to aid in their diagnosis.MethodsWe conducted a comprehensive review of the literature on CdLS along with performing whole-exome sequencing on two CdLS patients with distinct phenotypes, followed by Sanger sequencing validation and in-silico analysis.ResultsThe first case exhibited a classic CdLS phenotype, but the initial WES analysis of blood-derived DNA failed to identify any mutations in CdLS-related genes. However, a subsequent WES analysis of skin-derived DNA revealed a novel heterozygous mutation in the NIPBL gene (NM_133433.4:c.6534_6535del, p.Met2178Ilefs*8). The second case was presented with a non-classic CdLS phenotype, and WES analysis of blood-derived DNA identified a heterozygous missense variant in the SMC1A gene (NM_006306.4:c.2320G>A, p.Asp774Asn).ConclusionsThe study shows the importance of considering mosaicism in classic CdLS cases and the value of WES for identifying genetic defects. These findings contribute to our understanding of CdLS genetics and underscore the need for comprehensive genetic testing to enhance the diagnosis and management of CdLS patients.
| S-EPMC10787426 | biostudies-literature
Project description:Primary congenital glaucoma (PCG) and early onset glaucomas are one of the major causes of children and young adult blindness worldwide. Both autosomal recessive and dominant inheritance have been described with involvement of several genes including CYP1B1, FOXC1, PITX2, MYOC and PAX6. However, mutations in these genes explain only a small fraction of cases suggesting the presence of further candidate genes.To elucidate further genetic causes of these conditions whole exome sequencing (WES) was performed in an Italian patient, diagnosed with PCG and retinal detachment, and his unaffected parents. Sanger sequencing of the complete coding region of COL1A1 was performed in a total of 26 further patients diagnosed with PCG or early onset glaucoma. Exclusion of pathogenic variations in known glaucoma genes as CYP1B1, MYOC, FOXC1, PITX2 and PAX6 was additionally done per Sanger sequencing and Multiple Ligation-dependent Probe Amplification (MLPA) analysis.In the patient diagnosed with PCG and retinal detachment, analysis of WES data identified compound heterozygous variants in COL1A1 (p.Met264Leu; p.Ala1083Thr). Targeted COL1A1 screening of 26 additional patients detected three further heterozygous variants (p.Arg253*, p.Gly767Ser and p.Gly154Val) in three distinct subjects: two of them diagnosed with early onset glaucoma and mild form of osteogenesis imperfecta (OI), one patient with a diagnosis of PCG at age 4 years. All five variants affected evolutionary, highly conserved amino acids indicating important functional restrictions. Molecular modeling predicted that the heterozygous variants are dominant in effect and affect protein stability and thus the amount of available protein, while the compound heterozygous variants act as recessive alleles and impair binding affinity to two main COL1A1 binding proteins: Hsp47 and fibronectin.Dominant inherited mutations in COL1A1 are known causes of connective tissues disorders such as OI. These disorders are also associated with different ocular abnormalities, although recognition of the common pathology for both features is seldom being recognized. Our results expand the role of COL1A1 mutations in different forms of early-onset glaucoma with and without signs of OI. Thus, we suggest including COL1A1 mutation screening in the genetic work-up of glaucoma cases and detailed ophthalmic examinations with fundus analysis in patients with OI.
| S-EPMC4970237 | biostudies-literature