Medulloblastoma in a child with osteoma cutis - a rare association due to loss of GNAS expression.

OBJECTIVES: Inactivating GNAS mutations result in varied phenotypes depending on parental origin. Maternally inherited mutations typically lead to hormone resistance and Albright's hereditary osteodystrophy (AHO), characterised by short stature, round facies, brachydactyly and subcutaneous ossifications. Paternal inheritance presents with features of AHO or ectopic ossification without hormone resistance. This report describes the case of a child with osteoma cutis and medulloblastoma. The objective of this report is to highlight the emerging association between inactivating germline GNAS mutations and medulloblastoma, aiming to shed light on its implications for tumor biology and promote future development of targeted surveillance strategies to improve outcomes in paediatric patients with these mutations. CASE PRESENTATION: A 12-month-old boy presented with multiple plaque-like skin lesions. Biopsy confirmed osteoma cutis, prompting genetic testing which confirmed a heterozygous inactivating GNAS mutation. At 2.5 years of age, he developed neurological symptoms and was diagnosed with a desmoplastic nodular medulloblastoma, SHH molecular group, confirmed by MRI and histology. Further analysis indicated a biallelic loss of GNAS in the tumor. CONCLUSIONS: This case provides important insights into the role of GNAS as a tumor suppressor and the emerging association between inactivating GNAS variants and the development of medulloblastoma. The case underscores the importance of careful neurological assessment and ongoing vigilance in children with known inactivating GNAS variants or associated phenotypes. Further work to establish genotype-phenotype correlations is needed to inform optimal management of these patients.

Topical gene editing therapeutics using lipid nanoparticles: 'gene creams' for genetic skin diseases?

Patients living with inherited skin diseases have benefited from recent advances in DNA sequencing technologies that provide new or improved diagnostics. However, developing and delivering new treatments for the 'genodermatoses' remains challenging. The goal of creating topical preparations that can recover the inherent gene pathology remains largely aspirational. However, recent progress in two fields - the chemistry of topical delivery formulations (lipid nanoparticles) and the molecular biology of gene repair (CRISPR-Cas9, base and prime editing) - presents new opportunities to address this unmet need. In this review, we discuss how lipid nanoparticle delivery vehicles could be used to deliver gene-editing tools to formulate topical 'gene creams' suitable for the treatment of genodermatoses. We summarize the historical landscape of topical therapeutics and advances in gene editing that may herald an era of new therapies for patients with inherited skin disorders.

X-linked genodermatoses from diagnosis to tailored therapy.

Background: Genodermatoses are rare heterogeneous genetic skin diseases with multiorgan involvement. They severely impair an individual's well-being and can also lead to early death. Methods: During the progress of this review, we have implemented a targeted research approach, diligently choosing the most relevant and exemplary articles within the subject matter. Our method entailed a systematic exploration of the scientific literature to ensure a compre-hensive and accurate compilation of the available sources. Results: Among genodermatoses, X-linked ones are of particular importance and should always be considered when pediatric males are affected. Regardless of other syndromic forms without prevalence of skin symptoms, X-linked genodermatoses can be classified in three main groups: keratinization defects, pigmentation defects, and inflammatory skin diseases. Typical examples are dyskeratosis congenita, keratosis follicularis spinulosa decalvans, hypohidrotic ectodermal dysplasia, chondrodysplasia punctata, hypohidrotic ectodermal dysplasia, incontinentia pigmenti, chronic granulomatous disease, CHILD syndrome and ichthyosis. In this field, genetic diagnosis of the specific disease is important, also considering that numerous clinical trials of orphan drugs and genetic therapies are being proposed for these rare genetic diseases. Conclusions: Thus, this chapter starts from clinical to molecular testing and ends with a review of all clinical trials on orphan drugs and gene therapy for genodermatoses.

Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients.

Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disease caused by biallelic variants in the SLC2A10 gene (NG_016284.1) and characterised by tortuosity and elongation of the aorta and medium-sized arteries. It is considered an extremely rare disease; only 106 individuals with genetically confirmed ATS have been identified to date. Four cases of ATS from two families are described, contributing to the clinical delineation of this condition. A patient with microcephaly and a complex uropathy and two cases with diaphragmatic hernia are noticed. Regarding the vascular involvement, a predominant supra-aortic involvement stands out and only 1 patient with significant arterial stenoses was described. All presented severe tortuosity of the intracranial arteries. To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking treatment was prescribed. A not previously described variant (NM_030777.4:c.899T>G (p.Leu300Trp)) was detected in a proband; it has an allegedly deleterious effect in compound heterozygous state with the pathogenic variant c.417T>A (p.Tyr139Ter). The other 3 patients, siblings born to healthy consanguineous parents, had a variant in homozygous state: c.510G>A (p.Trp170Ter).

Dyschromatosis universalis hereditaria.

Reticulate pigmentary dyschromatoses primarily include dyschromatosis universalis hereditaria (DUH), dyschromatosis symmetrica hereditaria (DSH) (Reticulate acropigmentation of Dohi), and unilateral dermatomal pigmentary dermatosis, which differ in their patterns of distribution. The disease was initially described by Ichikawa and Hiraga in Germany in 1933. The prevalence of DUH is 0.3 per 100,000 with a female preponderance. The skin lesions usually appear in infancy or early childhood and cease to progress beyond adolescence. The subtypes DUH 1 and DUH 3 are found to have autosomal dominant inheritance, which is the most common inheritance pattern, while DUH 2 has an autosomal recessive pattern. The most common gene involved in DUH is ABCB6, while the other genes include SASH 1, PER 3, and KITLG (DUH type 2). DUH is characterized by multiple irregular hyperpigmented macules interspersed with hypopigmented macules in a mottled pattern over the trunk and extremities. The face is involved in 50% of individuals. Rarely, it can also involve hairs, nails, mucous membranes, palms, and soles. Other varied presentations include localized forms, localization of lesions to sun-exposed areas, large macules, uniform palmar hypopigmentation, diffuse hyperpigmentation with spotty depigmented macules, and unilateral involvement. DUH has been reported to be associated with various cutaneous and systemic diseases. The authors have observed cases of DUH associated with hepatocellular carcinoma, solitary keratoacanthoma, and dermoid cyst. The various diagnostic modalities include dermoscopy, histopathology, electron microscopy, and targeted gene sequencing. Though various treatment modalities like NBUVB and lasers have been tried, no treatment is promising.

Inherited Reticulate Pigmentary Disorders.

Reticulate pigmentary disorders (RPDs) are a group of inherited and acquired skin conditions characterized by hyperpigmented and/or hypopigmented macules. Inherited RPDs include dyschromatosis symmetrica hereditaria (DSH), dyschromatosis universalis hereditaria (DUH), reticulate acropigmentation of Kitamura (RAK), Dowling-Degos disease (DDD), dyskeratosis congenita (DKC), Naegeli-Franceschetti-Jadassohn syndrome (NFJS), dermatopathia pigmentosa reticularis (DPR), and X-linked reticulate pigmentary disorder. Although reticulate pattern of pigmentation is a common characteristic of this spectrum of disorders, the distribution of pigmentation varies among these disorders, and there may be clinical manifestations beyond pigmentation. DSH, DUH, and RAK are mostly reported in East Asian ethnicities. DDD is more common in Caucasians, although it is also reported in Asian countries. Other RPDs show no racial predilection. This article reviews the clinical, histological, and genetic variations of inherited RPDs.

Retyping and molecular pathology diagnosis of dyschromatosis universalis hereditaria.

Dyschromatosis universalis hereditaria (DUH) is characterized by diffuse symmetrically distributed hypopigmented macules mixed with hyperpigmentation. DUH is divided into three types by Online Mendelian inheritance in man (OMIM) that is, DUH1 (OMIM 127500), DUH2 (OMIM 612715) and DUH3 (OMIM 615402) according to the different linkage regions. Although each condition possesses corresponding phenotypic characteristics and the prognosis for each is somewhat different, these disorders are highly overlapped and difficult to differentiate in the clinical setting. Our latest study reveals a novel DUH subtype that presents a mild phenotype of pigmentation anomalies and is named PER3rs772027021 SNP related DUH or DUH4 by us, which make the DUH subtype can be further retyped. Heterozygous distribution or mosaic-like distribution of melanin is a newly discovered pathological features that is uniquely demonstrated in the affected layers of DUH1 and DUH4 patients. In this review, DUH is further divided into four subtypes according the causative genes and their mutational sites, and the mutation regions described in the previous reports. To make an accurate diagnosis, we suggest that Sanger sequencing or the target region sequencing (TRS) to the candidate causative genes related melanogenesis may be the most effective and convenient method of clinical diagnosis or/and prenatal diagnosis for DUH and DUH-like patients. More importantly, heterozygous distribution or mosaic-like distribution of melanin can be utilized for differential diagnosis of DUH. We also investigate the underlying molecular mechanism to form mosaic-like melanin in the affected layers of hyper- and/or hypo-pigmented macules from DUH1 and DUH4 patients. This review provides a molecular and pathological delineation of four types of DUH and aims to establish a concise diagnostic strategy to allow clinical dermatologists to make an accurate diagnosis.

Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population.

Importance: VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes. Objective: To determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach. Design, Setting, and Participants: This retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022. Exposures: Exome sequencing was performed. Main Outcomes and Measures: Outcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays. Results: In 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669). Conclusions and Relevance: This study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.

Superimposed mosaicism in cutaneous sarcoidosis: A hypothesis.

Sarcoidosis is a chronic granulomatous disorder affecting the lungs, skin, and many other organs. Twin studies suggest that genetic factors account, to a large degree, for the etiology of the disorder. Hence, theoretically, we could postulate that the phenomenon of superimposed mosaicism in the form of a pronounced segmental involvement, overlaying the disseminated non-segmental lesions, should also occur in sarcoidosis. Indeed, one case suggesting superimposed mosaicism in cutaneous sarcoidosis was found in the literature and is reassessed here.

Clinical and molecular diagnosis of genodermatoses: Review and perspectives.

Genodermatoses are a complex and heterogeneous group of genetic skin disorders characterized by variable expression and clinical and genetic heterogeneity, rendering their diagnosis challenging. DNA-based techniques, like whole-exome sequencing, can establish a diagnosis in 50% of cases. RNA-sequencing is emerging as an attractive tool that can obtain information regarding gene expression while integrating functional genomic data with regard to the interpretation of variants. This increases the diagnostic rate by an additional 10-15%. In the present review, we detail the clinical steps involved in the diagnosis of genodermatoses, as well as the current DNA-based technologies available to clinicians. Herein, the intention is to facilitate a better understanding of the possibilities and limitations of these diagnostic technologies. In addition, this review could guide dermatologists through new emerging techniques, such as RNA-sequencing and its applications to familiarizing them with future techniques. Currently, this multi-omics approach is likely the best strategy designed to promote the diagnosis of patients with genodermatoses and discover new skin disease genes that could result in novel targeted therapies.

[VEXAS syndrome : when do we have to consider it ?] / Syndrome VEXAS : quand y penser ?

VEXAS syndrome was recently discovered in patients who developed late in adulthood an inflammatory syndrome with fever, cytopenias, dysplastic bone marrow, cutaneous and pulmonary neutrophilic inflammation, arthritis, chondritis, or vasculitis. It is the result of an inactivating somatic mutation affecting methionine codon 41 of the UBA1 gene which encodes an ubiquitin activating enzyme (E1). Systemic corticosteroids generally reduce symptoms, while other immunosuppressive drugs only have limited long-term effects. Azacitidine is a promising treatment, but further studies are warranted. Here, we describe 2 new cases including one associated with pyoderma gangrenosum and cryoglobulinemia.

Le syndrome VEXAS (Vacuoles, E1 Enzyme, X-Linked, Auto- Inflammatory, Somatic Syndrome) a été récemment découvert chez des patients développant tardivement à l'âge adulte un syndrome inflammatoire associé à de la fièvre, des cytopénies, une moelle osseuse dysplasique, une inflammation neutrophilique cutanée et pulmonaire, des arthrites, des chondrites ou des vasculites. Il est le résultat d'une mutation somatique inactivatrice affectant le codon méthionine 41 du gène UBA1 qui encode une enzyme E1 activant l'ubiquitine. Les corticostéroïdes systémiques permettent généralement de diminuer les symptômes alors que les autres immunosuppresseurs ont un effet limité à long terme. L'azacitidine est l'un des traitements ayant démontré une efficacité, cependant de nouvelles études sont souhaitables. Nous décrivons ici 2 cas dont l'un est associé à un pyoderma gangrenosum et une cryoglobulinémie.

Evaluating the variety of GNAS inactivation disorders and their clinical manifestations in 11 Chinese children.

BACKGROUND: The GNAS gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of GNAS inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis. METHODS: We enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations. RESULTS: Among these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright's hereditary osteodystrophy (AHO) phenotype. GNAS abnormalities were detected in all 11 patients, including nine cases with GNAS gene variations and two cases with GNAS methylation defects. These GNAS variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > A, were found to be novel. This data was then used to assign a GNAS subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH. CONCLUSIONS: Evaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of GNAS mutations significantly. In addition, our results suggest that when GNAS gene sequencing is negative, GNAS methylation study should be performed. Early genetic detection is required for the differential diagnosis of GNAS disorders and is critical to the clinician's ability to distinguish between heterotopic ossification in the POH and AHO phenotype.

Severe dysplasminogenemia due to homozygous PLG Ala620Thr variant in a Korean woman without a history of venous thromboembolism: A case report and literature review.

RATIONALE: Plasminogen plays an important role in fibrinolysis and is encoded by the PLG gene. The missense variant PLG Ala620Thr is the major cause of dysplasminogenemia in East Asian countries, including Korea. Although dysplasminogenemia was first reported in a Japanese patient with recurrent venous thromboembolism (VTE), subsequent studies have not demonstrated any clear association between the PLG Ala620Thr variant and the risk of VTE. To the best of our knowledge, this is the first report of a homozygous PLG Ala620Thr variant case from Korea. PATIENT CONCERNS: Here, we report a Korean family with PLG Ala620Thr mutation. The proband was a 34-year-old man who presented with multiple thrombotic arterial embolism and cardiac myxoma. INTERVENTIONS: Laboratory workup, including coagulation profile and PLG gene sequencing, was carried out for the affected family. DIAGNOSIS AND OUTCOME: The proband carried a heterozygous PLG Ala620Thr variant with decreased plasminogen activity of 65%. His 53-year-old mother, who had no reported history of VTE, was homozygous for the PLG Ala620Thr variant with decreased plasminogen activity of just 25%. Decreased plasminogen activity indicates dysplasminogenemia. LESSONS: We believe that this clinically silent homozygous case supports the previous findings that isolated PLG Ala620Thr variant does not confer a significant risk of VTE.

A novel pathogenic variant in the corneodesmosin gene causing generalized inflammatory peeling skin syndrome with marked eosinophilia and trichorrhexis invaginata.

Generalized inflammatory peeling skin syndrome (PSS) is a rare autosomal recessive genodermatosis caused by loss-of-function disease-causing variants of the corneodesmosin gene (CDSN), resulting in excessive shedding of the superficial layers of the epidermis. We describe a case of generalized inflammatory PSS in an infant, presenting at day two of life with ichthyosiform erythroderma and superficial peeling of the skin. Hair microscopy showed trichorrhexis invaginata. Normal amounts of skin LEKT1, a product of SPINK5 on immunohistochemical staining excluded a diagnosis of Netherton syndrome. Genetic analysis revealed a homozygous novel complete CDSN deletion, estimated 4.6 kb in size, supporting the diagnosis of generalized inflammatory PSS.