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Primary localised cutaneous nodular amyloidosis is a rare form of amyloidosis characterised by amyloid deposition in the skin but a lack of further organ involvement; therefore, it is not a systemic disease that progresses to complication. Limited knowledge exists on the causes and outcomes of long-term cutaneous nodular amyloidosis patients. This study reports a case of a woman in her late 80s presenting with a primary cutaneous nodular amyloidosis, with yellow, white plaques and a focal area of violaceous nodules along the inferior lumbar spine. Notably, this rash has been present for nearly 40 years. Histopathological examination revealed amyloid deposits, but further examination showed no amyloid systemic involvement. Recognition of primary nodular amyloidosis through skin biopsy is essential, and current clinical recommendations are to perform pathology examinations to make the diagnosis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: We present the histopathology of 12 skin biopsies from 6 patients with vacuoles, enzyme E1, X-linked, autoinflammatory, somatic syndrome and review the literature. The age of these 6 men ranges from 62 to 83 years (median of 70 years). UBA1 mutation was documented in all 6 patients. Multiple organ systems were involved with constitutional symptoms noted in 4 of 6 patients (67%), cutaneous involvement in 6 of 6 patients (100%), hematologic abnormalities in 6 of 6 patients (100%), pulmonary involvement in 4 of 6 patients (67%), musculoskeletal abnormalities in 3 of 6 patients (50%), vascular thrombosis in 2 of 6 patients (33%), ocular involvement in 2 of 6 patients (33%), and gastrointestinal involvement in 5 of 6 patients (83%). Of the 6 presented patients, neutrophilic dermatosis was seen in 3 biopsies, histiocytoid neutrophilic dermatosis in 1 biopsy, neutrophilic dermatosis with vasculitis in 1 biopsy, neutrophilic and granulomatous dermatitis in 2 biopsies, septal panniculitis consistent with erythema nodosum in 2 biopsies, and nonspecific patterns in 3 biopsies. In summary, neutrophilic dermatosis, small-vessel vasculitis, and panniculitis are frequent histopathologic patterns noted in decreasing frequency in skin biopsies of the patients with vacuoles, enzyme E1, X-linked, autoinflammatory, somatic syndrome. However, the histopathologic findings can be diverse, nonspecific in some instances, and varied among different biopsies obtained from the same patient., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Conflicts of interest Dr Piguet has received honoraria or fees for consulting and/or speaking for AbbVie, Almirall, Celgene, Janssen, Novartis, and Pfizer and has received departmental support for Cardiff University from AbbVie, Almirall, Alliance, Beiersdorf UK Ltd, Biotest, Celgene, Dermal, Eli Lilly, Galderma, Genus Pharma, Globe Micro, Janssen-Celag, La Roche-Posay, L'Oreal, LEO Pharma, Meda, MSD, Novartis, Pfizer, Sinclair Pharma, Spirit, Stiefel, Samumed, Thornton Ross, TyPham, and UCB and for University of Toronto from Sanofi. Dr Croitoru has received honoraria or fees for consulting and/or speaking for AbbVie, Amgen, Bausch Health, Boehringer-Ingelheim, Novartis, Pfizer, Sanofi-Regeneron, and UCB. Drs Huang, McMullan, and Maazi have no conflicts of interests to declare.

Background: Amyloidosis is characterized by extracellular amyloid protein deposition. When amyloidosis intersects with basal cell carcinoma (BCC), it introduces complex diagnostic challenges. This study explored the overlap between primary localized cutaneous amyloidosis (PLCA) and BCC, examining amyloid deposits in BCC, systemic amyloidosis risk in PLCA, and various treatment methods., Methods: Two case studies were discussed, followed by a literature review, in which PubMed, Web of Science, EMBASE, and the Cochrane Library databases were utilized. The search, covering studies from infinity up to January 2024, focused on "cutaneous amyloidosis," "basal cell carcinoma," and related terms. Articles in English detailing the clinical presentation, diagnostic methods, treatment, and outcomes of cutaneous amyloidosis mimicking BCC were included. Data extraction and synthesis were performed by two independent reviewers., Case Series: This study highlighted two cases exemplifying the complexity of diagnosing BCC and PLCA. The first case (a 64-year-old with a nodule on the cheek) and the second (a 67-year-old with a nodular lesion on the upper lip cheek) were initially suspected as BCC and were later identified as PLCA upon histopathological examination., Discussion: The diagnosis of amyloidosis within BCC nodules remains a diagnostic challenge. Although their coexistence is relatively prevalent, their local recurrence rates remain debatable. Various diagnostic and therapeutic approaches have been suggested, such as topical creams and phototherapy. However, none have garnered conclusive and consistent evidence to establish reliable clinical application., Conclusion: The findings emphasized the importance of considering alternative pathologies in differential diagnoses. Future research should focus on understanding systemic amyloidosis risks and optimizing care for both conditions., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Cervical arterial tortuosity is associated with adverse outcomes in Loeys-Dietz syndrome and other heritable aortopathies., Methods and Results: A method to assess tortuosity based on curvature of the vessel centerline in 3-dimensional space was developed. We measured cervical carotid tortuosity in 65 patients with Loeys-Dietz syndrome from baseline computed tomography angiogram/magnetic resonance angiogram and all serial images during follow-up. Relations between baseline carotid tortuosity, age, aortic root diameter, and its change over time were compared. Patients with unoperated aortic roots were assessed for clinical end point (type A aortic dissection or aortic root surgery during 4 years of follow-up). Logistic regression was performed to assess the likelihood of clinical end point according to baseline carotid tortuosity. Total absolute curvature at baseline was 11.13±5.76 and was relatively unchanged at 8 to 10 years (fold change: 0.026±0.298, P =1.00), whereas tortuosity index at baseline was 0.262±0.131, with greater variability at 8 to 10 years (fold change: 0.302±0.656, P =0.818). Baseline total absolute curvature correlated with aortic root diameter ( r =0.456, P =0.004) and was independently associated with aortic events during the 4-year follow-up (adjusted odds ratio [OR], 2.64 [95% CI, 1.02-6.85]). Baseline tortuosity index correlated with age ( r =0.532, P <0.001) and was not associated with events (adjusted OR, 1.88 [95% CI, 0.79-4.51]). Finally, baseline total absolute curvature had good discrimination of 4-year outcomes (area under the curve=0.724, P =0.014), which may be prognostic or predictive., Conclusions: Here we introduce cervical carotid tortuosity as a promising quantitative biomarker with validated, standardized characteristics. Specifically, we recommend the adoption of a curvature-based measure, total absolute curvature, for early detection or monitoring of disease progression in Loeys-Dietz syndrome.

Background: Stiff skin syndrome (SSS) is a rare disease characterized by thickened, indurated skin and limited joint movement. Multiple diverse phenotypes have been reported, and the correlation of severity with the clinical heterogeneity and histopathological findings of SSS needs to be refined., Objective: To define subtypes based on clinical features and predict the prognosis of a new SSS classification., Methods: Eighty-three patients with SSS were retrospectively reviewed for clinicopathological manifestations and routine laboratory workup, including 59 cases obtained from a PubMed search between 1971 and 2022 and 24 cases diagnosed in our department between 2003 and 2022., Results: Among the 83 patients, 27.7, 41, and 31.3% had classic widespread, generalized segmental, and localized SSS, respectively. Joint immobility was present in 100, 71, and 20% of classic, generalized, and localized cases, respectively. Histopathologic findings were common among the 3 groups, and based on that, we further found a difference in the distribution of proliferative collagen. 54.5% of classic and 50% of generalized cases occurred throughout the dermis or the subcutis, whereas 76% of localized cases were mainly involved in the reticular dermis or subcutis. In patients with incipient localized SSS, 42% (21/50) developed generalized SSS, and only 6% (3/50) progressed to classic SSS, whereas more than half of the incipient generalized SSS cases (60.6%, 20/33) developed classic SSS., Limitations: This retrospective study was limited to previously published cases with limited data., Conclusions: We propose a distinct clinical classification characterized by lesion distribution, including classic widespread, generalized segmental, and localized SSS, associated with disease severity and prognosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Variations in ZNF469 have been associated with Brittle Cornea Syndrome that presents with bluish sclera, loss of vision after trivial trauma, arachnodactyly, and joint laxity., Materials and Methods: Detailed medical and family history, physical examination, and molecular analysis., Results: A 21-year-old female presented with bluish discoloration of sclera, diminution of vision following trivial trauma in childhood along with hearing loss and systemic features of arachnodactyly and joint laxity. Clinical diagnosis of brittle cornea syndrome was made which was molecularly proven using next-generation sequencing which identified compound heterozygosity in ZNF469 for pathogenic and likely pathogenic nonsense variants. One variant namely NM&#95;001367624.2:c.5882dup was identified in the exon 3 which was novel and classified as likely pathogenic according to American College of Medical Genetics (ACMG) criteria for variant classification. Another variant NM&#95;001367624.2:c.8992C>T in the exon 2 was classified as pathogenic for Brittle Cornea Syndrome 1., Conclusions: The report adds to the allelic heterogeneity in ZNF469 causative of Brittle Cornea Syndrome 1 and shall acquaint the physicians about this potentially vision threatening, underdiagnosed, rare syndrome.

Skin cancers are associated with a large number of genodermatoses. Existing knowledge and guidelines on the presentations of these genodermatoses focus disproportionately on White patients. Our goal is to identify notable characteristics in location, frequency, and severity of cutaneous findings along with the median age of skin cancers in skin-of-color (SOC) patients with skin-cancer-associated genodermatoses to improve diagnosis rates. We searched for genodermatoses on six databases. Each case report or case series was reviewed, including reports, published in English, containing adult patient descriptions. Duplicate manuscripts were removed using EndNote. The following case-level data were collected from the manuscripts: age, gender, patient country or region of origin, author country/continent of residence, skin cancer-related, and other key dermatologic features. 381 published articles, with a total of 578 SOC patients, met criteria for inclusion. SOC patients can present with fewer classic findings, such as a lower incidence of basal cell carcinomas (44%) in SOC Gorlin syndrome patients than palmar pits (66%) and mandibular cysts (66%). Differences between SOC populations were also noted, such as leukoplakia being more common in Asian dyskeratosis congenita patients (80%) in comparison to African dyskeratosis congenita patients (44%). SOC patients also have varying onset of skin cancer depending on the genodermatosis, from a median of 25 years of age in Rothmund-Thomson syndrome to 53 in Muir-Torre syndrome. In this review, SOC patients with genodermatoses can have varying presentations. Being cognizant of these characteristics may lead to earlier diagnosis and interventions to mitigate skin-cancer-related morbidity in SOC patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Arterial tortuosity syndrome is an extremely rare hereditary connective tissue disorder. We present a case of an incidentally diagnosed aneurysm of the aortic root and the ascending aorta caused by arterial tortuosity syndrome, which was confirmed genetically. The aneurysm was repaired surgically. One year after the procedure, there was no further dilation of the aorta or formation of new aneurysms.

Competing Interests: Conflicts of interest the authors declare no conflicts of interest.

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.

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., (© 2023 the International Society of Dermatology.)

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 PER3 rs772027021 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., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2022 European Academy of Dermatology and Venereology.)

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., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

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.

Perifolliculitis capitis abscedens et suffodiens (PCAS) is a chronic skin inflammatory disease characterized by relapsing folliculitis and painful, fluctuant abscesses, sinus tracts, and scars. The treatment of PCAS is challenging and clinical practice varies a lot, and how to choose the best treatment for PCAS is a real problem for clinicians. We reviewed articles providing treatment options for patients with PCAS in different databases. Dermatologists may find this review helpful to meet the challenges of PCAS management, but there is still a lack of authoritative guidelines. In the future, more robust randomized control trials are needed to determine the best treatment for PCAS., (© 2022 Wiley Periodicals LLC.)

Ligneous conjunctivitis is a rare form of chronic, recurrent conjunctivitis characterized by wood-like, fibrinous pseudomembranes, which may be associated with systemic disease manifestations. It has been associated with congenital plasminogen (PLG) deficiency that is inherited with an autosomal recessive pattern due to mutations in the PLG gene and a variety of other genes, leading to disturbed wound healing. In this case report, we present the clinical, laboratory, and histopathological findings of a 36-year-old female patient who presented at the ophthalmology department with complaints of redness, irritation for the previous few weeks, and appearance of membranous lesions mainly on the tarsal conjunctivae. During biomicroscopic examination we found thick, yellowish-white pseudomembranes, and conjunctival proliferation with ligneous induration on the conjunctiva, located on the upper eyelids. Histopathological evaluations showed up ligneous conjunctivitis and laboratory evaluation confirmed a severe plasminogen deficiency (PLG < 2%). The patient was treated with topical fresh frozen plasma (FFP), topical steroids, heparin eye drops, and artificial tear drops daily, without systemic therapy.

Background: Primary cutaneous amyloidosis (PCA) is apruritic and potentially disfiguring disorder; this disease is usually diagnosed clinically due to its common occurrence. However, for cases with atypical presentations or for those physicians not familiar with PCA, the diagnosis can be a challenge., Objective: To observe the characteristics of PCA under dermoscopy and reflectance confocal microscopy (RCM) in order to gain experience and reference for clinicians to facilitate diagnosis., Methods: The typical lesions of 110 patients with primary cutaneous amyloidosis were observed by dermoscopy and RCM, and scanning results were recorded. Thirty patients followed by complete excision for histopathological analysis., Results: A total of 110 patients with clinically diagnosed PCA were enrolled. Forty-seven patients had lesions consistent with macular amyloidosis and 63 with lichen amyloidosus. The dermoscopic findings of PCA shared a common feature, each 'macule' was composed of a central hub pattern surrounded by brownish pigmentation, The pattern of the central hub could be brown, white, scar-like and structureless area. RCM features of total patients consisted of dermal papilla present cloud-like agglomerate which are high refractive index., Conclusions: Dermoscopy and reflectance confocal microscopy can be used in the diagnosis of PCA, which can provide a basis for doctors to diagnose., (© 2022 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

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., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

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&#95;212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565&#95;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., (© 2022. The Author(s).)