BACKGROUND: VEXAS syndrome, characterized by a UBA1 gene mutation, is a rare and severe systemic inflammatory disease predominantly affecting men. Since its initial description in 2020, it has been noted for its broad clinical phenotype and frequent misdiagnosis.
METHODS: A 76-year-old Caucasian male patient diagnosed with VEXAS syndrome is presented in this case report. He presented with typical symptoms including pulmonary manifestations (infiltrates and effusions), systemic inflammation, and haematological abnormalities. The diagnosis was challenging due to the disease\'s heterogeneous presentation, often resembling autoimmune or haematological diseases. This patient\'s case featured ground-glass opacities and pleural effusions, underlining the significant pulmonary involvement seen in 50-67% of VEXAS patients. His condition was further complicated by recurrent fever and systemic inflammation affecting multiple organs.
CONCLUSIONS: VEXAS syndrome demands an aggressive treatment approach due to its high mortality rate and refractory nature. This case underscores the importance of including VEXAS syndrome in differential diagnoses, particularly for patients with systemic inflammation and pulmonary symptoms, and calls for multidisciplinary management and extensive research to understand its full range of clinical phenotypes.

VEXAS syndrome is an adult-onset autoinflammatory disease associated with hematologic symptoms. The disease affects primarily males, and leads to death of a significant proportion of the patients. VEXAS syndrome is caused by a somatic mutation of the UBA1 gene in hematopoietic progenitor cells. The clinical picture of the syndrome consists of a number of organ manifestations including those akin to rheumatic diseases, arthritis, myalgia, vasculitis and chondritis.

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Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently recognized multisystem disorder caused by somatic mutations in the UBA1 gene.
A retrospective cohort study was conducted on all patients with VEXAS syndrome evaluated at our institution from June 2020 through May 2022. Medical records and chest imaging studies were reviewed.
We identified 45 subjects with median age of 68 years (range, 57-89), all men. Prior to VEXAS diagnosis, most patients had been diagnosed with various hematologic, rheumatologic, and dermatologic disorders. Most patients (84%) demonstrated canonical UBA1 methionine-41 (p.Met41) somatic mutations in hematopoietic cells. Fever (82%), skin lesions (91%), and respiratory symptoms (93%) were common presenting features. Chest CT manifested abnormalities in 91% of patients including parenchymal opacities in 25 (74%), most commonly ground-glass opacities (47%), along with mediastinal lymphadenopathy (29%), airway abnormalities (29%), and pleural effusion (24%). Pulmonary function test results available in 18 (40%) patients demonstrated mild restrictive impairment or normal results. Bronchoalveolar lavage and lung biopsy performed in a minority of patients demonstrated neutrophilic alveolitis and parenchymal inflammation, respectively. All patients received glucocorticoid therapy with at least partial response, but relapses were common and other immunosuppressive agents were employed in most patients. Pulmonary involvement appeared to improve in patients who received tocilizumab and JAK inhibitors.
The pulmonary manifestations in VEXAS are relatively nonspecific and nonsevere, occur in the context of systemic inflammation and are responsive to escalation in glucocorticoid dosing.

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Background: Infantile X-linked spinal muscular atrophy (SMAX2) is a rare type of spinal muscular atrophy associated with UBA1 variants. Methods: Clinical imaging and neurophysiological tests were performed on a Chinese patient with SMAX2. Further, focused panel sequencing of UBA1 was carried out on samples of both the proband and his maternal relatives. Results: The proband, a 4-year-old boy with the SMAX2 phenotype, suffered from reduced exercise capacity since infancy. His other symptoms included speech difficulties, severe nasal tone, reduced distal muscle strength, areflexia, and inadequate sucking ability. The brain MRI of the proband\'s showed normal results but the electromyography results showed multiple peripheral neurogenic lesions. Five male members of the proband\'s family were affected with the SMAX2 phenotype. They presented similar symptoms and had experienced a long and autonomous life. Molecular analysis revealed a novel missense variant (c.1617G>A, p.Met539Ile) in the exon 15 of UBA1. The proband\'s mother, as well as grandmother, carried the heterozygous missense UBA1 variant; whereas, the male patients from the family carried the hemizygotic variant. Conclusions: The affected members in this Chinese family showed unique features such as extended life span, no fractures, and cramps as compared with previously reported SMAX2 cases. The novel missense variant (c.1617G>A (p.Met539Ile) in UBA1 highlights the critical role of this gene in causing SMAX2 phenotype.

X-linked infantile spinal muscular atrophy (SMAX2), OMIM 301830, is a rare, severe form of spinal muscular atrophy, caused by variants in the Ubiquitin like modifier-activating enzyme 1 (UBA1) gene. Clinical features reported to date include marked hypotonia, areflexia, arthrogryposis, contractures, myopathic facies and tongue fibrillations. Previous reports have included a history of contractures. We report a male patient presenting following a normal pregnancy with typical symptoms of X-linked infantile spinal muscular atrophy including hypotonia, weakness, areflexia and respiratory insufficiency, however contractures were absent. There was a significant family history of neuromuscular disease on the maternal side, with several male relatives all dying before the age of six months. Creatine Kinase was mildly elevated, MRI Brain was normal and neurophysiological testing revealed a diffuse motor neuronopathy. Genetic testing for SMN1 gene was normal. UBA1 sequencing revealed a maternally inherited hemizygous familial variant [c.1681G>A p. (Asp561Asn)], which has not been previously reported.

Infantile X-linked spinal muscular atrophy (SMAX2) is a rare form of spinal muscular atrophy manifesting as severe hypotonia, areflexia, arthrogryposis, facial weakness and cryptorchidism, and frequently accompanied by bone fractures. We present a male patient with SMAX2 who presented with typical symptoms at birth, preceded by reduced fetal movements in the second and third trimesters of pregnancy. Clinical examination revealed a myopathic face with a characteristic tent-shaped open mouth, tongue fibrillations, profound muscle weakness, areflexia, multiple contractures, mild skeletal abnormalities and cryptorchidism. In the first days of the patient\'s life, fractures of the right femur and right humerus were found; however, calcium-phosphate metabolism and densitometric examination were normal. Molecular analysis revealed a de novo c.1731C>T substitution in the UBA1 gene, which was localized in exon 15, the specific hot spot for mutation.