Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) syndrome is a central nervous system (CNS) inflammatory disease characterized by contrast-enhanced MRI findings of salt-and-pepper-like lesions predominantly affecting the brainstem and cerebellum. We report two patients with CLIPPERS-like brain MRI findings who carried the same missense UNC13D variant in one allele along with deleterious variants in the opposite allele. Patient 1, a 23-year-old female, presented at 15 years of age with neurological symptoms and an MRI showing spontaneously resolving, contrast-enhancing lesions in the cerebellum. At age 16, the patient experienced an episode with systemic manifestations followed by recurrent CNS lesions that responded to steroid therapy. At age 22, the patient developed punctate to nodular contrast-enhancing lesions in the brainstem, cerebellum, and cerebrum, findings consistent with CLIPPERS. Patient 2, an 18-year-old female, presented at age 11 with ataxia and dysarthria, and an MRI showing multiple contrast-enhancing lesions in the cerebellum and brainstem, consistent with CLIPPERS MRI findings. Cerebellar biopsy revealed perivascular CD4+ T-lymphocyte infiltration, and the patient responded to steroid therapy, leading to an initial diagnosis of CLIPPERS. These patients were suspected of having inborn errors of immunity and were identified to have compound heterozygous UNC13D variants along with downregulated Munc13-4 protein. Both patients underwent allogeneic hematopoietic cell transplantation, with patient 1 remaining neurologically stable for two years post-transplantation, while patient 2 experienced a post-transplant relapse requiring steroid therapy. These cases highlight that biallelic variants in the UNC13D gene may cause CNS-predominant inflammation that mimics CLIPPERS. [Image: see text] The online version contains supplementary material available at 10.1007/s10875-026-01988-1.

Sagliker syndrome represents a rare and severe manifestation of secondary renal osteodystrophy in patients with end-stage chronic kidney disease. We present the case of a 26-year-old woman on peritoneal dialysis with a one-year history of progressive craniofacial deformity involving both the maxilla and mandible. Laboratory tests demonstrated markedly elevated parathyroid hormone levels (1,936 pg/mL). Cranial CT revealed a diffuse "salt and pepper" pattern, serpiginous lytic trabecular changes, and focal ground-glass areas in the calvarium. Correlation of severe hyperparathyroidism with these characteristic imaging features confirmed Sagliker syndrome. Early recognition is essential to prevent irreversible deformities and long-term morbidity. The patient was managed through a multidisciplinary approach, including medical optimization of secondary hyperparathyroidism, followed by total parathyroidectomy due to persistent biochemical abnormalities and progressive craniofacial deformity.

The diffuse neuroendocrine system (DNES) consists of dispersed neuroendocrine (NE) cells that bridge nervous, immune, and endocrine pathways across organs. Evolutionarily, DNES traces to primitive metazoans where single cells combined neural and immune roles, later diversifying into specialized vertebrate NE cells. Hallmark traits include dense-core granules, amine metabolism, "salt-and-pepper" chromatin, and regulation by ASCL1, NEUROG3, and INSM1. Remarkable plasticity allows immune and epithelial cells to acquire NE features under stress, while carcinomas exploit this program to form aggressive neuroendocrine tumors (NETs) and resist therapy. Canonical neuroimmune circuits, the Vagus-driven inflammatory reflex and hypothalamic-pituitary-adrenal stress axis, illustrate DNES coordination of systemic responses. Clinically, DNES-derived neoplasms span multiple organs, produce diverse hormonal syndromes, and are managed with somatostatin analogues, epigenetic drugs, and emerging immunotherapies. Recognizing DNES as a diffuse, integrative regulatory network clarifies mechanisms of chronic inflammation and cancer evolution and offers novel therapeutic entry points for disorders ranging from asthma to pancreatic neuroendocrine carcinomas.

Imaging of salivary glands (SG), particularly Salivary Glands Ultrasonography (SGUS) is increasingly used in patients with suspected Sjogren's disease (SD). SGUS is the first-line imaging modality. Numerous studies have highlighted this non-invasive, non-irradiating, and low-cost imaging modality. The OMERACT group has established a classification of SG structural damage based on B-mode findings, ranging from grade 0 (normal) to 3 (severe structural damage). SGUS abnormalities (≥ grade 2) have been reported in approximately 63 % of patients with SD. More recently, Hocevar et al. described a Doppler-based classification assessing SG parenchymal vascularization, graded from 0 (normal) to 3 (Doppler signals occupying the entire glandular surface) and could be used as a marker of disease activity and as a biomarker of response to therapy. Moreover, SGUS can be useful for looking for complications such as lymphoma. New ultrasound techniques are currently being developed, including elastography for assessing tissue stiffness, analysis of microvascularization using contrast-enhanced ultrasound with microbubbles, and analysis of minor salivary glands using the ultra-high frequency probe. The combination of several US modalities enhances both sensitivity and specificity of the technique, allowing for the development of a comprehensive multimodal imaging approach. Other imaging techniques can be performed for SD, such as MRI of the parotid glands, allowing analysis of the glandular parenchyma ("salt and pepper" appearance), and certain sequences (DWI-MR) should be performed when lymphoma or other tumors are suspected. 18-FDG PET-CT may be useful to detect systemic manifestations or complications in SD and new PET tracers are currently being developed.

Rubella retinopathy is an ocular manifestation of congenital rubella syndrome characterized by diffuse mottling of the retinal pigment epithelium classically described as a "salt-and-pepper" fundus.