BACKGROUND: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene.
METHODS: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing.
RESULTS: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein.
CONCLUSIONS: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition.

OBJECTIVE: Within the large umbrella of histiocytosis are a few similar yet heterogenous entities involving the orbit and periocular tissues with or without systemic infiltration, termed adult onset xanthogranuloma or orbital xanthogranuloma. Due to rarity of these conditions, different classifications in use, diverse clinical presentations and still unknown etiology, the aim of this paper was to provide an up-to-date literature review of the actual understanding of histiocytosis and its subgroups involving the orbit and periocular area, diagnostic strategies and therapeutic modalities.
METHODS: We present a review of literature and small case series comprising four patients diagnosed and treated in the period from 2001 until 2023 in our hospital. Clinical files of 4 patients with adult-onset xanthogranulomatous disease of the orbit and ocular adnexa (AOXGD) were reviewed retrospectively. Clinical, laboratory, radiological, histopathological, and immunohistochemical findings were reexamined.
RESULTS: Reviewing medical records of our patients with AOXGD, we found significant overlap between histiocytosis and different immune disorders. A broad workup should be considered in these patients as they can harbour severe immune disfunctions and hematologic disorders. Preferred treatment modality depends on a histopathologic type of AOXGD, clinical presentation and systemic involvement and should be conducted multidisciplinary.
CONCLUSIONS: The diagnosis is often delayed because of its rarity and diverse clinical findings. Development of molecular genetic tests, detection of BRAF V600E mutation and different types of kinase mutations, mutations in transcriptional regulatory genes as well as tyrosine kinase receptors have shed a new light on the etiopathogenesis and potential targeted treatment of histiocytosis.

Cutaneous Rosai Dorfman disease (CRDD) is a rare histiocytic disorder that shows distinctive clinical presentation and prognosis. Sufficient data is currently lacking regarding evidence-based management of CRDD. This systematic review aims to provide a comprehensive overview of CRDD, focusing on treatment approaches and outcomes. PubMed and Scopus databases were searched for studies on CRDD from June 1st, 2013 to May 31st, 2023. Articles describing cases of CRDD confirmed with histological examination were eligible for inclusion. All interventions for CRDD were analyzed. The primary outcome measure was the response of cutaneous lesions to treatment including complete response (CR), partial response (PR), and no response. The secondary outcome measures were mortality rate, relapse rate, and the occurrence of adverse events related to CRDD treatment. Eighty-seven articles describing 118 CRDD cases were included. The mean age was 48.2±16.8 years. The sex ratio (F/M) was 1.53. Nodular (46.6%) erythematous (45.3%) lesions, located on the face (38.1%) were the most prevalent presentations. Associated hematological malignancies were noted in 8 (6.8%) cases. Surgical excision was the most prevalent intervention (51 cases) with CR in 48 cases. Systemic corticosteroids were used in 32 cases with 20 CR/PR, retinoids in 10 cases with 4 CR/PR, thalidomide in 9 cases with 5 CR/PR, methotrexate in 8 cases with 7 CR/PR while observation was decided in 10 cases with 6 CR/PR. Factors independently associated with the absence of response to treatment were facial involvement (OR = 0.76, p = 0.014), and cutaneous lesion size (OR = 1.016, p = 0.03). This systematic review shows distinctive clinical characteristics of CRDD and provides insights into the appropriate management of the disease. It allowed a proposal of a treatment algorithm that should be interpreted in the context of current evidence and would help practitioners in treating this rare disease.

Langerhans cell histiocytosis (LCH) is a rare condition in adults, especially when it is limited to a single area of the skull, known as solitary calvarial involvement. In this case report, we present a unique instance of LCH affecting the parietal bone with a pus-draining fistula. This is a rare and unusual presentation at this location, which has been scarcely reported in medical literature. A 30-year-old woman with no prior comorbidity presented with complaints of headache that persisted for a year. She also had swelling on her scalp and a yellowish discharge for 3 weeks, but no neurological problems were observed. Radiology revealed thinning of the calvaria, with ragged margins along the inner table, multiple focal erosions, and involvement of overlying soft tissue and bony sequestrum. The patient underwent biparietal craniotomy and excision of the lesion. The histopathology report showed LCH. After 8 months of follow-up, there was no recurrence. The management of solitary calvarial involvement by LCH with masquerading presentation as a scalp infection can be achieved through complete excision of the lesions, resulting in a favorable outcome.

Erdheim-Chester Disease (ECD) is a rare form of histiocytosis characterized by xanthomatous infiltration of affected organs. We present a case of a 62-year-old man with ECD initially presenting with constrictive pericarditis. Comprehensive imaging revealed systemic involvement, including the skeleton, orbit, pituitary, lung, kidney, and retroperitoneum, despite the absence of related symptoms. The diagnosis of ECD was eventually confirmed through histopathological evidence from a CT-guided biopsy. The patient responded well to interferon-α2b treatment, with gradual symptom amelioration and improvement in imaging and laboratory findings over a 5-month follow-up period. This case highlights the importance of considering ECD in the differential diagnosis of constrictive pericarditis and the utility of multimodal imaging for accurate diagnosis and management of this rare disease. The patient\'s positive response to treatment also highlights the potential for effective management of ECD, particularly with early diagnosis and intervention.

Langerhans cell histiocytosis (LCH) is a rare disease with limited treatment options. We present a case involving a 57-year-old woman afflicted with an isolated LCH bone osteolytic lesion. A single bisphosphonate infusion significantly alleviated pain, and follow-up scans via CT, PET-CT, and MRI revealed a substantial recalcification of the lesion. Conducting an extensive literature review, we identified 46 cases documenting the efficacy of bisphosphonates in the context of LCH. These findings have raised interest in bisphosphonate infusion as a simple therapeutic alternative in similar situations, with benefits in terms of bone recalcification and pain control for individuals with LCH.

Intravascular lymphomas are rare disease conditions that exhibit neoplastic lymphoid cells that are confined mainly to the lumens of small capillaries and medium-sized vessels. The majority of the intravascular lymphomas are of B-cell origin, but they can include NK/T-cell and CD30+ immunophenotypes. In the histologic differential diagnosis are benign proliferations such as intralymphatic histiocytosis and intravascular atypical CD30+ T-cell proliferation. In this review, we discuss the clinical, histopathologic, and molecular findings of intravascular B-cell lymphoma, intravascular NK/T-cell lymphoma, intralymphatic histiocytosis, and benign atypical intravascular CD30+ T-cell proliferation.

Crystal-storing histiocytosis (CSH) is a rare condition in which crystals accumulate in the cytoplasm of histiocytes and is usually associated with a lymphoplasmacytic neoplasm. Cutaneous CSH is extraordinarily rare and limited to case reports in the literature. We report two cases of this disease with cutaneous involvement. Case 1 was a 65-year-old male with a 4-month history of a pruritic eruption that started as a solitary pink to skin-colored indurated plaque on the anterior neck before progressing to involve the whole neck, chest wall, and face. Case 2 was a 54-year-old woman with a history of unspecified \"lymphoma\" who presented with a soft nodule on the forearm. Biopsies from both cases had similar findings and showed a proliferation of epithelioid cells with pink cytoplasm and intracellular crystalline structures infiltrating the dermis and subcutaneous fat. In the first case, the cells were positive for CD43, CD45, CD68, and IgG kappa, and in the second case, the crystals were positive for IgG lambda. Based on these findings, the patients were diagnosed with cutaneous CSH. We highlight this rare diagnosis and the importance of investigating an underlying lymphoplasmacytic neoplasm.

Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis involving the central nervous system in 5% of cases. Spinal location occurs in less than 1% of extranodal RDD and can be responsible for neurological manifestations. We present a systematic review of cases of isolated spinal RDD. We also report a new case of isolated spinal RDD revealed by spinal cord compression.
The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the MEDLINE and SCOPUS databases and included case reports and case series describing isolated RDD of the spine.
There were 53 patients with isolated spinal RDD (including our case). The mean age was 35.85±16.48 years. Neurological deficit was the most frequent clinical presentation (89%). RDD lesions were mainly located in the thoracic spine (51%), then the cervical spine (32%). The lesion was reported to be extradural (57%), intradural extramedullary (26%), intramedullary (7%), and in the vertebral body (10%). Histological examination showed emperipolesis in 73%. Histocytes were positive for S-100 protein in 83%. Treatment was based on surgery 96%), radiotherapy, chemotherapy, and adjunctive steroid therapy were indicated in four, one, and eight cases. After a mean follow-up period of 14.84±13.00 months, recurrence of RDD was noted in 15%.
Spinal RDD is a rare condition, requiring meticulous histological examination for accurate diagnosis. Complete surgical resection is the treatment of choice. Adjuvant chemotherapy and radiotherapy can also be indicated in patients demonstrating partial improvement following surgery.

Anaplastic Lymphoma Kinase (ALK) has been implicated in several human cancers. This review aims at mapping the available literature on the involvement of ALK in non-glial tumors localized in the posterior cranial fossa and at identifying diagnostic, prognostic, and therapeutic considerations. Following the PRISMA-ScR guidelines, studies were included if they investigated ALK\'s role in primary CNS, non-glial tumors located in the posterior cranial fossa. A total of 210 manuscripts were selected for full-text review and 16 finally met the inclusion criteria. The review included 55 cases of primary, intracranial neoplasms with ALK genetic alterations and/or protein expression, located in the posterior fossa, comprising of medulloblastoma, anaplastic large-cell lymphoma, histiocytosis, inflammatory myofibroblastic tumors, and intracranial myxoid mesenchymal tumors. ALK pathology was investigated via immunohistochemistry or genetic analysis. Several studies provided evidence for potential diagnostic and prognostic value for ALK assessment as well as therapeutic efficacy in its targeting. The available findings on ALK in posterior fossa tumors are limited. Nevertheless, previous findings suggest that ALK assessment is of diagnostic and prognostic value in medulloblastoma (WNT-activated). Interestingly, a substantial proportion of ALK-positive/altered CNS histiocytoses thus far identified have been localized in the posterior fossa. The therapeutic potential of ALK inhibition in histiocytosis warrants further investigation.