Histiocytosis and Inflammatory Manifestations in Patients with H Syndrome

Histiocytosis and Inflammatory Manifestations in Patients with H Syndrome- a Multinational Collaboration

H syndrome is a rare genetic disorder predisposing to histiocytosis. Our knowledge of the clinical spectrum of these patients is based on case reports and small patient series. Patients with H syndrome have been treated with a range of immunomodulatory and chemotherapeutic agents, with limited success. We aim to comprehensively assess the clinical manifestations and patterns of treatment response in a multinational cohort of patients with H syndrome.

Study Overview

• Status: Recruiting
• Conditions: H Syndrome

Detailed Description

H syndrome is a rare inflammatory genetic disorder predisposing to histiocytosis, caused by germline biallelic loss-of-function mutations in SLC29A3, encoding the protein equilibrative nucleoside transporter 3 (ENT3). ENT3 transports nucleosides from lysosomes to the cytoplasm following lysosomal degradation of nucleic acids. Results from our previous study (under review) suggest a model in which impaired nucleoside trafficking aberrantly activates nucleoside-sensing Toll-like receptors, leading to persistent activation of ERK, driving histiocytosis. This constitutes a novel signaling pathway leading to activation of ERK and histiocytosis, in the absence of somatic mutations in MAPK cascade genes. Our knowledge of the heterogenous clinical spectrum of these patients is based on case reports and small patient series. Patients with H syndrome have been treated with a range of immunomodulatory and chemotherapeutic agents, with limited success. Improvement following therapy with tocilizumab, an IL6-receptor antibody, has recently been reported in isolated case reports. There is a lack of data on MEK inhibitor therapy in these patients. We aim to comprehensively assess the clinical manifestations and patterns of treatment response in a multinational cohort of patients with H syndrome.

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Sarah Elitzur, MD; Phone Number: +97239253766; Email: sarhae@clalit.org.il
• Study Contact Backup: Name: Naomi Litichever, PhD; Phone Number: +97239253705; Email: naomilitichever@clalit.org.il

Study Locations

• Israel
  • Petah Tikva, Israel
    • Recruiting
    • Schneider Children's Medical Center
    • Contact: Sarah Elitzur, MD; Phone Number: 97239253766; Email: sarhae@clalit.org.il
    • Contact: Naomi Litichever, PhD; Phone Number: 97239253705; Email: naomilitichever@clalit.org.il

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Any patient with a genetically confirmed diagnosis of H syndrome (two pathogenic or likely pathogenic germline SLC29A3 variants)

Description

Inclusion Criteria: Any patient with a genetically confirmed diagnosis of H syndrome -

Exclusion Criteria:

-

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response to therapy	complete response/partial response/stable disease/progressive disease	6 months

Collaborators and Investigators

• Sponsor: Rabin Medical Center
• Investigators: Study Director: Sarah Elitzur, MD, Schneider Children'ds Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: December 15, 2024
• First Submitted That Met QC Criteria: December 15, 2024
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 15, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: SLC29A3
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Pathologic Processes; Joint Diseases; Disease; Lymphatic Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Ear Diseases; Hearing Loss; Hearing Disorders; Syndrome; Histiocytosis; Hearing Loss, Sensorineural; Contracture
• Other Study ID Numbers: RMC-0230-24

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No