New cases expand the genotype, phenotype and therapeutic landscape of H syndrome

Over 15 years ago, the molecular cause of multiple clinical syndromes (Faisalabad histiocytosis, sinus histiocytosis with massive lymphadenopathy, H syndrome and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome) was elucidated through the discovery of biallelic mutations in SLC29A3 (encoding nucleoside transporter hENT3). These mutations are the common aetiology of a wide range of clinical presentations.1-4 SLC29A3-related histiocytosis-lymphadenopathy plus syndrome or H syndrome (OMIM #602782) is highly polymorphic and typically multisystemic, with histiocytic organ infiltration commonly identified.5 This condition is associated with significant morbidity, often involving potentially life-threatening organ infiltration (e.g. cardiomyopathy). Currently, there are no standardized treatment recommendations nor approved therapies for this condition. Small case series have reported variable efficacy of numerous immune-suppressive therapies and, more recently, mitogen-activated protein kinase (MEK) inhibitors.5, 6 Here, we report on a cohort of five patients (two families) with novel biallelic mutations in SLC29A3 and highlight striking variations in phenotype and response to targeted therapies, even within the same family. The patients' phenotypes and responses to targeted therapies are summarized in Figure 1. The following paragraphs provide further details about our cohort. Patient I.1 is the index case of family I (Canadian First Nations origin). He developed hyperpigmented and indurated skin lesions with hypertrichosis on the inner thighs and scrotum from age 7. A skin biopsy was consistent with histiocytosis, showing CD68+ and CD31+ histiocytes, with a few S100+ cells. The sample tested positive for the V600E BRAF mutation on immunohistochemistry. Investigations also revealed a chronic inflammatory syndrome, extensive subcutaneous and muscle involvement, peri-aortic numerous retroperitoneal and mediastinal lymphadenopathy and hypermetabolic lung nodules on Positron Emission Computed Tomography (PET-CT) (Figure S1A) (see Ref [7] for a detailed description of this patient). Histiocytes were also found in broncho-alveolar lavage. Clinical sequencing of a panel of genes revealed a biallelic deletion of exons 3–6 of SCL29A3. The patient was initially treated with sirolimus (target level: 7–10 ng/mL), with slow progression of the lesions over the next 5 years (associated with compliance problems) (Figure S1B,C). Next, tocilizumab (162 mg/week, subcutaneously [SC]) was initiated, effectively suppressing chronic biological inflammation over the next 2 years, but it failed to improve other infiltrative manifestations (Figure 2A; Figure S1D). Under this treatment, the patient also developed acute peripheral neuropathy resembling Guillain–Barré syndrome, with favourable evolution after Intravenous Immunoglobulins (IVIG). Trametinib was introduced at an initial dose of 1 mg daily, tapered to 0.5 mg daily because of acne. After 6 months, there was a significant improvement in skin infiltration. The cutaneous and subcutaneous infiltration has also significantly abated on PET-CT (Figures 1 and 2B; Figure S1E). Patient I.2 was tested positive for the same biallelic deletion at age 6, following her brother's (I.1) diagnosis, in the context of limited cutaneous hyperpigmentation and muscle infiltration in the lower limbs. Mild hypoacusia was also noted. Lesions remained stable for 1.5 years on sirolimus, but ultimately progressed. Mild chronic inflammatory syndrome also persisted. After transient monotherapy with steroids, she was switched to tocilizumab (162 mg/week, subcutaneous (SC)). After 2.5 years on this therapy, there is resolution of the inflammatory syndrome, but slowly progressive infiltration of the (sub)cutaneous and muscle infiltration in lower limbs (Figure 1; Figure S2A–D). Treatment with MEK inhibitor is being considered. The third child (I.3) of family I was found to carry the same biallelic deletion during family screening. Antenatal ultrasound had detected a benign cardiac malformation (inferior vena cava interruption with hemi-azygous draining into the left superior vena cava). The first cutaneous signs appeared at the age of 2. By age 3, she presented with syncope due to ventricular tachycardia amid diffuse hypertrophic cardiomyopathy (Figure S3A–D). She received steroids and tocilizumab along with antiarrhythmics. Implantable pacemaker and defibrillator were placed. Three and a half years later, she has shown a favourable evolution under tocilizumab (162 mg/2 weeks, SC) and metoprolol, with only mild right ventricular hyperplasia on ultrasound. Patient II.1 presented at age 45 with a progressive scalp mass, headaches and vision loss. Investigations showed a large scalp mass infiltrating the parieto-occipital bone and intracranial spaces (Figure 2C,D). Thoraco-abdominal CT scan showed periaortic and retroperitoneal infiltration (involving the kidneys and pancreas) and lymphadenopathy, overall suggestive of retroperitoneal fibrosis (Figure 2E,F). A biopsy of the scalp mass revealed an abnormal proliferative lymphocyte population positive for CD20, BCL-2 and BCL-6, without histiocytes, BRAF or CD68+ cells. Polymerase chain reaction (PCR) confirmed a clonal population expressing a specific gamma light chain. Biopsies of the pancreas and a coeliac lymph node showed acellular fibrous tissue, without malignant cells. A diagnosis of scalp follicular lymphoma with cranial and intracranial expansion was made, in addition to retroperitoneal and periaortic fibrosis. Given the family history of retroperitoneal fibrosis in the sister (see patient II.2), sequencing of SLC29A3 was performed and showed a biallelic deletion of exons 3–6. The patient was treated with an R-CHOP plus methotrexate regimen. Treatment of the infiltrative lesions surrounding the optic nerve with anakinra was moderately successful. The patient died after five chemotherapy cycles due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia despite maximum intensive care, steroids and tocilizumab. We first met patient II.2 (the twin sister of patient II.1) at age 46 years, for familial genetic testing. She was diagnosed at 14 years old with idiopathic retroperitoneal fibrosis leading to bilateral iliac venous thrombosis and uretero-hydronephrosis requiring a nephrostomy. She had been treated with various steroid doses since her diagnosis. She also reported a history of lower leg oedema and purpuric lesions. At age 22, she underwent triple arthrodesis of both feet for severe pes plano with rocker bottom deformity. She later developed refractory seronegative arthropathy of the interphalangeal joints and was treated with long-term steroids (5–10 mg daily), hydroxychloroquine, sulfasalazopyrin, leflunomide, rituximab (three doses of 500 mg/m2, at month 0, 1 and 6) and abatacept (125 mg SC during 4.5 years). Sequencing of SLC29A3 was performed, confirming the same biallelic deletion of exons 3–6. At age 47 years (during therapy with abatacept and leflunomide), she presented with persistent fever, lymphadenopathies and general malaise. Investigations were remarkable for pancytopenia, undetectable fibrinogen and elevated ferritin levels (>1500 μg/L). Bone marrow aspiration revealed significant haemophagocytosis. A broad workup for secondary haemophagocytosis was negative. A diagnosis of haemophagocytic lymphohistiocytosis (HLH) was made, presumably related to H syndrome. She first received high-dose steroids (1 g/day intravenous (IV) methylprednisolone for 5 days, then 60 mg/day progressively tapered to 5 mg/day over 2 months) and anakinra for 14 days (up to 400 mg daily), then was switched to tofacitinib (20 mg/day). She has been stable over the last 2.5 years under low-dose prednisone (5 mg/day) and tofacitinib (tapered to 10 mg/day) (Figure 1). In summary, this report describes five cases of H syndrome caused by a novel SLC29A3 variant (exons 3–6 deletion) and emphasizes how the broad clinical heterogeneity (including within families) makes the assessment of treatment response and disease monitoring challenging in this disorder. In our series, interleukin-6 receptor (IL6-R) inhibitors, Janus Kinase (JAK) inhibitors and trametinib have shown promising efficacy on specific manifestations. Three of five patients in this series have suffered from a life-threatening manifestation. While HLH and lymphoma are classical complications of canonical inborn errors of immunity or other histiocytic disorders, this is the first description of lymphoma and the second case of HLH in H syndrome.8 New therapeutic options for H syndrome are arising, with still no clear guidelines for treating this disease. Based on a small series and reports from the literature, inflammatory symptoms seem to respond to IL6-R blockade or JAK inhibition, while histiocytic organ infiltration may be more refractory.9 Recently, three patients with organ infiltration (i.e. central nervous system, skin, heart) had a favourable response to MEK inhibitors after follow-ups ranging from 1 month to 2 years (2/3 having previously failed tocilizumab).5, 9, 10 In addition, a significant proportion of manifestations seem independent from the inflammatory pathogenesis and/or irreversible under current therapies (i.e. endocrine and orthopaedic involvement). Developing better evidence on treatment efficacy and/or guidelines will be challenging in this highly heterogeneous disorder, but should be possible through collaborations and detailed reporting of treatment responses. CT: data collection, writing the original draft, literature review. JB, PMC, HC, JD, MK, GM, JP and ST: data generation and curation, reviewing the original draft. GC and FT: data generation and curation, reviewing the original draft and supervision. We thank the patients and their families for participating in this study. We confirm that no artificial intelligence technology has been used at any stage of the conception or writing of this manuscript. CT is partly funded by WBI World (Bourses d'excellence, Wallonie-Bruxelles International) and Fondation CHU Sainte-Justine. The authors have no conflicts of interest to disclose. The patients were included in the study according to the CHU Sainte-Justine Institutional Review Board (protocol reference #3195). 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