A Case of SLC29A3 Spectrum Disorder—Unresponsive to Multiple Immunomodulatory Therapies

Mistry, Anoop; Matthews, Bipin; Laws, Philip; Goodfield, Mark; Savic, Sinisa

doi:10.1007/s10875-016-0301-6

Cited by 16 publications

(13 citation statements)

References 13 publications

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“…Hypergammaglobulinemia is frequently described in patients with H syndrome, presumably as a manifestation of systemic inflammation, but selective subclass deficiency of IgG2 and IgG4 (Patient 2) is a novel finding and may or may not be a characteristic of H Syndrome. One other case report documented a low number of B memory cells, as in Patient 2, but the clinical significance of this finding is not clear [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Generally speaking, autoantibody formation does not seem to be characteristic of H syndrome, although one patient in the literature was originally diagnosed to have systemic lupus erythematosus on the basis of positive anti-double-stranded DNA antibodies [ 17 ]. IDDM is clearly associated with H syndrome, although in contrast to Patient 3, most of the patients have not had autoantibodies detected [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…Given the complexity of H Syndrome, there is a lack of consensus regarding its treatment. Despite recognition of the inflammatory nature of H syndrome, treatment has been largely unsuccessful [ 2 , 17 ]. Per previous reports, patients tend to respond poorly to agents directed against IL-1 or TNF-alpha such as anakinra, canakinumab and adalimumab, and colchicine or NSAIDs provide only partial relief [ 2 , 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…In this report, Patient 2 and 5 had a striking response to treatment with tocilizumab, a humanized monoclonal antibody directed against the IL-6 receptor, including reduction in hyperpigmentation and subcutaneous fibrosis, acceleration of growth velocity, and improvement in inflammatory indices, scrotal induration, and microcytic anemia. In contrast, Mistry et al recently reported a patient with SLC29A3 mutations who did not have clinical improvement with tocilizumab, despite normalization of the patient’s CRP [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

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H syndrome: 5 new cases from the United States with novel features and responses to therapy

et al. 2017

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BackgroundH Syndrome is an autosomal recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, and induration with numerous systemic manifestations. The syndrome is caused by mutations in SLC29A3, a gene located on chromosome 10q23, which encodes the human equilibrative transporter 3 (hENT3). Less than 100 patients with H syndrome have been described in the literature, with the majority being of Arab descent, and only a few from North America.Case presentationHere we report five pediatric patients from three medical centers in the United States who were identified to have H syndrome by whole exome sequencing. These five patients, all of whom presented to pediatric rheumatologists prior to diagnosis, include two of Northern European descent, bringing the total number of Caucasian patients described to three. The patients share many of the characteristics previously reported with H syndrome, including hyperpigmentation, hypertrichosis, short stature, insulin-dependent diabetes, arthritis and systemic inflammation, as well as some novel features, including selective IgG subclass deficiency and autoimmune hepatitis. They share genetic mutations previously described in patients of the same ethnic background, as well as a novel mutation. In two patients, treatment with prednisone improved inflammation, however both patients flared once prednisone was tapered. In one of these patients, treatment with tocilizumab alone resulted in marked improvement in systemic inflammation and growth. The other had partial response to prednisone, azathioprine, and TNF inhibition; thus, his anti-TNF biologic was recently switched to tocilizumab due to persistent polyarthritis. Another patient improved on Methotrexate, with further improvement after the addition of tocilizumab.ConclusionH syndrome is a rare autoinflammatory syndrome with pleiotropic manifestations that affect multiple organ systems and is often mistaken for other conditions. Rheumatologists should be aware of this syndrome and its association with arthritis. It should be considered in patients with short stature and systemic inflammation, particularly with cutaneous findings. Some patients respond to treatment with biologics alone or in combination with other immune suppressants; in particular, treatment of systemic inflammation with IL-6 blockade appears to be promising. Overall, better identification and understanding of the pathophysiology may help devise earlier diagnosis and better treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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H syndrome: 5 new cases from the United States with novel features and responses to therapy

et al. 2017

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“…The second patient (HS2) is a 26-year-old female of consanguineous Pakistani descent. A detailed description of the patient's clinical features and treatment history has been published previously [16]. Briefly, the patient first came to medical attention at the age of 2 years after presenting with a self-limiting, well-delineated telangiectatic rash.…”

Section: H Syndromementioning

confidence: 99%

Identification of Critical Transcriptomic Signaling Pathways in Patients with H Syndrome and Rosai-Dorfman Disease

et al. 2020

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Biallelic mutations in SLC29A3 cause histiocytosis-lymphadenopathy plus syndrome, also known as H syndrome (HS). HS is a complex disorder, with ~ 25% of patients developing autoinflammatory complications consisting of unexplained fevers, persistently elevated inflammatory markers, and unusual lymphadenopathies, with infiltrating CD68+, S100+, and CD1a− histiocytes, resembling the immunophenotype found in Rosai-Dorfman disease (RDD). We investigated the transcriptomic profiles of monocytes, non-activated (M0), classically activated (M1), and alternatively activated macrophages (M2) in two patients with HS, one without autoinflammatory (HS1) and one with autoinflammatory complications (HS2). RNA sequencing revealed a dysregulated transcriptomic profile in both HS patients compared to healthy controls (HC). HS2, when compared to HS1, had several differentially expressed genes, including genes associated with lymphocytic-histiocytic predominance (e.g. NINL) and chronic immune activation (e.g. B2M). The transcriptomic and cytokine profiles of HS patients were comparable to patients with SAID with high levels of TNF. SERPINA1 gene expression was found to be upregulated in all patients studied. Moreover, higher levels of IFNγ were found in the serum of both HS patients when compared to HC. Gene ontology (GO) enrichment analysis of the DEGs in HS patients revealed the terms “type I IFN,” “IFNγ signaling pathway,” and “immune responses” as the top 3 most significant terms for monocytes. Gene expression analysis of lymph node biopsies from sporadic and H syndrome-associated RDD suggests common underlying pathological process. In conclusion, monocytes and macrophages from both HS patients showed transcriptomic profiles similar to SAIDs and also uniquely upregulated IFNγ signature. These findings may help find better therapeutic options for this rare disorder.

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Atypical comorbidities in a child considered to have type 1 diabetes led to the diagnosis of SLC29A3 spectrum disorder

et al. 2022

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Introduction SLC29A3 spectrum disorder is an autosomal, recessively inherited, autoinflammatory, multisystem disorder characterized by distinctive cutaneous features, including hyperpigmentation or hypertrichosis, hepatosplenomegaly, hearing loss, cardiac anomalies, hypogonadism, short stature, and insulin-dependent diabetes. Case presentation Herein, we report a 6-year-old boy who presented with features resembling type 1 diabetes mellitus, but his clinical course was complicated by IgA nephropathy, pure red cell aplasia, and recurrent febrile episodes. The patient was tested for the presence of pathogenic variants in 53 genes related to monogenic diabetes and found to be compound heterozygous for two SLC29A3 pathogenic variants (p. Arg386Gln and p. Leu298fs). Conclusion This case demonstrated that SLC29A3 spectrum disorder should be included in the differential diagnosis of diabetes with atypical comorbidities, even when the distinctive dermatological hallmarks of SLC29A3 spectrum disorder are entirely absent.

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A Case of SLC29A3 Spectrum Disorder—Unresponsive to Multiple Immunomodulatory Therapies

Cited by 16 publications

References 13 publications

H syndrome: 5 new cases from the United States with novel features and responses to therapy

H syndrome: 5 new cases from the United States with novel features and responses to therapy

Identification of Critical Transcriptomic Signaling Pathways in Patients with H Syndrome and Rosai-Dorfman Disease

Atypical comorbidities in a child considered to have type 1 diabetes led to the diagnosis of SLC29A3 spectrum disorder

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