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

Abstract

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.

Off-label use of tocilizumab to treat non-juvenile idiopathic arthritis in pediatric rheumatic patients: a literature review

“…The condition, caused by a mutation in SLC29A3, is characterized by severe autoinflammation and the increased production of pro-inflammatory cytokines. Four patients with PHID whose disease manifestations had emerged at the age of 2–5 years were treated with tocilizumab [77, 78]. In the three patients who received a TNF inhibitor after MTX or cyclosporin, the symptoms continued.…”

H syndrome: Clinical, histological and genetic investigation in Tunisian patients

“…Since 2014, 17 patients have been reported. 11,20,[23][24][25][26][27][28][29][30] Molho-Pessach et al 5 emphasized that the finding of several different mutations in a small geographic region implies that H syndrome may be rather common and underdiagnosed owing to the fact that many patients have a very mild clinical presentation. In our context, geographic endogamy is frequent in Tunisia, especially in rural areas where it could reach 90% and familial endogamy or interrelated marriages are profoundly rooted with an estimated rate of 30% of all kind of unions.…”

Homozygosity for a novel large deletion in SLC29A3 in a patient with H syndrome

“…Treatment options reported in the literature include systemic corticosteroids, methotrexate, cyclosporine, cyclophosphamide, interferon alfa, colchicine, interleukin‐1 receptor antagonists, canakinumab, adalimumab, nonsteroidal anti‐inflammatory drugs, tocilizumab, and radiotherapy, primarily for the inflammatory features of the disorder . Treatment with tocilizumab may show the most promise as partial to complete response has been reported with the use of this drug …”

“…[9][10][11] Treatment with tocilizumab may show the most promise as partial to complete response has been reported with the use of this drug. 10,12 Our patient had been evaluated and followed for many years by many specialists without consideration of H syndrome. However, given the characteristic cutaneous features, he was readily diagnosed when seen in our dermatology clinic.…”