Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome

Abstract

Mutations in SLC29A3 lead to pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy plus syndrome. We report a new association of PHID syndrome with severe systemic inflammation, scleroderma-like changes, and cardiomyopathy. A 12-year-old girl with PHID syndrome presented with shortness of breath, hepatosplenomegaly, and raised erythrocyte sedimentation rate and C-reactive protein. An echocardiogram showed biventricular myocardial hypertrophy, and cardiac magnetic resonance imaging showed circumferential late gadolinium enhancement of the myocardium. No systemic amyloid deposits were observed on a whole-body serum amyloid P scintigraphy scan. Abdominal ultrasound revealed intra-abdominal fat surrounding the solid organs, suggesting a possibility of evolving lipodystrophy with visceral adiposity. PHID syndrome is a novel monogenic autoinflammatory syndrome (AIS) associated with severe elevation of serum amyloid. Lipodystrophy, cutaneous sclerodermatous changes, and cardiomyopathy were also present in this case. In contrast to other AIS, blockade of interleukin-1 and tumor necrosis-α was ineffective.

The H Syndrome: Molecular Diagnosis Using Next-Generation Sequencing

“…This multisystem disorder is caused by mutations in the SLC29A3 gene, which encodes nucleoside transporter hENT3 (1). Patients with this syndrome were initially described in families of Arab and Bulgarian origin having consanguineous parents (1,2). A few patients have been reported from India (3,4).…”

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

“…Here a 12 year old girl presented scleroderma-like changes, cardiomyopathy, hepatosplenomegaly, and raised erythrocyte sedimentation rate and CRP. Although she was found to have significantly elevated serum amyloid A, no systemic amyloid deposits were observed on a whole-body serum amyloid P scintigraphy scan [11]. More recently, Fujita et al reported a male patient with characteristics of H syndrome in addition to Raynaud's phenomenon and retroperitoneal fibrosis [12].…”

“…In Melki's case colchicine, anakinra, canakinumab and adalimumab were sequentially tested with no clinical response; non-steroidal anti-inflammatory drugs however did reduce the frequency of pyrexial episodes [10]. Similarly anakinra and anti-TNF blockade were also not effective in the patient with cardiomyopathy, hepatosplenomegaly and raised SAA [11]. In Fujita's patient prednisolone had some effect in treating skin lesions [12].…”

Untangling the Web of Systemic Autoinflammatory Diseases

“…The clinical onset is in early childhood with pigmented skin lesions, hypertrichosis, and insulin-dependent diabetes mellitus without any autoantibodies. Other symptoms may include short stature, delayed puberty, and exocrine pancreatic insufficiency [94, 95]. Recently, PHID syndrome has also been associated with lipodystrophy, abnormal distribution of perivisceral fat, scleroderma-like skin modifications, and cardiomyopathy resulting from chronic inflammation, resistant to anti-TNF- α and anti-IL-1 therapy [94].…”

“…Recently, PHID syndrome has also been associated with lipodystrophy, abnormal distribution of perivisceral fat, scleroderma-like skin modifications, and cardiomyopathy resulting from chronic inflammation, resistant to anti-TNF- α and anti-IL-1 therapy [94]. In regard to treatment, adalimumab and anakinra have produced little benefit in controlling systemic inflammation of PHID syndrome, while new therapeutic horizons might derive from the use of agents acting directly against macrophages, such as etoposide [95]. …”