Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5 variants with variable neurological presentations

Abstract

Spondyloenchondrodysplasia (SPENCD) is an immune-osseous disorder caused by biallelic variants in ACP5 gene and is less commonly associated with neurological abnormalities such as global developmental delay, spasticity and seizures. Herein, we describe five new patients from four unrelated Egyptian families with complex clinical presentations including predominant neurological presentations masking the skeletal and immunological manifestations. All our patients had spasticity with variable associations of motor and mental delay or epilepsy. All except for one patient had bilateral calcification in the basal ganglia. One patient had an associated growth hormone deficiency with fair response to growth hormone therapy (GH) where the height improved from −3.0 SD before GH therapy to −2.35 SD at presentation. Patients had different forms of immune dysregulation. All patients except for one had either cellular immunodeficiency (3 patients) or combined immunodeficiency (1 patient). Whole exome sequencing was performed and revealed four ACP5 variants: c.629C > T (p.Ser210Phe), c.526C > T (p.Arg176Ter), c.742dupC (p.Gln248ProfsTer3) and c.775G > A (p.Gly259Arg). Of them, three variants were not described before. Our study reinforces the striking phenotypic variability associated with SPENCD and expands the mutational spectrum of this rare disorder. Further, it documents the positive response to growth hormone therapy in the studied patient.

Case report: Refractory Evans syndrome in two patients with spondyloenchondrodysplasia with immune dysregulation treated successfully with JAK1/JAK2 inhibition

“…The presented cases by us and others ( 3 , 4 , 12 , 19 – 21 ) support the use of JAK-inhibitors as an effective targeted therapy for patients with SPENCDI and severe cytopenias. Lack of effective biomarkers to capture the clinical response to JAK-inhibitors (e.g.…”

“…Both parents were identified as heterozygous asymptomatic carriers of one of the variants ( Figures 2B, C ; Supplementary Materials ; Supplementary Table 1 ). Based on the favorable therapeutic response of other patients with type I interferonopathies to JAK inhibitors ( 3 , 4 , 12 , 19 – 21 ), and the shared pathophysiologic hallmarks of SPENCDI with other type I interferonopathies ( 14 , 22 ), a therapeutic trial with the JAK1/JAK2 inhibitor ruxolitinib was initiated (0.4 mg/kg/day). Within a week from initiation of therapy, the patient reported significantly improved energy levels.…”

“…The patient was subsequently referred to an oncologist and diagnosed with smoldering multiple myeloma. These findings prompted a review of the literature that revealed that approximately half of the patients with SPENCDI also report hypergammaglobulinemia ( 2 , 4 , 12 , 13 , 20 , 22 ).…”

“…Clinically, the syndrome exhibits a broad phenotypic variability, but most patients present with skeletal and immune manifestations. Adaptative immune dysregulation and autoinflammation comprise the prevailing immune phenotype ( 1 – 4 , 6 – 8 ) although immunodeficiency has also been reported ( 5 , 9 ). In addition, SPENCDI can manifest with neurologic symptoms ( 1 , 2 , 4 , 6 , 8 ).…”

“…Adaptative immune dysregulation and autoinflammation comprise the prevailing immune phenotype ( 1 – 4 , 6 – 8 ) although immunodeficiency has also been reported ( 5 , 9 ). In addition, SPENCDI can manifest with neurologic symptoms ( 1 , 2 , 4 , 6 , 8 ). Immune dyscrasias, most commonly manifesting as cytopenias and SLE-like symptoms ( 10 – 12 ), are often recalcitrant and refractory to conventional immunomodulatory therapies ( 1 , 2 , 6 , 10 , 13 ).…”