Stormorken Syndrome Caused by a p.R304W STIM1 Mutation: The First Italian Patient and a Review of the Literature

Abstract

Stormorken syndrome is a rare autosomal dominant disease that is characterized by a complex phenotype that includes tubular aggregate myopathy (TAM), bleeding diathesis, hyposplenism, mild hypocalcemia and additional features, such as miosis and a mild intellectual disability (dyslexia). Stormorken syndrome is caused by autosomal dominant mutations in the STIM1 gene, which encodes an endoplasmic reticulum Ca²⁺ sensor. Here, we describe the clinical and molecular aspects of a 21-year-old Italian female with Stormorken syndrome. The STIM1 gene sequence identified a c.910C > T transition in a STIM1 allele (p.R304W). The p.R304W mutation is a common mutation that is responsible for Stormorken syndrome and is hypothesized to cause a gain of function action associated with a rise in Ca²⁺ levels. A review of published STIM1 mutations (n = 50) and reported Stormorken patients (n = 11) indicated a genotype-phenotype correlation with mutations in a coiled coil cytoplasmic domain associated with complete Stormorken syndrome, and other pathological variants outside this region were more often linked to an incomplete phenotype. Our study describes the first Italian patient with Stormorken syndrome, contributes to the genotype/phenotype correlation and highlights the possibility of directly investigating the p.R304W mutation in the presence of a typical phenotype. Highlights - Stormorken syndrome is a rare autosomal dominant disease.- Stormoken syndrome is caused by autosomal dominant mutations in the STIM1 gene.- We present the features of a 21-year-old Italian female with Stormorken syndrome.- Our review of published STIM1 mutations suggests a genotype-phenotype correlation.- The p.R304W mutation should be investigated in the presence of a typical phenotype.

Keywords: STIM1; muscle; myopathy; stormorken syndrome; tubular aggregate myopathy.

Figure 1

Morphological and ophthalmological findings in a 21-year-old Italian female with Stormorken syndrome. (A) Close-up photo of the patient's eyes showing bilateral and symmetric miosis. (B) Photo of the patient's feet showing partial syndactyly of the second and third toes.

Figure 2

(A) Axial T1 image at the pelvis showing atrophy and moderate fatty replacement involving the gluteus maximus, particularly on the right side (black arrow); (B) axial T1 MR image at the level of the calf showing the relative sparing of the muscles with only moderate involvement of the gastrocnemii lateralis (dotted white arrow); (C,D) coronal and axial T1 MR images at the level of the cingular girdle showing mild fatty infiltration in the subscapularis muscles.

Figure 3

Histological, histochemical and ultrastructural findings. (A) A Modified Gomori Trichrome stain (40X) showing tubular aggregates and a lack of tubular aggregates. (B) NADH (40X) reaction showing many cytoplasmic dark stained areas. (C,D) (C: 12000X) (D: 20000X) EM. Subsarcolemmal evidence of tubular aggregates (asterisks). (E) small accumulations of PAS positive material was detected in some fibers. (F) SDH staining showed no accumulations even in the described vacuolated areas. Scale bar: (A,B) 12.5 μm (C) 0.42 μm (D) 0.25 μm (E, F) 25 μm.

Figure 4

DNA sequencing analysis of the patient and her parents demonstrating a de novo heterozygous transition in the patient with the common c.910C>T mutation in STIM1.