Stormorken Syndrome

A number sign (#) is used with this entry because Stormorken syndrome (STRMK) is caused by heterozygous mutation in the STIM1 gene (605921) on chromosome 11p15.

Heterozygous mutation in the STIM1 gene can also cause isolated tubular aggregate myopathy-1 (TAM1; 160565).

Description

Stormorken syndrome is an autosomal dominant disorder characterized by mild bleeding tendency due to platelet dysfunction, thrombocytopenia, anemia, asplenia, tubular aggregate myopathy, congenital miosis, and ichthyosis. Additional features may include headache or recurrent stroke-like episodes (summary by Misceo et al., 2014).

Clinical Features

Stormorken et al. (1985) described a curious syndrome of thrombocytopathy with bleeding diathesis, asplenia evidenced by Howell-Jolly bodies in the red cells of the blood smear and absence of spleen by computerized tomography, striking miosis, muscle fatigue, migraine, dyslexia, and ichthyosis. The syndrome was observed in 3 generations--a grandmother, mother, and son--but was reliably reported in 3 members of the next earlier generation. There was no male-to-male transmission. Misceo et al. (2014) reported follow-up of the family reported by Stormorken et al. (1985) and demonstrated that the grandmother was not affected. The affected son had dysmorphic features, including deep-set eyes, hypotelorism, and a prominent nose.

Misceo et al. (2014) reported a Japanese mother and daughter and 2 unrelated Caucasian men with Stormorken syndrome. The Japanese women, previously described by Mizobuchi et al. (2000), had nasal hemorrhage in childhood or adolescence, miosis, ichthyosis, splenic hypoplasia, and mild limb muscle weakness. Laboratory studies showed increased serum creatine kinase consistent with myopathy, anemia, and thrombocytopenia. Muscle biopsy of the daughter showed myogenic changes and tubular aggregates. A Caucasian male presented with a subarachnoid hemorrhage at age 20, and later developed additional intracranial aneurysms. He also had recurrent extreme headaches associated with neurologic signs. Additional findings included anemia, thrombocytopenia, asplenia, increased serum creatine kinase, and miosis. An unrelated Caucasian man presented with adult-onset diffuse myalgia. He had had a therapeutic splenectomy due to purpura and also showed miosis. Both men had deep-set eyes, hypotelorism, and a large nose. None of the patients had immunologic abnormalities.

White (2003, 2003) and White and Ahlstrand (2003, 2003) reported detailed platelet studies of a mother and son with prolonged thrombocytopenia. These initial reports stated that they had no clinical bleeding problems, no hemorrhagic episodes, and no need for transfusional support. Laboratory studies showed low platelet numbers and moderately increased platelet volume. Electron microscopic studies showed that the platelets contained 2 types of giant organelles present in platelets and in megakaryocytes in the bone marrow. These organelles, which were electron-opaque, appeared to arise from fragments of the endoplasmic reticulum. The authors determined that the organelles were not aberrant dense bodies and that they contained high levels of calcium and phosphorus as well as peroxidase and acid phosphatase activity, suggestive of a lysosomal disorder. Markello et al. (2015) reported follow-up of this family (family A), which now included an affected son of the previously studied son. This report stated that the original mother and son both had bruising in early childhood; the mother had epistaxis, heavy menstrual periods, and postpartum hemorrhage requiring transfusions. Both patients also had a myopathy affecting the proximal and distal muscles, upgaze palsy, impaired pupillary reactions, and increased serum creatine kinase. Muscle biopsies showed myopathic changes, including marked variation in fiber size, endomysial fibrosis, fatty infiltration, and internalized nuclei; there was no evidence of a mitochondrial disorder.

White and Gunay-Aygun (2011) reported a 4-year-old girl with thrombocytopenia since birth and a proximal myopathic disorder. Electron microscopy of patient platelets showed 2 types of organelles: giant electron-opaque organelles and huge target organelles, similar to those observed in the patients reported by White (2003, 2003) and White and Ahlstrand (2003, 2003). The abnormal organelles appeared to develop in the rough and smooth endoplasmic reticulum of parent megakaryocytes and to mature in the dense tubular system of circulating platelets. The disorder was designated York platelet syndrome (YPS). White et al. (2013) reported a 4-year-old boy with YPS and a mitochondrial myopathy. Platelets in this child showed the characteristic electron-opaque organelles, but not the target type; the platelets were also nearly devoid of alpha granules.

Morin et al. (2014) reported a French father and son and a German mother and daughter with Stormorken syndrome. In the first family, a newborn presented with thrombocytopenia and skin rash. At age 6 years, he had deep-set eyes with miosis and muscle weakness. Laboratory studies showed increased creatine kinase, mild hypocalcemia, and thrombocytopenia. The patient had moderate learning difficulties. The father had short stature, severe miosis, hypotelorism, asplenia, increased serum creatine kinase, and thrombocytopenia. Muscle biopsy of both patients showed findings consistent with tubular aggregates that stained with antibodies against STIM1, STIM2 (610841), ORAI1 (610277) and ORAI2 (610929). In the German family, the 19-year-old mother had miosis, thrombocytopenia, asplenia, mild muscle weakness, low serum calcium, and urticarial skin eruptions. She also had impaired cognition. The 2.5-year-old daughter had miosis and thrombocytopenia, but no evidence of muscle weakness.

Markello et al. (2015) reported 4 additional patients from 3 unrelated families with YPS. Three had onset of easy bruising associated with thrombocytopenia in infancy; 1 had abnormal platelet morphology on electron microscopy. All patients had walking difficulties due to myopathy as well as increased levels of serum creatine kinase. Platelet aggregation studies, performed on 2 unrelated patients, showed impaired responses to ADP, collagen, arachidonic acid, and epinephrine, but normal responses to thrombin.

Inheritance

The transmission pattern of Stormorken syndrome in the families reported by Misceo et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 6 patients from 4 unrelated families with Stormorken syndrome, including the families reported by Stormorken et al. (1985) and Mizobuchi et al. (2000), Misceo et al. (2014) identified a heterozygous missense mutation in the STIM1 gene (R304W; 605921.0008). The mutation was found in the first 2 families by exome sequencing. Patient platelets showed increased calcium content and lack of induction of store-operated calcium entry (SOCE), suggesting that the mutation results in constitutive activation of the ORAI1 (610277) calcium channel with resultant inhibition of further activation.

Simultaneously and independently, Nesin et al. (2014) identified a heterozygous R304W mutation in the STIM1 gene in 2 unrelated patients with Stormorken syndrome. Patient cells showed constitutive activation of the CRAC calcium channel as well as suppression of fast calcium-dependent inactivation, consistent with a gain of function. Nesin et al. (2014) postulated that disordered and sustained calcium entry over long periods of time results in an environment in the sarcoplasmic reticulum that is hostile to protein folding, thus initiating the formation of tubular aggregates.

In 4 patients from 2 unrelated families with Stormorken syndrome, Morin et al. (2014) identified a heterozygous R304W mutation in the STIM1 gene. Patient fibroblasts and HEK293 cells transfected with the mutation showed an increase in resting cytosolic calcium levels and a modest increase in store-operated calcium entry compared to controls, consistent with a gain-of-function effect. Molecular modeling predicted that the mutation caused a structural defect that may affect the conformation and disrupt the inhibitory state.

In 7 patients from 4 unrelated families with Stormorken syndrome, referred to as York platelet syndrome, Markello et al. (2015) identified 2 different heterozygous missense mutations in the STIM1 gene (I115F, 605921.0009 and R304W). Each of these mutations had previously been reported, I115F in a patient with tubular aggregate myopathy-1 (TAM1; 160565) and R304W in patients with Stormorken syndrome. Markello et al. (2015) did not perform functional studies of the variants, but they noted that the R304W mutation had been shown to cause a gain of function.