[CIS PIDD] [cis-pidd] STIM1 gene defect

Thu Jan 19 19:27:47 EST 2017

Dear Cindy,

The mutation is very conservative and not in a region previously associated with either LOF or GOF mutations in STIM1. It is located close to an inhibitory region in the C terminus of STIM1, and the mutation could potentially result in constitutive or more pronounced STIM1 activation (and thus Ca2+ influx). However, the clinical phenotype and your lab/biopsy findings indeed show a mixture of both GOF and LOF symptoms:

As you know, both LOF and GOF cause a muscular disease with different manifestations and morphological features. The elevated CPK levels are consistent with GOF although tubular aggregates seem to be missing in your patient. In LOF, several patients had a type II fiber atrophy (this would be visible on ATPase or NADH staining https://www.ncbi.nlm.nih.gov/pubmed/20004786). The increased lipid content in the muscle biopsy is consistent with LOF in STIM1 (our unpublished data) but you would also expect impaired mitochondrial (ETC) function.

The infections are consistent with LOF (although many of your lab results are normal). How are T cell proliferation [TCR stimulation, +/- IL2] and cytokine production? On the other hand, none of the published patients with GOF mutations in STIM1 (or ORAI1) have immunodeficiency, so this really argues for a LOF.

Does the patient have either of the following:
- Tooth defects (enamel attrition as in hypocalcified amelogenesis imperfecta)? If abnormal, you could send me pictures and I have them evaluated by an experienced colleague at the NYU Dental College.
https://www.ncbi.nlm.nih.gov/pubmed/20004786
- Anhidrosis or hypohidrosis? I would recommend a sweat test.
https://www.ncbi.nlm.nih.gov/pubmed/27721237

If not done yet and of interest, we could do Calcium flux measurements in PBMC of your patient to determine the functional effects of the mutation.

Kind regards,

Stefan Feske, MD
Associate Professor, Department of Pathology
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York University School of Medicine
550 First Avenue, Smilow 316
New York, NY 10016
Ph: +1-212-263-9066
E-mail: feskes01 at nyumc.org<mailto:feskes01 at nyumc.org>
Website: http://labs.pathology.med.nyu.edu/feske-lab/

From: CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
Reply-To: CIS-PIDD <cis-pidd at lyris.dundee.net>
Date: Thursday, January 19, 2017 at 6:41 PM
To: CIS-PIDD <cis-pidd at lyris.dundee.net>
Subject: [cis-pidd] STIM1 gene defect

Hello,

I thank you in advance for any guidance you might be able to provide on the significance  of this mutation (heterozygous variant of uncertain significant in STIM1 p.A534V (c.1601C>T)) and next best steps for this nearly 3-year old male.  While STIM1 has been associated with a SCID-like phenotype (homozygous LOF) and tubular aggregate myopathy (heterozygous GOF), my patient doesn’t fit either perfectly.

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Family history: 3 siblings who died of SMA Type I (brother died at 4 years old; twins died 1 hour after birth).  He has a 5 year old brother who is healthy.  Dad, who has muscle pain that started later in life and elevated CPK levels (5,000 at one point) has the same STIM1 mutation as the patient.

Patient History:  The patient was diagnosed in utero as a carrier for SMN gene.  He was born at 37 weeks' gestation, weighing 6 pound 9 ounces.  At 7 months, he developed noisy breathing both in the day or night. He was found to have an endotracheal cleft. He had a swallowing evaluation that revealed dysphagia with aspiration (which has now resolved).  GT was placed during this time and he remains dependent upon it due to oral aversion.

Around age 1, he developed a foot lesion that took 1-year to heal.  He also began having frequent infections (cellulitis and abscesses) at his G-tube site that were very poor to heal and chronic pain there.  Only 1 skin infection was cultured and grew yeast and rare coag-negative staph, bacillus species.  He routinely does bleach baths.  G-tube revision (x2) did not help the G-tube pain and infection.  Frequency of G-tube site infections is almost every 1 month as has been so for about 2-years.  He had a muscle biopsy, and this site got infected as well.  He has had multiple pneumonias, but all improved after aspiration was identified.  He has had C. dif, thrush, molluscum, and RSV.  Starting around age 2, he began have frequent otitis media, but this resolved are PE tubes.  No other infections.

At a year of age, Mom noted that he had brief jerking and twitching during sleep. Twitching would wake him from sleep.  He would cry and complain of pain and not let anyone touch him.  Pain is worst in his legs; also present at the G-tube site.  During the day, he will have episodes of shaking that can last several hours.  He takes hydrocodone for painful symptoms and baclofen.  Gabapentin and nerve blocks did not work.  The pain is still debilitating both during the day and night.

He has mild atopic dermatitis, asthma, and allergic rhinitis (dog, cockroach, mold).   He has hyperhidrosis of hands and feet.

He does NOT have:  autoimmunity, bleeding diathesis, spleen hypoplasia/aplasia, muscular hypotonia, or lymphoproliferative disease

Labs:
-Nuclear DNA testing/WES:  reinterpretation showed STIM1 heterozygous mutation p.A534V (c.1601c>T) in patient (and father) and FUBP1 heterozygous mutation p.Q223B (c.667 C>G).
-CPK 200 to 300 (LLN is 159)
-Immunology testing with normal:  CBC/manual; IgG, IgA, IgM, and IgE; vaccine titers for tetanus, diphtheria, strep (8/23), Hib; neutrophil oxidative burst; lymphocyte enumeration (including surface markers on neutrophils, CD11/18; Naïve (CD45RA) and memory (CD45RO) T-cell enumeration not assessed); CMP; CH50; DOCK8 flow; T mitogens; Zinc
-Muscle biopsy showed mitochondrial proliferation and electron chain analysis also showed increased activity, but no specific complex deficiency was found. There was increased lipid content.
-Mitochondrial Respiratory Chain Enzymes: No deficiencies of respiratory chain activity. Citrate Synthase activity was elevated, suggesting mitochondrial proliferation.
-Mitochondrial DNA sequencing: Normal
-Muscle EM: Scattered cells exhibiting disorganized contractile elements. Some internalized nuclei. Many myocytes are found with subsarcolemmal accumulations of mitochondria displaying atypically arranged cristae (Father's muscle biopsy:  Normal muscle, although there was a modest increase in cells with centralized nuclei).

Imaging:
-MRI Brain: normal
-CT abdomen:  normal
-CXR: normal

Again, I would be grateful for any advice in caring for this boy and/or experience you might have with STIM1 defects.

Cindy Salm Bauer, MD
Division of Allergy and Immunology, Department of Pediatric Pulmonology
Phoenix Children's Hospital
Assistant Professor, Department of Medicine, Mayo Clinic Arizona
1919 East Thomas Road / Phoenix, AZ  85016 / Tel:  602-933-4063
cbauer at phoenixchildrens.com<mailto:cbauer at phoenixchildrens.com>

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