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

[CIS-PIDD]

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

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