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A child with hyper-IgM syndrome and multiple endocrinopathies with mutations in signal transducer and activator 5B (STAT5B), phosphatidylinositol 3-kinase catalytic subunit delta (PIK3CD) and phosphatidylinositol 3-kinase regulatory subunit 1 (PIK3R1)
Sunday, March 5, 2017: 2:15 PM
Rooms B308-B309 (Georgia World Congress Center, Building B)
Miranda L. Curtiss, MD PhD, , ,
Rationale:   Mutations in STAT5B are associated with combined immunodeficiency, autoimmunity, and growth hormone insensitivity.  Mutations in PI3KCD and PI3KR1 result in activated protein kinase C delta syndrome.  We present a patient with absent IL-2-induced STAT5 phosphorylation, hyper-IgM syndrome, and mutations in STAT5B, PIK3CD, and PIK3R1.

Methods: Whole exome sequencing was performed by Hudson Alpha Genomics Center.  Confirmatory genetic testing by direct sequencing of PIK3CD exon 6 and PIK3R1 exon 11 was performed by the UAB Medical Genomics Laboratory.  STAT5 phosphorylation assay and STAT5B sequencing was performed by Seattle Children’s Immunology Diagnostic and Medical Genomics Laboratories.

Results: This patient with hypogammaglobulinemia, short stature requiring growth hormone replacement, hypothyroidism, polycystic ovarian syndrome, chronic sinusitis, bronchiectasis, and multiple episodes of pneumonia was placed on IVIG at 9 years age. Stimulation of her PBMC with IL-2 failed to induce STAT5 phosphorylation.  Sequencing of STAT5B revealed a heterozygous intronic variant of unknown significance upstream of exon 6; c.[551-5T>C/T]. Whole exome sequencing identified one heterozygous missense alteration in PIK3CD:c.[638C>T], p.[Pro213Leu] also present in her father and one heterozygous splicing mutation PIK3R1:c.[1425+2R>G] present in no other family members that were confirmed with direct sequencing of PIK3CD exon 6 and PIK3R1 exon 11. 

Conclusions: We present a case of hyper-IgM syndrome, multiple endocrinopathies, and sinopulmonary infections associated with mutations in STAT5B, PIK3CD, and PIK3R1.  We believe this patient’s complex phenotype may represent the sequelae of abnormal STAT5 signaling in the context of abnormal PIK3 activation.  Further studies to characterize the functional consequence of these mutations is needed.