A novel STAT3 splice-site variant in a kindred with autosomal dominant hyper IgE syndrome

Data compiled prospectively and retrospectively from patient medical records were entered into the Canadian Centre for Primary Immunodeficiency Registry and Tissue Bank, which has been approved by the SickKids Research Ethics Board (protocol no. 1000005598). Patient and family members provided written informed consent.

Lymphocyte proliferative responses to mitogens, including PHA, anti-CD3 and anti-CD28 antibodies, were determined by thymidine incorporation (Alsalamah et al. 2019). All assays were performed in triplicate and were compared with random normal controls.

Genomic DNA was isolated from patient peripheral blood leukocytes using the Geneaid genomic DNA extraction kit (Geneaid Mini Kit; Sensi Capital Corp, Toronto, Ontario, Canada). Patient variant was identified via whole exome sequencing using Illumina HiSeq2500 GATK 1.1.28 sequencing platform (Merico 2016), and confirmed by Sanger sequencing using DTCS Quick Kit on an automated sequencer (Beckman-Coulter CEQ 8000). Variants were later confirmed by a clinical laboratory.

A 12-year-old male was first referred to us for evaluation of a rash and recurrent infections. The first concern noted by his parents was a severe blistering rash since birth. This was present since the first day of life, leading to a neonatal intensive care unit admission where he was treated with intravenous (IV) antibiotics. Over the course of his life the rash persisted, starting as erythematous patches spanning his entire body which would evolve into large coalescing pustules, with no clear trigger. He had been treated continuously with steroid creams and had received many courses of oral antibiotics for secondary skin infections, eventually being prescribed prophylaxis with cephalexin. Additionally, since 6 months of age, he experienced various infections. These included multiple acute otitis media episodes necessitating myringotomy tubes, an episode of severe pneumonia requiring hospital admission, and multiple skin abscesses. At the age of 12, he had an episode of sacroiliac osteomyelitis with Staphylococcus aureus bacteremia, treated with 6 weeks of IV and then oral antibiotics. He additionally experienced 2 lower limb fractures with minimal trauma.

Review of the patient’s past medical history revealed that he was born at term following an uncomplicated pregnancy. Parents confirmed delayed loss of two primary teeth which required extraction by a dentist. His medications included cephalexin for skin infection prophylaxis and vitamin D. He had received all childhood immunizations with no difficulty, and had no allergies.

Family history included a father with environmental allergies, and a healthy mother. Parents were Canadians of English/Scottish ancestry and non-consanguineous. He had 2 healthy male full siblings.

On initial physical examination, the patient showed areas of skin excoriation, as well as multiple boils on his arms and legs, most notably on his knees. Ear exam had evidence of bilateral middle ear effusions. The remainder of his exam was unremarkable, with no abnormal facial features, high-arched palate or scoliosis. A full panel of laboratory investigations was performed (Table 1). Overall, the patient had eosinophilia and elevated IgE, with mixed specific vaccine responses. He received a clinical diagnosis of hyper IgE syndrome, with a Grimbacher score of 48, highly suggestive of the disease (Grimbacher et al. 1999).

The proband’s only son presented to us for evaluation at the age of 6 months for a severe rash and recurrent infections. Similar to his father, he developed a rash starting on the second day of life, initially diagnosed as severe seborrheic dermatitis of his scalp, ears and neck, as well as a pustular rash affecting his trunk. He had received multiple courses of treatment with topical steroids, as well as topical and oral antibiotics. He also had 2 infantile episodes of thrush which resolved after treatment with nystatin. At the age of 6 months, he was admitted to hospital for treatment of a febrile pneumonia which progressed to culture-negative sepsis. He was treated successfully with IV antibiotics. No further past medical history was reported. Upon review in our clinic, he was noted to have extensive eczema/excoriation, with a few pustules noted, but again no abnormal facial features or high-arched palate. Laboratory investigations (Table 1) identified elevated IgE, as seen in the patient’s father. His Grimbacher score at the time of presentation was 28.

The proband underwent whole exome sequencing on a research basis, revealing a heterozygous novel splice-site variant in STAT3: c.1110-3C>G, affecting intron 11, predicted to result in defective splicing of exon 12 in the DNA-binding domain (DBD). The variant was confirmed in a clinical laboratory, and later identified in the proband’s son as well.

The proband is currently 27 years old, while his son is 6 years old. Both have been prophylactically receiving trimethoprim-sulfamethoxazole as anti-Staphylococcal coverage, and have remained stable with no severe infections on this prophylactic treatment.