A 14-year-old Filipina girl of Chinese descent was referred to our hospital due to severe dermatitis with warty lesions. The patient was born to a 34-year-old primigravida, and the mother and the father are first-degree cousins, hence she was born from a consanguineous union (Supplementary Figure 1). Her younger brother who had severe molluscum infection died of brain abscess at 5 years old. She presented with dry erythematous skin and pruritic scales from 3rd day of life, and was diagnosed with atopic dermatitis. At 5 years old, the skin continued to be thickened and lichenified over the entire body. This was associated with food allergy to egg, milk, peanut, chocolate, shellfish, and fish. The patient developed pulmonary tuberculosis, which was successfully treated with quadruple anti-Koch's therapy including isoniazid, rifampicin, pyrazinamide, and ethambutol for 6 months. At 7 years old, the patient developed multiple furuncles, with abscesses, impetigo, and cellulitis. Administration of antibiotics improved the symptoms; however, she developed multiple skin-colored papulonodular skin lesions with central umbilication on the entire skin (Supplementary Figure 2A). She was diagnosed with systemic molluscum contagiosum. Within 1 year of follow-up, the patient showed persistent atopic dermatitis, and developed opacification of the left eye, accompanied by dimming of her vision (Supplementary Figure 2B). Yellowish purulent discharges were noted from both eyes. Her condition was complicated by severe atopic dermatitis, persistent allergic rhinitis, asthma, suspected multiple food and drug allergies, recurrent sinopulmonary infections, recurrent skin and soft tissue abscesses, mucocutaneous fungal lesions, and extensive giant molluscum contagiosum lesions. Therefore, the patient was suspected to have an underlying PID.
The patient was stunted but did not show signs of wasting. She did not have dysmorphic facial features or retained primary teeth, but had an oral thrush. She also had a symmetric chest expansion, with rhonchi, coarse crackles, and wheezes over both lungs. Tender, fluctuant, erythematous abscesses were observed on the scalp, as well as in some areas of the trunk.
Laboratory tests revealed normal counts of blood neutrophils and lymphocytes, but eosinophil count was elevated with 1,176 cells/muL (Supplementary Table 1). Serum IgG and IgA levels were 1,841 and 181 mg/dL, respectively, whereas IgM level was low (10 mg/dL, normal range: 50-350). Intriguingly, serum IgE level was extremely elevated (>5,000 kU/L). Although kappa-deleting recombination excision circles were normal, T-cell receptor excision circles (TRECs) were undetectable, indicating an impaired T-cell function. Chest X-ray showed no pneumatoceles, and the bacterial cultures of samples collected from eye and skin wound were positive for Staphylococcus aureus.
Based on the elevated IgE and eosinophil levels, the patient was suspected to have HIES. According to the National Institute of Health (NIH) scoring system for HIES, the patient scored 49, which indicated a probable HIES (>40) (Supplementary Table 2). However, this score may also be suggestive of AD-HIES. The patient, however, did not have any retained primary teeth, scoliosis, or a characteristic face; features that were frequently observed in patients with STAT3-deficient AD-HIES. To clinically distinguish between DOCK8-deficient HIES and AD-HIES, the DOCK8 scoring system was applied (Supplementary Table 3). The patient scored 111.08 (cut off: <30), which strongly suggested a DOCK8 defect, which is a form of T-cell deficiency.
After obtaining a written informed consent from the parents, genetic analysis was performed. Whole-exome sequencing identified a homozygous large deletion of exons 2-4 in the DOCK8 gene, which was confirmed by multiplex polymerase chain reaction (PCR) on genomic DNA for DOCK8 coding regions (Figure 1A). PCR with a forward primer in intron 1 and reverse primer in intron 4 amplified the breakpoint regions. Sanger sequencing of this product revealed a deletion of 80,133 bp with an insertion of "T" (Figure 1B). The 3' breakpoint is located in an Alu transposable element, but the 5' breakpoint is not located in any transposable elements (Figure 2). Both parents were heterozygous for the same allele with the large deletion, indicating that they were obligate carriers (Supplementary Figure 3).
The patient had recurrent abscesses, persistent pruritus, and extensive molluscum contagiosum lesions despite the good adherence to the treatment regimen instituted. The result of the exome sequencing bolstered the need for HSCT for the patient to survive. Unfortunately, she died of severe sepsis at the age of 14 years.