Journal of Clinical Immunology

, Volume 31, Issue 2, pp 272–280

Clinical Aspects and Genetic Analysis of Taiwanese Patients with the Phenotype of Hyper-Immunoglobulin E Recurrent Infection Syndromes (HIES)

Authors

    • Primary Immunodeficiency Care And Research (PICAR) InstituteChang Gung Memorial Hospital and University College of Medicine
    • Department of Pediatric Allergy, Immunology and RheumatologyChang Gung Memorial Hospital and University College of Medicine
    • Primary Immunodeficiency Care And Research (PICAR) InstituteChang Gung Memory Hospital and University College of Medicine
  • Jing-Long Huang
    • Primary Immunodeficiency Care And Research (PICAR) InstituteChang Gung Memorial Hospital and University College of Medicine
    • Department of Pediatric Allergy, Immunology and RheumatologyChang Gung Memorial Hospital and University College of Medicine
  • Shy-Jae Lin
    • Department of Pediatric Allergy, Immunology and RheumatologyChang Gung Memorial Hospital and University College of Medicine
  • Kuo-Wei Yeh
    • Department of Pediatric Allergy, Immunology and RheumatologyChang Gung Memorial Hospital and University College of Medicine
  • Li-Chen Chen
    • Department of Pediatric Allergy, Immunology and RheumatologyChang Gung Memorial Hospital and University College of Medicine
  • Meng-Ying Hsieh
    • Department of Pediatric NeurologyChang Gung Memory Hospital and University College of Medicine
    • Graduate Institute of Medical ClinicsChang Gung Memory Hospital and University College of Medicine
  • Yhu-Chering Huang
    • Department of Pediatric InfectionChang Gung Memorial Hospital and University College of Medicine
  • Ho-Chang Kuo
    • Department of Pediatric Allergy, Immunology and RheumatologyChang Gung Memorial Hospital and University College of Medicine
  • Kunder D. Yang
    • Department of Pediatric Allergy, Immunology and RheumatologyChang Gung Memorial Hospital and University College of Medicine
  • Hong-Ren Yu
    • Department of Pediatric Allergy, Immunology and RheumatologyChang Gung Memorial Hospital and University College of Medicine
  • Tang-Her Jaing
    • Primary Immunodeficiency Care And Research (PICAR) InstituteChang Gung Memorial Hospital and University College of Medicine
    • Department of Pediatric Hematology and OncologyChang Gung Memorial Hospital and University College of Medicine
    • Department of DermatologyChang Gung Memorial Hospital and University College of Medicine
    • Primary Immunodeficiency Care And Research (PICAR) InstituteChang Gung Memory Hospital and University College of Medicine
Article

DOI: 10.1007/s10875-010-9479-1

Cite this article as:
Lee, W., Huang, J., Lin, S. et al. J Clin Immunol (2011) 31: 272. doi:10.1007/s10875-010-9479-1

Abstract

Background

Hyper-immunoglobulin E recurrent infection syndromes (HIES) has characteristic features and identified mutations. This study investigated clinical features and causal candidate mutations in Taiwanese patients with the HIES phenotype on referral base over 23 million inhabitants.

Patients and Methods

Clinical manifestations of the HIES phenotype, severity scoring, immunological functions and candidate genes of signal transducer and activator of transcription 3 (STAT3), tyrosine kinase 2 (TYKZ), and dedicator of cytokineses 8 (DOCK8) were analyzed.

Results

Between 1985 and 2009, six sporadic and two siblings met HIES criteria (onset age: 2–54 months; severity score: 31–65) out of 187 patients with primary immunodeficiencies. Five patients with the autosomal dominant (AD)-HIES phenotype presented as pneumatocoele, bronchiectasis, retained primary teeth, minor trauma fracture, scoliosis, coronary aneurysm, and lymphoma. Three with the autosomal recessive (AR)-HIES phenotype and impaired lymphocyte proliferation function had herpes simplex virus infection, molluscum contagiosum, and cerebral vasculitis. Notably in one patient with the AR-HIES phenotype, unintentional lead component in traditional application herbs for accelerating wound healing deposited in basal ganglia and aggravated involuntary movement relative to cerebral vacculitis. Those with mildly elevated memory T cells and decreased memory B cells trended to develop arteritis. Of five AD-HIES patients, three were mortalities from acute myocardial infarction, Proteus mirabilis, and Staphylococcus aureus sepsis. Only one had de novo novel STAT3 (Gln 469 Arg) mutation with “relative” lower HIES STAT3 score.

Conclusions

Known genetic defects responsible for the HIES phenotype are not so common in Taiwan. This may infer genetic variations in different ethnicities although selection bias and under-diagnosis for HIES with known genetic defects could be contribution factors.

Keywords

Hyper IgE recurrent infection syndrome (HIES)STAT3, TYK2, DOCK8, primary immunodeficiency diseases (PIDs)TaiwanChinesemolecular analysis

Introduction

Hyper-immunoglobulin E recurrent infection syndromes (HIES) is a rare primary immuno-deficiency characterized by the clinical triad of recurrent staphylococcal skin abscesses, recurrent respiratory tract infections, and high serum IgE concentrations (>2,000 IU/mL). Autosomal dominant (AD) and recessive (AR) forms have been described [1, 2]. Moreover, the AR-HIES is presumed to have recurrent viral infections and neurologic complications.

The first monogenetic defect of HIES, identified by Minegishi et al. [3] in 2006, was a homozygous mutation of receptor-associated cytoplasmatic tyrosine kinase (TYK2) in a Japanese adolescent male. Born of consanguineous parents and with the AR-HIES phenotype, he had the unusual presentation of Bacille Calmette–Guerin and salmonella infections [3]. However, the first “Job’s syndrome” with the AD-HIES phenotype proposed by Davis et al. [4] in 1966, with extremely high serum IgE levels mentioned by Buckley et al. [5] in 1972 was finally discovered to have Signal transducer and activator of transcription 3 (STAT3) mutations demonstrated by Ochs et al. [6] in 2007.

There were persistent efforts by two excellent groups of Minegishi et al. [7] and Holland et al. [8] for several years to resolve the molecular defects of the majority of AD-HIES patients by exploring the autosomal dominant STAT3 mutation. However, TYK2 mutation to date was identified in only one AR-HIES Japanese patient [9]. In 2009, point mutations and deleted interval of the dedicator of cytokines 8 (DOCK8), encoding a protein possibly involved in the regulation of the actin cytoskeleton, were identified by Zhang et al. [10] to discover most of AR-HIES with increased susceptibility to molluscum contagiosum and herpes infection [11].

These identified genetic mutations of TYK2, STAT3, and DOCK8 began to clarify the multi-system nature of the HIES in Caucasian, Japanese, and Turkish patients [612], but no comprehensive analysis had been undertaken among the Chinese descent.

This study retrospectively reviewed the clinical aspects and immunologic functions of Taiwanese patients with the HIES phenotype in a 25-year period, and performed genetic analysis by known candidate genes of TYK2, STAT3, and DOCK8.

Patients and Methods

Patients

As part of the long-term comprehensive study in primary immunodeficiencies (PIDs) from 1985 to 2009, patients who fulfilled the diagnostic criteria with the characterized triads were enrolled. They were assigned a score based on the clinical severity, using a previously described scoring system designed by Grimbacher et al. [13, 14] and classified into the four affected statuses by Holland et al. [8]: 0–15 unaffected, 16–39 possibly, 40–59 probably, and >59 definitely affected. The “HIES STAT3 score” including pneumonia, newborn rash, pathologic bone fractures, characteristic face, and cathedral palate was also calculated for our patients to predict STAT3 mutations [15]. Those patients with increased susceptibility to molluscum contagiosum, herpes infection or/and vasculitis were categorized into the subgroup of AR-HIES phenotype.

Immunologic Evaluation

The institutional review board and Human Investigation Committee approved the study, and the patients or their parents provided informed consent. Around 15 mL venous blood was collected into heparin-containing syringes and delivered to the laboratory within 24 h. Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll–Hypaque density gradient centrifugation (Amersham Pharmacia Biotech, Piscataway, NJ, USA) and frozen for further analysis if necessary. Basic immunologic laboratory tests, including blood smears, differential counts, immunoglobulin levels and immunoglobulin G subclass titers were measured. Lymphocyte proliferation functions were performed as previously described [1618]. Lymphocyte subsets (all antibodies purchased from Pharmingen, San Jose, CA, USA), including CD3+, CD4+, CD8+, CD19+, CD45, CD45RO+, CD45RA+, CD27+, CD16+, CD56+ (natural killer), and activated lymphocytes (CD3+ HLADR+), were assessed by flow cytometry. The B-lymphoblastoid cell lines and interleukin (IL)-2-dependent T cell lines were also established.

Sequencing Analysis

Total RNA was extracted from the PBMCs or from established lymphoblastoid cell lines by TRIzol (Life Tech. Carlsbad, CA, USA). Reverse transcription of mRNA followed by polymerase chain reaction (RT-PCR) was performed as previously described [18]. The primers sequences of TYK2, STAT3, and DOCK8 were based on human genome sequences and designed in Table I. If a specific mutation was identified after RT-PCR amplification, the genomic DNA was amplified and confirmed again.
Table I

Designed primers covering the coding regions of STAT3, TYK2, and DOCK8

Gene (GeneBank)

Forward (5′)

Backward (3′)

STAT3 (NM_139276)

CGC CCG TCC CCG GCA CAC G

ACG CCG GTC TTG ATG ACG AG

CCG ATG CTG GAG GAG AGA AT

GAG ATA GAC CAG TGG AGA CA

CAG CAG CTG AAC AAC ATG TC

AGG AGG GCA GGG GAA CAA AAC AAC ACA AGA

TYK2 (NM_003331)

CTA AGT GGC TTG CTT GAG

GCT CCA GGC ACT TGT TGT

AAG AAG GCC AAG GCT CAC

AAG CAG ATC TCC AGG AGG

CAA GCT GAG TGA TCC TGG

AGG AGT AAG GCA CAC GGT

DOCK8 (NM_2034473)

GAG CAT AAG TAC CTC TGG (F-232)a

AAC CAC AGA GTC CAC ATC (B-1396)

CCA AGC TGA ATC CTT CTG (F-1267)

GAG GAG TTC AGG CAG ATG AT (B-2460)

GAC AAC CAC CTG GAG AAG (F-2381)

AGC CAG TTC TGT GAA GAG GA (B-3616)

CTG AGA ATC CTC TGT AGC CA (F-3401)

CAG GAC TTG GTG ACA TAG GT (B-4648)

GGT GCT GGT GAA TTC TCT GA (F-4501)

TAG TGG TCA GGA CTG TGT TC (B-5876)

GGC CTA CAT ACA GAT CAC (F-5692)

GAG TGT ACA GTC AGT CCT GG (B-6518)

aThe numbers in primers were based on the location of DOCK mRNA (NM_2034473)

Results

Clinical Features

During the 25-year study period (1985–2009), a large cohort of 187 Taiwanese patients with PIDs was referred or consulted for molecular diagnosis and treatment [16, 19, 20]. Among them, patients with higher IgE level (excluding allergy diseases) were Wiskott–Aldrich syndrome in 15, HIES in eight, Omen syndrome in two, and Comel–Netherton syndrome in one patient. In the eight HIES patients (six sporadic and two sibling patients; five females), the age at onset was 30.8 ± 19.0 months (range: 2–54 months) in Table II. There was no consanguineous marriage but only one family relation—two sisters (P2 and P3). All had severity scores >30 (range from 31 to 65) compatible with the moderate-to-severe phenotype and classified into three affected statuses, including four possibly, two probably and two definitely affected status based on Holland et al. scoring in Table II. HIES STAT3 score was calculated from 26.65 to 36.65.
Table II

Clinical features of Taiwanese patients with hyper-IgE recurrent infection syndrome (HIES) by scoring system

Disease pattern

AR-HIES

AD-HIES

Patient/sex

P1/F

Score

P2/F

Score

P3/F

Score

P4/M

Score

P5/M

Score

P6/F

Score

P7/F

Score

P8/M

Score

Onset age (months)

54

 

32

 

26

 

40

 

2

 

4

 

42

 

46

 

At year (A.C.)

1970

 

1996

 

1998

 

1985

 

1987

 

1988

 

1989

 

1994

 

Now

Alive 39 Y

 

Alive 15 Y

 

Alive 12 Y

 

Dead 13 Y

 

Dead 11 Y

 

Dead 16 Y

 

Alive 24 Y

 

Alive 15 Y

 

Characteristics

  Highest serum-IgE level

12782

10

11787

10

14482

10

14389

10

7842

10

18980

10

22178

10

17948

10

  Skin abscesses

3–4

4

>4

8

3–4

4

>4

8

>4

8

>4

8

3–4

4

>4

8

 Pneumoniac (episodes over lifetime)

1

2

1

2

1

2

>3

8

>3

8

2

4

0

1

2

 Parenchymal lung anomalies

0

Bronchi

3

0

0

Pneuma

8

Pneuma

8

0

0

 Retained primary teeth

0

0

0

0

0

0

0

>3

8

  Scoliosis, maximum curvature

0

0

0

0

0

>20°

8

0

0

  Fractures with minor traumac

0

0

0

0

0

>2

8

0

0

  Highest eosinophil count

1245

6

746

3

879

6

340

0

1820

6

5600

6

1147

6

1650

6

  Characteristic facec

Present

5

Present

5

Present

5

Mild

2

Mild

2

0

0

Present

5

  Midline anomaly

0

0

0

0

0

0

0

0

  Newborn rashc

0

0

0

0

Present

4

0

Present

4

0

  Eczema (worst stage)

++

2

+++

4

+++

4

+++

4

+++

4

+++

4

+++

4

++

2

Upper respiratory infections per year

1

0

3

1

1

0

4–6

2

4

2

1

0

2

0

0

0

  Candidiasis

0

Oral

1

0

0

0

Oral

1

Nails

3

0

  Other serious infections

0

Severe

4

0

0

Severe

4

Severe

4

0

0

  Fatal infection

0

0

0

0

0

Present

4

0

0

  Hyperextensibility

0

0

0

0

0

0

0

0

  Lymphoma

0

0

0

0

Hodgkin

4

0

0

0

  Increased nasal widtha

>2 SD

3

>2 SD

3

>2 SD

3

>2 SD

3

1–2 SD

1

0

0

>2 SD

3

  High palatec

Present

2

Present

2

Present

2

0

0

0

0

0

  Total

 

34

 

46

 

36

 

37

 

61

 

65

 

31

 

44

  Affected statusb

 

Possibly

 

Probably

 

Possible

 

Possible

 

Definitely

 

Definitely

 

Possibly

 

probably

  HIES STAT3 scorec

26.65

26.65

26.65

36.65

26.65

28.32

36.65

21.65

Pneuma pneumatocele, bronchi bronchiectasis, SD standard deviation

aCompared with age- and sex-matched Caucasians controls [33].

bFour affected status were based on Holland et al. [8]: 0–15 unaffected, 16–39 possibly affected, 40–59 probably affected, >59 definitely affected.

cHIES STAT3 score containing pneumonia, newborn rash, pathologic bone fracture, characteristic face and cathedral palate were calculated by Woellner et al. [15].

HIES Patients with Increased Virus Infections Resembling the AR-HIES Phenotype

Generalized molluscum contagiosum (in P1, Fig. 1a), recurrent herpes simplex virus (HSV) type II expanding from the urogenital regions (in sisters P2 and P3, Fig. 1b), and vasculitis syndrome compatible to decreased intra-cerebral blood perfusion (in P2, Fig. 1c) was distinct characteristics of the AR-HIES phenotype. Refractory molluscum contagiosum did not response well to systemic acyclovir, famcyclovir, interferon-alpha, and even local cryotherapy. Neither acyclovir nor gamcyclovir sufficiently controlled the urogenital HSV infection. She by herself tried Chinese herbs unintentionally with high levels of lead applied on the lesions for over a year. Unexpectedly, the lead was heavily absorbed and deposited in the basal ganglia (Fig. 2), thus augmenting her involuntary movement of dystonia and tremor relative to cerebral vasculitis. Chelating agents like parenteral dimercaprol and calcium disodium EDTA expelled the serum lead but the involuntary movement improved limit despite the serum lead level had returned to the normal range.
https://static-content.springer.com/image/art%3A10.1007%2Fs10875-010-9479-1/MediaObjects/10875_2010_9479_Fig1_HTML.gif
Fig. 1

a Molluscum contagiosum developed throughout the skin in patient P1. The left window of close observation showed small 2–5 mm nodules. b Herpes simplex virus type II infection extended from the urogenital region to the trunk and extremities in patient P2. There were active granuloma-like nodules with ∼7–10 mm central erythema while hypo-pigmentation patterns were healing. c The Tc-99 m-ethyl cysteinate dimmer (ECD) brain perfusion of single photon emission computed tomography (SPECT) study in patient P2 showed relatively mild decreased uptake of radioactivity in the left temporo-parietal cortex and left cerebellum, compatible with vasculitis. d Enhancement CT of patient P4 revealed right and left dilated coronary arteries (aneurysm or arteritis) in the proximal orifices of the ascending aorta (arrowheads)

https://static-content.springer.com/image/art%3A10.1007%2Fs10875-010-9479-1/MediaObjects/10875_2010_9479_Fig2_HTML.jpg
Fig. 2

T1WI brain computed tomography imaging of patient P2 showed hyper-intensity signals in the globus pallidus and posterior limb of the left internal capsule in the prominent cerebral fissures and cisterns. Lead absorbed from Chinese herbal medicine deposited in the basal ganglia and presented with these features. The lacunar infarction in the right caudate nucleus body was related to the vasculitis

Aside from prophylactic antibiotics for Staphylococcus aureus infection, regular monthly intravenous immunoglobulin (IVIG) infusion was given for those with refractory otitis media (P2 and P3).

HIES Patients Without Increased Virus Infections Resembling the AD-HIES Phenotype

The AD-HIES phenotype in our five patients contained dilated coronary aneurysm (in P4, Fig. 1d) and overwhelming autoimmune hemolytic anemia (in P4), Hodgkin’s lymphoma (P5), recurrent respiratory infections leading to irreversible pneumatocele and bronchiectasis (in P5 and P6), minor trauma fracture and scoliosis (P6), retained primary teeth (P8), but without midline anomalies or joint hyper-extensibility. Monthly IVIG benefited two patients with recurrent severe skin infections (P4 and P7). Aseptic meningitis due to IVIG infusion interrupted such maintenance treatment in patient P7.

Of the three mortalities at the adolescent age, one (P4) died of acute myocardial infarction due to dilated coronary artery (aneurysm) or/and aortic arteritis. The other (P5) died of Proteus mirabilis sepsis while receiving polychemotherapy (mechlorethamine, oncovine, procabarzine, and prednisone) and radiotherapy for Hodgkin’s lymphoma. The third (P6) did of S. aureus sepsis.

Immune Function Assessment

Immune anomalies overlapped in AR- and AD-HIES patients. Higher IgG levels (in P2 and P4) reflected active polyclonal immune response in autoimmune diseases (in Table III), inferring frequent or ongoing autoimmune activation. P2 with decreased IgG4 subclass had recurrent HSV and otitis media and responded better to IVIG than that of her sister (P3) with normal IgG4 level [21]. Overall, lymphocytic subsets were almost normal except for the percentage of mildly elevated memory T cells (P1, P4, and P8) and decreased memory B cells in the study patients (P1, P2, P4, and P8). Impaired lymphocyte proliferation in patients (P2 and P3) with the AR-HIES phenotype correlated to recurrent skin virus infections.
Table III

Basic immunologic functions on diagnosis in Taiwanese HIES patients

Patient/Sex

AR-HIES

AD-HIES

Normal range

P1/F

P2/F

P3/F

P4/M

P5/M

P6/F

P7/F

P8/M

Immunoglobulins (mg/dL)

IgG

1770

1650

2430

2747

908

1656

1370

887

660–1532

IgG1

813

1410

1670

NA

NA

NA

786

634

280–1740

IgG2

534

174

349

NA

NA

NA

512

157

110–550

IgG3

158

78

110

NA

NA

NA

62

42

22–320

IgG4

47

7

335

NA

NA

NA

51

35

7–530

IgA

276

162

199

253

263

114

196

136

45–236

IgM

55

31

34

147

103

167

257

92

33–242

Absolute lymphocyte count (mm3)a

1037

576

1140

4054

3640

4480

1858

4460

1400–5400

CD3 (%)

81

35.4

50.9

65.4

73.3

80.2

63.4

79.8

49–84

CD4 (%)

62.6

21.4

25.2

32.1

35.4

48.1

32.5

38.7

28–46

CD8 (%)

22.1

13.7

23.1

24.5

32.9

29.5

25.7

33.2

12–35

CD19 (%)

5.0

39.6

38.2

21.5

20.7

14.0

22.7

12.8

6–37

CD16CD56 (%)

7.5

10.5

6.3

9.1

5.6

8.4

8.9

9.7

3–22

Memory T cells (%)

43.3

14.9

26.5

44.1

NA

NA

30.9

43.6

15–41

Memory B cells (%)

0.31

1.2

2.0

1.1

NA

NA

3.1

0.6

1.4–10.8

Activated lymphocyte (%)

17.9

27.9

17.3

NA

NA

NA

19.7

22.6

4–49

Lymphocyte proliferation (stimulation index)b

PHA

97.8

29.5

25.4

85.4

31.8

135.2

97.2

76.9

32–118

ConA

35.4

17.8

21.4

NA

23.3

40.7

54.9

43.2

25–64

PWM

32.9

NA

NA

NA

10.7

47.1

42.5

37.4

12–52

Candida

6.3

1.5

2.1

7.9

NA

NA

9.7

8.4

2–13

BCG

2.1

1.1

1.4

NA

NA

NA

5.6

4.7

2–14

NA not available

aT-memory percentage = CD3 + CD45RO ± all lymphocytes; B-memory percentage = [CD19 + CD27 + CD19 + CD27+ and CD19 + CD27-]/all lymphocytes; Activated lymphocyte percentage = CD3 + HLADR + all lymphocytes

bLymphocyte proliferation functions were performed from frozen PBMCs in P4, P5, and P6

Mutation Analysis

Sequencing STAT3, TYK2, and DOCK8 genes in all patients revealed, in STAT3 gene, the de novo 1406th nucleotide of A heterozygous substituted by G in the exon 15 (in P8; Fig. 3a), which resulted in the missense mutation of Gln469Arg (Q469R) in the DNA-binding domain. In IL-6 stimulated (20 ng/ml) CD3+ lymphocytes, this mutant phosphorylated STAT3 expression was lesser than those of healthy controls by flow cytometry (Fig. 3b). The other TYK2 and DOCK8 sequencings were all wild type. Normal DOCK8 expression was performed after RT-PCR amplification and Western blot and representatively demonstrated in Fig. 4a and b.
https://static-content.springer.com/image/art%3A10.1007%2Fs10875-010-9479-1/MediaObjects/10875_2010_9479_Fig3_HTML.gif
Fig. 3

a In patient P8, the 1406th nucleotide of A substituted by G in the exon 15 of STAT3 gene caused the heterozygous missense mutation at the 469 amino acid of Gln replaced by Arg in the DNA-binding domain. b In CD3+ lymphocyte gating, permeabilized and stained with Alexa Fluor 647 conjugated mouse anti-tyrosine 705 phosphorylated STAT3 (pY705-STAT3) mAb (BD Biosciences, Pasadena, CA, USA), P8 patient with the heterozygous Q469R STAT3 mutation decreased phosphorylation in protein expression (25.4% vs. 67.3%) and mean fluorescent intensity (MFI; 43.4 vs. 60.3) after IL-6 (20 ng/ml) stimulation for 20 min, compared to that from healthy controls. Gray line meant the unstimulated status and black line with gray background did the IL-6 stimulation status. Duplicate experiments were performed

https://static-content.springer.com/image/art%3A10.1007%2Fs10875-010-9479-1/MediaObjects/10875_2010_9479_Fig4_HTML.gif
Fig. 4

a DOCK expression was demonstrated by RT-PCR amplification with six pairs of designed primers to cover the coding region. The products of 1164, 1193, 1298, 1247, 1375, and 826 nucleotides were sequencing to compare that from the healthy controls and Genebank. b DOCK8 protein expression was also detected by Western blot. Whole cell lysates extracted from patients (representative P1, P2, and P3) and healthy controls were resolved on the SDS-PAGE gel, and probed with antibodies against DOCK8 (Santa Cruz Biotechnology Inc, Santa Cruz, CA, USA) and actin (Sigma-Aldrich, Saint Louis, MI, USA). The amount of DOCK8 was almost equal in patients and controls. Actin was used as the loaded control, 30 μg each lane. C positive control(s), N negative control without templates, M leading marker, P patient(s)

Discussion

This is the first study from a referral medical center over a 25-year period to investigate Taiwanese HIES patients. The severity score is 31–65 scores and similar to those of American, European, and Japanese patients [611]. As expected as other ethnic groups with the AR-HIES phenotype, cutaneous viral infections of molluscum contagiosum, and HSV are common but difficult to eradicate [2, 22, 23]. HSV-induced urogenital granuloma in our patients P2 and P3, finally remitted after local acyclovir, antibiotics, and steroid to inhibit concomitant bacterial pathogens and chronic inflammation. Additional cyclosporin A and monthly IVIG interrupt the vicious cycle of itching and scratching to prevent recurrent cellulites or/and pyoderma [24, 25]. Interestingly, the patient with lower IgG4 (in P2), not her sister with normal IgG4 (in P3), has better response to IVIG infusion. Thus, responsive treatment is individualized in heterogeneous HIES patients even in sibling patients.

In line with the finding of increased CD4+ effector memory cells in a 30-year-old HIES woman reported by Gupta et al. [26], the lymphocyte subpopulation dynamics of the expansion of T-memory pools (in P2) and reduction of B-memory pools (in P2 and P4) trend to enhance vasculitis development. Unexpectedly accompanying cerebral vasculitis and infarction in this P2, lead deposition in her basal ganglia has aggravated the irreversible involuntary movements. Traditional Chinese ointments with unqualified components for wound healing should be carefully considered because the HIES patients usually deal with recurrent cutaneous infections breaking skin barriers, thus heavily absorbing enormous amounts of potentially harmful components.

For non-Chinese HIES prognosis, the mortality of AR-HIES is almost half and attributable to devastating neurological complications from ruptured cerebral arteritis, and necrotizing encephalitis [2]. In contrast, a common cause of mortality in AD-HIES patients is sudden and massive hemoptysis from pneumatoceles with superimposed by pseudomonas and aspergillus infections. During 5-year period (1998–2003) form the NIH report, only six AD-HIES patients were fatal of hemoptysis [27]. The better prognosis in AD-HIES is not consistent with the diagnosed patients here because three teenage AD-HIES patients died of acute myocardial infarction due to coronary aneurysm (in P4), P. mirabilis sepsis despite poly-chemotherapy for Hodgkin lymphoma (in P5) and S. aureus sepsis (in P6), respectively.

HLA-identical bone marrow stem cell transplantation (BMT) has been recommended for AD-HIES patients with malignant transformation and for AR-HIES with refractory severe complications [14]. Before 2009, only two HIES patients have received BMT—one 46-year-old man with B-cell lymphoma [28] and a 7-year-old girl with refractory disease [29]. The man died of interstitial pneumonitis after transplantation and the girl again suffered from recurrent skin abscesses with pre-transplant IgE levels [28, 29]. The unsuccessful experience has made our patient (P5) prefer to poly-chemotherapy for lymphoma at that time. She unfortunately succumbed to P. mirabilis sepsis during the status of poly-chemotherapy. In this year, hematopoietic stem cell transplantation rescued two STAT3-defective patients from high-grade non-Hodgkin’s lymphoma [30] and two DOCK8-deficient patients from refractory cutaneous infections, especially molluscum contagiosum [31]. Such beneficial transplantation should encourage those HIES patients with the threat of malignant transformation and refractory infections to take a relatively wiser opinion.

Sequencing known genetic defects of STAT3, TYK2, and DOCK8 prompts the recognition of HIES patients for adequate management before irreversible sequelae occurred. In Chinese descent AD-HIES, de novo STAT3 mutations were identified in two patients to date: one with Q469R mutation in Taiwan (P8) and the other with H437P mutation in mainland China [32]. Both were located at the DNA-biding site (exon 15) and behaved as the dominant negative manner. Our patient with Q469R mutation and relatively lower “HIES STAT3 score” was earlier presented in the 13th Asian Pacific Congress of Pediatrics in Shanghai, China, 2009. Overall in Taiwan, the other seven patients who had higher severity scores of AD-HIES phenotype encompassing pneumatocele, minor trauma fractures or/and scoliosis and AR-HIES phenotype including molluscum contagiosum and recurrent herpes infections had wild type STAT3, TYK2, and DOCK8. Whether or not unresolved molecules impair Jak-STAT-mediated cytokine signals and affect DOCK8-associated GTPase-actin cytoskeletion reorganization causing these HIES remains unclear. In this situation, the lower percentage of identifying mutations in Taiwanese HIES (1/8; 12.5%) attenuates its practical application for early diagnosis. Close follow-up of the HIES phenotype should then be the cornerstone of intervention at this juncture.

Applying the distribution pattern (8/187) of HIES patients [19] and the incidence of PIDs (2.17 per 100,000 live births) [15] to 23 million Taiwanese inhabitants, it is estimated that around 21 HIES patients (approximate 1.0 HIES per 1,000,000 live births) should be recognized. In other words, the lower percentage of identifying mutations in Taiwanese HIES may be ascribed to selection bias and under-diagnosis for HIES patients with defective genes, especially AR hereditary patterns of TYK2 and DOCK8 although genetic variations exist in different ethnicities and consanguineous marriage for increased AR penetrance is extremely rare in Chinese culture.

Acknowledgments

The authors wish to thank all of the patients and their families for their kind cooperation, as well as their physicians for the referrals. This study was supported by the Chang Gung Medical Research Progress Grant CMRPG 490011 and the National Science Council (Grants NSC 99-2314-B-182-003-MY3 and NMRPD190315).

Conflict of interest

All of the authors declare no conflicts of interest.

Copyright information

© Springer Science+Business Media, LLC 2010