Type I hereditary angioedema in Taiwan – clinical, biological features and genetic study.

Background: Hereditary angioedema (HAE) is a rare, autosomal dominant inherited disease which is caused by a genetic deficiency of C1 esterase inhibitor (C1 INH). There have only been a few case reports in Taiwan to date. Objective: To describe the clinical features of type I HAE in Taiwanese patients. Methods: Three unrelated Taiwanese families with type I HAE are reported, and one case of a family from a review of PubMed was reviewed. Clinical manifestations, diagnostic examinations, management and genetic studies were analyzed. Results: Including this report, 19 patients had low C1 INH and low C4 levels and were diagnosed with type I HAE. Only 11 (57.9%) patients were symptomatic. Recurrent skin swelling and edema over the four extremities or trunk were reported in all symptomatic patients (100%). 45.5% of the patients recalled laryngeal attacks and one patient died from asphyxia. 18.2% of the patients experienced abdominal symptoms. The age at the beginning of clinical symptoms ranged from 5 to 30 years (mean ± SD: 20.82 ± 7.88 years). The diagnosis tended to be delayed (range from 1 to 39 years; mean ± SD: 8.45 ± 11.04 years). Nine patients had a mutant C1 INH gene, and two patients received long-term prophylaxis with danazol. Conclusion: The prevalence of hereditary angioedema in Taiwan is low. Persons with low levels of C1 INH who were clinically symptomatic accounted for only 57.9% of the cases in our study, which is far lower than previous reports from other countries. Ethnic differences may be the reason for this finding. Further genomic studies are needed to elucidate the genetic penetrance of C1 INH deficiency in Taiwan.

Clinical manifestations and BTK gene defect in 4 unrelated Taiwanese families with Bruton’s disease.

Background and objective: X-linked agammaglo-bulinemia (XLA, also called Bruton’s disease) is is an X-linked recessive disorder characterized by recurrent bacterial infections, usually occurring in the first few years of life. Here, we report the results of a BTK gene mutation screening study that was performed in Taiwanese families with the BTK gene defect to further understand the inheritance patterns of XLA patients in Taiwan and to avoid new cases of XLA within families. Materials and methods: In this study, 52 members of 4 unrelated Taiwanese families with the BTK gene defect were enrolled. We studied the immunologic reports of 6 symptomatic living male patients with confirmed BTK gene defects and correlated the findings with their clinical symptoms. The genomic DNA of the subjects was subjected to direct sequencing mutation analysis. Results: We screened 52 members of 4 unrelated Taiwanese families with the BTK gene defect for BTK gene mutation and found that there were 6 symptomatic living patients with a confirmed defect, 7 symptomatic deceased patients highly suspected to have had the defect and 11 asymptomatic female carriers. Conclusions: This is the first report in a series of the thorough screening for the BTK mutation and its carrier status in 4 unrelated Taiwanese families. One pedigree of our study comprises 4 generations. A complete BTK gene mutation study for the patient’s family members is strongly suggested.

Juvenile scleroderma: experience in one institution.

Background: Scleroderma is a chronic connective tissue disease characterized by hardened or scaly skin and widespread abnormalities of the viscera, which is rare in the pediatric age group. Objective: In this study, we retrospectively reviewed 23 pediatric patients suffering systemic (SSc) and localized (LS) scleroderma. Methods: Twenty-three patients were enrolled and were diagnosed with SSc or LS from March 1993 to September 2009 in the Department of Pediatrics at Mackay Memorial Hospital in Taipei, Taiwan. These diagnoses were based on the criteria of the American College of Rheumatology and the clinicalmanifestations of hard skin. Data recorded included sex, age-at-onset, age-at-diagnosis, laboratory data, family history, trauma history, treatment, and outcomes. Results: Three patients suffered SSc and 20 patients had LS, including 16 girls and 7 boys. Mean age-at-onset was 6.55±3.28 years old. Antinuclear antibodies were positive in 15 patients. Tests for anti-Scl-70 antibodies were positive in 1 patient with SSc. One boy had en coup de sabre combined with a posterior fossa tumor. Twenty-two patients were treated with D-penicillamine. Oral prednisolone and methotrexate were added, if indicated. One girl with LS developed proteinuria after Dpenicillamine treatment. All patients with localized disease ultimately documented a softening of their skin lesions. Conclusions: While scleroderma is rare in children, the prognosis of SSc is poor but better than for adults. The prognosis for LS is usually benign, however, the skin may become progressively indurated and it may not only be a skin disease. No progression from LS to SSc was observed in our study.

Factors for high-risk asthma in Taiwanese children.

Background: Asthma is one of the major causes of death in otherwise healthy young individuals. However, many of these deaths may have been prevented by more aggressive treatment. To determine factors correlated with a high risk of death in Taiwanese children with atopic asthma. Methods: Taiwanese children aged 5-18 years, diagnosed with atopic asthma were enrolled in the study. Atopic asthma was diagnosed and immunoglobulin E (IgE) specific to antigens from any 1 of 8 allergens was measured (i.e. Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat and dog dander, cockroach, egg white, milk and fish). High-risk asthma was defined as asthma requiring admission to a hospital or a visit to an emergency department. The study tried to determine the association of high-risk asthma with allergy-related parameters (e.g. asthma severity, asthma score, total serum IgE levels, serum levels of allergenspecific IgE, eosinophil count) and pulmonary function in Taiwanese children. Results: One thousand one hundred and twenty-two Taiwanese children were evaluated. Those with higher asthma severity, asthma symptom score, serum levels of IgE specific to D. pteronyssinus and D. farinae, higher total serum IgE levels, and lower FEF25-75% (forced expiratory flow, 25-75%) values were considered to be members of the highrisk asthma group. Conclusions: The characterization of risk factors has enabled us to identify high-risk asthma in Taiwanese children, which will facilitate the treatment of these children in the future.

Changes in serum specific IgG4 and IgG4/ IgE ratio in mite-sensitized Taiwanese children with allergic rhinitis receiving short-term sublingual-swallow immunotherapy: a multicenter, randomized, placebo-controlled trial.

The aim of this study was to evaluate the clinical and immunologic effects of sublingual-swallow immunotherapy (SLIT). A six-month, multicenter, double-blind, placebo-controlled trial was carried out in 59 patients aged 6 to 18 years with allergic rhinitis who were sensitized to mites only. Patients were randomly assigned to placebo or SLIT with a standardized Dermatophagoides pteronyssinus (D.p.)/D. farinae (D.f) 50/50 extract. Nasal symptom scores and use of medications were recorded. Skin sensitivity, mite-specific IgE, IgG4, and IgG4/IgE were evaluated before and after treatment. The skin sensitivity, total nasal symptom scores and medication consumption did not differ significantly after treatment. Specific IgG4 (both p <0.001) and IgG4/IgE to D.p. and D.f (p = 0.010, p = 0.001, respectively) increased significantly in the treatment group. Specific IgE increased significantly in both placebo and SLIT groups after treatment but did not differ between the two groups. The medication was well tolerated. SLIT did not significantly improve clinical manifestations of allergic rhinitis when used for 6 months. We demonstrated SLIT did significantly increase specific IgG4 and IgG4/IgE compared to treatment with placebo.

Hereditary angioedema: a Taiwanese family with a novel gene mutation.

Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a deficiency of C1 esterase inhibitor (C1-INH). Affected individuals have attacks of swelling involving almost any part of the body. We studied a family with 15 living members, including a 16-year-old girl who had 3 attacks of angioedema in 2 years. Her paternal uncle had died of asphyxiation during an attack 15 years previously. We analyzed the blood of each family member for C3, C4, and C1-INH levels and sequenced the SERPING1 (formerly C1NH) gene that codes for C1-INH. Six individuals had decreased serum levels of C4 and C1-INH, and they were all found to have a single nucleotide A deletion at codon 210 of the gene, 1210fsX210, a novel mutation that accounts for the HAE in this family.

Buckwheat anaphylaxis: an unusual allergen in Taiwan.

IgE-mediated hypersensitivity to buckwheat is common in Korea, Japan, and some other Asian countries. However, buckwheat is not a common allergen in Taiwan. We report a woman with asthma who had anaphylactic shock, generalized urticaria, and an acute exacerbation of asthma five minutes after ingesting buckwheat. The patient underwent skin prick and Pharmacia CAP testing (Uppsala, Sweden) for specific IgE to buckwheat, white sesame and soybean as well as other common allergens in Taiwan including Dermatophagoides pteronyssinus (Dp), D. farinae (Df), cat and dog dander, cockroach, egg white, cow milk and codfish. The patient had a strongly positive skin prick test response to buckwheat and positive reactions to Dp and latex. Specific IgE results were class 6 for buckwheat, class 4 for Dp and Df, and class 2 for dog dander, wheat, sesame and soybean. Results of an open food challenge with white sesame and soybean were negative. Although buckwheat is a rare allergen in Taiwan, it can cause extremely serious reactions and should be considered in patients presenting with anaphylaxis after exposure to buckwheat.

A randomized controlled trial of cetirizine plus pseudoephedrine versus loratadine plus pseudoephedrine for perennial allergic rhinitis.

The purpose of this study was to compare the safety and efficacy of cetirizine plus pseudoephedrine (C+P) with loratadine plus pseudoephedrine (L+P) in the treatment of perennial allergic rhinitis. This was a double blind, randomized, parallel trial with an active control. Subjects aged 12 to 70 years with perennial allergic rhinitis for at least 2 years were enrolled and randomized to receive either of the active study medications plus a placebo resembling the other, twice daily for 4 weeks. Nasal total symptom scale (NTSS) including sneezing, rhinorrhea, nasal itching and nasal stuffiness is evaluated by subjects daily and at baseline, 2 weeks, and 4 weeks by the investigator as efficacy measurement. A total of 51 eligible patients were enrolled and 45 patients completed the treatment course. Both groups had significant reductions in NTSS after 4 weeks of treatment as assessed by the subjects, but there was no significant difference between the two groups (mean +/- SD) reduction of 4.25 +/- 2.45 with C+P vs. 3.52 +/- 2.41 with L+P, p = 0.215. As assessed by the investigator, sneezing was significantly better at 2 weeks (-1.13 vs. -0.52, p = 0.028) and nasal congestion at 4 weeks (-1.71 vs. -1.19, p = 0.031) in subjects treated with C+P compared to those treated with L+P. There were 37 treatment-related adverse events (5 in 4 subjects in the C+P group and 32 in 16 subjects in the L+P group). It was concluded that both cetirizine plus pseudoephedrine and loratadine plus pseudoephedrine are efficacious for perennial allergic rhinitis in Taiwanese subjects. Relief of sneezing and nasal congestion may be marginally better with the cetirizine preparation, which also seemed to be slightly better tolerated, although the incidence of side effects did not differ significantly.

DiGeorge syndrome associated with solitary median maxillary central incisor.

DiGeorge syndrome is a primary immunodeficiency disease characterized by dysgenesis of the thymus and parathyroid glands, conotruncal cardiac anomalies, and other dysmorphic features. Although most patients have a common microscopic deletion in chromosome 22q11.2, marked clinical variability exists. A solitary median maxillary central incisor (SMMCI) is a rare dental anomaly which may be an isolated occurrence or associated with congenital nasal airway abnormalities or holoprosencephaly. We report a patient with DiGeorge syndrome who was diagnosed at nearly 1 month of age and was later found to have a solitary median central incisor. Initially, the patient presented with recurrent episodes of respiratory distress attributed to partial airway obstruction, one of the phenotypic features of SMMCI. A fluorescence in situ hybridization study showed a chromosome 22q11.2 deletion.

Disseminated Bacille Calmette-Guérin disease as the initial presentation of X-linked severe combined immunodeficiency--a case report.

Bacille Calmette-Guerin (BCG) vaccination is used to prevent severe M. tuberculosis infection. It has been used in many countries for a long time. However, complications do occur, including localized abscesses, regional lymphadenitis and disseminated disease. The latter is often associated with underlying immunodeficiency. We report an 8-month-old male infant presenting with cough and fever who had had a generalized pigmented skin rash for one month. Skin biopsy revealed mycobacterial infection, but his response to treatment was poor and he had a persistent mild fever. Immunological studies revealed an IgG of 49 mg/dl, IgA 4 mg/dl, IgM 28 mg/dl, IgE < 1 mg/dl, CD3 1.1%, CD4 0.6%, CD8 0.6%, CD19 93.9%, CD57 1.1%, activated T cells 0.9%, and CH50 < 6.3%. These findings are compatible with the diagnosis of T(-)B(+)NK- severe combined immunodeficiency. Sequence analysis was performed and showed the presence of missense mutation in IL2Rgamma gene. An X-linked recessive inheritance pattern was proved by sequence analysis of his mother and grandmother. In order to identify the strain of the microorganism, we reviewed pathology of the skin biopsy which consisted of diffuse histiocytic infiltrate with poorly formed granulomas and no necrosis and used polymerase chain reaction (PCR) with the stain-positive clinical specimen and verify the organism found in the child's biopsy as M. bovis BCG strain. The diagnosis of disseminated BCG disease must be considered in any infant with cutaneous mycobacterial lesions, especially with atypical histologic findings. Such a patient's immunologic status should be evaluated and further family study is suggested. A high index of suspicion is needed to make a timely diagnosis, as early intervention with intensive treatment and bone marrow transplantation may be life-saving.

De novo mutation causing X-linked hyper-IgM syndrome: a family study in Taiwan.

X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency disorder caused by mutations of the gene encoding the CD40 ligand (CD40L). It is characterized by recurrent infections with markedly decreased serum IgG, IgA and IgE levels but normal or elevated IgM levels. We report the clinical manifestations and complete immune studies in the first family with molecularly proven XHIM in Taiwan. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgA, and IgE were noted in his plasma specimen: IgM, 128 mg/dl; IgG, 18 mg/dl; IgA, 4 mg/dl); IgE, 1 IU/ml. Whole blood flow cytometry when he was 21 months old showed that only a small percentage (0.48%) of his in vitro-activated CD4+ T cells expressed CD40L. When he was 3 years old, repeated flow cytometry showed essentially the same result (0.4%), compared with his father's CD40L expression of over 85%. The patient's mother had moderately decreased CD40L expression (74.4%). Hyper-IgM syndrome was confirmed by CD40L mutation analysis in the boy, which revealed a Lys 96 stop (nucleotide A307T) in exon 2 of CD40L, with a truncated protein resulting in the loss of the entire TNF domain. His mother was a carrier and apparently the individual in whom the mutation originated. Eleven other family members, including the patient's father, sister, and grandmother, and the mother's sisters and their children, all had normal results on CD40L mutation analysis. The patient has remained without significant bacterial infection on a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, although he has had recurrent oral ulcers and neutropenia. Bone marrow transplantation is planned.

Focal seizures as an unusual presentation of neonatal lupus erythematosus.

Neonatal lupus erythematosus is an uncommon passive autoimmune disease in which there is a transplacental passage of anti-Ro/SSA and/or anti-La/SSB maternal autoantibodies. Common clinical manifestations include cardiac disease, notably congenital heart block, cutaneous lupus lesions, hematologic disorders, and hepatobiliary disease. During the past decade, however, it has become clear that central nervous disease may also be a manifestation of neonatal lupus. We report a male neonate with the disease who had focal seizures in addition to cutaneous lupus, anemia, and thrombocytopenia. Brain ultrasound revealed normal ventricular size without a midline shift or intracranial or intraventricular hemorrhage. A brain CT showed generalized low density involving the periventricular and deep white matter. A sleep EEG revealed rare spikes axial to the right parietal lobe. The neonate had a high titer of antinuclear antibodies (1:640) with a speckled pattern, anti-Ro/SSA and anti-La/SSB antibodies, but no anti-dsDNA antibodies. He was given anti-convulsant drugs with dramatic improvement of his symptoms. One month later, a sleep EEG was normal, and he had no further seizures.