Shyh-Dar Shyur

Clinical characteristics and survival of trisomy 18 in a medical center in Taipei, 1988–2004†

Trisomy 18 is the second most common autosomal trisomy in newborns. The birth prevalence of this disorder is approximately 1 in 3,000 to 1 in 8,000, and the life span of the majority of patients is less than 1 year. As information regarding outcome in trisomy 18 is rather fragmentary in the literature, this study is aimed at investigating the survival and natural history of trisomy 18. We also evaluated the survival age and management of trisomy 18 in two different periods, before and after the implementation of National Health Insurance (NHI) program. Thirty‐nine cases of trisomy 18 were collected in Mackay Memorial Hospital in a 17‐year period, from 1988 to 2004. Delivery data, survival age, management before and after the implementation of NHI program, structural defects, image findings and cytogenetic results were analyzed by medical and nurses records. The diagnosis of trisomy 18 was based on the prenatal amniocentesis or postnatal chromosome analysis. Three patients had trisomy 18 mosaicism. Since cardiovascular and central nervous systems are the most common organ systems involved in this disorder, 31 patients received brain ultrasonography and heart ultrasonography for evaluation of their multiple anomalies after admission. All patients except one died in their first year due to severe malformations of the cardiovascular or central nervous systems. The median survival age was 6 days. We found a longer survival with female patients than with male patients (P < 0.05). Implementation of NHI program in the more recent decade of this study period was associated with longer survival of trisomy 18 (P < 0.05). The three most common structural defects were clenched hands (95%), rocker bottom feet (90%), and low set or malformed ears (90%). Low birth weight was present in 90%. By cardiac ultrasonography, the top four heart defects were ventricular septal defect (94%), patent ductus arteriosus (77%) and atrial septal defect (68%). However, ten cases (32%) had complex congenital heart defects. By brain ultrasonography, the most common brain lesion was cerebellar hypoplasia (32%), followed by brain edema (29%), enlarged cisterna magna (26%) and choroid plexus cysts (19%). Although most patients with trisomy 18 die within the first few weeks after birth, it is important to recognize that a small but notable percentage of these patients will survive the first year. When prenatal or postnatal decisions need to be made, the possibility of long‐term survival should be included in any discussion to enable families to make the most appropriate decision.

The polymorphisms of interleukin 17A (IL17A) gene and its association with pediatric asthma in Taiwanese population.

Background:  The interleukin 17A (IL17A) gene, located on chromosome 6p and linked to asthma phenotype, is a highly potential candidate gene conferring asthma susceptibility. The purpose of this study was to investigate the genetic association between single nucleotide polymorphisms (SNPs) of IL17A and asthma in Taiwanese children.

Identification of variations in the human phosphoinositide 3‐kinase p110δ gene in children with primary B‐cell immunodeficiency of unknown aetiology

Our recent study demonstrated that defects in p110δ result in B‐cell immunodeficiency that is very similar to that observed in BTK‐deficient mice. We revealed that the p110δ fit the B‐cell signal transduction complex and played a non‐redundant role in the development and function of B cells. In humans, most children with primary B‐cell immunodeficiency have mutations in the BTK, whereas a few have defects in the components of the B‐cell signal transduction complex. But little is known about the genetic variation of p110δ in children with defects in B‐cell immunodeficiency of unknown aetiology. Sixteen patients from 15 unrelated families and 112 normal controls underwent sequence analysis to identify genetic variations of the p110δ. Allele frequency in each group was also analysed and compared. We identified five single base‐pair polymorphic nucleotide exchanges in both patient and control groups with similar allele frequencies, which did not contribute to the immunodeficiency. Three of them are novel (m.953A>G, m.1200C>T and m.1561A>G), and the m.953A>G and m.1561A>G nucleotide exchanges are non‐synonymous (N253S and T456A, respectively). The novel m.1561A>G was in complete linkage disequilibrium with the known m.873A>G in our study of Taiwanese group. In addition, one novel single base‐pair missense mutation, m.3256G>A (E1021K), was identified in one boy with typical clinical features of primary B‐cell immunodeficiency and could not be found in either his family or the normal control population. By atomic structural analysis of the amino acid as well as the alignment comparison between species, it resulted in the replacement of the negative‐charged amino acid E with the positive‐charged amino acid K at codon 1021, located in the highly conservative and important catalytic functional domain. Our findings could shed light on further understanding the polymorphisms of p110δ in B‐cell immunodeficiency and different populations. Moreover, the 3256G>A missense mutation raised the attention and warranted further extensive analysis to elucidate the role of p110δ in human immunodeficiency.

Systemic anaphylaxis after the ingestion of pancake contaminated with the storage mite Blomia freemani

BACKGROUND Systemic anaphylaxis after the ingestion of mite-contaminated food has rarely been reported. OBJECTIVE To describe an 8-year-old boy in whom systemic anaphylaxis developed shortly after the ingestion of pancakes prepared with commercial pancake flour. METHODS The patient underwent skin prick testing for house dust mites and with uncontaminated and mite-contaminated pancake flour. Specific IgE for mites and the main ingredients of the pancake flour were also evaluated, with titers for Der p 1, Der f 1, and Blo t 5 quantitated using immunochemical methods. A sample of pancake flour was examined microscopically for mites. RESULTS The patient had positive skin prick test results to contaminated pancake flour extract (1 g/5 mL), Dermatophagoides pteronyssinus, and Dermatophagoides farinae but a negative skin test response to uncontaminated pancake flour. The patients serum specific IgE analysis was positive for antibodies to dust and storage mite allergens. There was no response, however, to the main ingredients of the pancake mix. Microscopic examination of the pancake flour revealed the storage mite Blomia freemani. Using an immunochemical assay, we found that the contaminated flour contained 5.4 microg/g of the allergen Blo t 5 but no Der p 1 or Der f 1. CONCLUSIONS This patients anaphylactic episode was the result of ingestion of the storage mite B. freemani. To our knowledge, this is the first reported systemic hypersensitivity reaction caused by this mite anywhere in the world.

Neurogenic diabetes insipidus in children with hypoxic encephalopathy: Six new cases and a review of the literature

Hypoxic encephalopathy is rarely mentioned as a cause of neurogenic diabetes insipidus (DI) in children. We here report six cases of DI which occurred after severe hypoxic/ischaemic brain damage and include a review of the literature on 28 paediatric cases of neurogenic DI due solely to severe hypoxia/ischaemia. Airway obstruction, haemorrhagic shock and sudden infant death syndrome are the three major causes of hypoxia/ischaemia. The ages (25/28) ranged from 0.03 to 18 years (mean 7.27 years, median 5 years). The intervals between the hypoxic insult and the onset of DI (23/28) ranged from 0.08 days (2 h) to 13 days (mean 4.07 days, median 3.5 days). Linear regression analysis revealed no significant correlation between the age and the interval. Nineteen cases (82.6%) developed DI within 6 days after the hypoxic/ischaemic insult. Only two neonates survived with developmental delay. The remaining 26 cases died.ConclusionNeurogenic DI can be caused by hypoxia/ischaemia and is an ominous sign of severe brain damage in children with hypoxic encephalopathy. It is important to recognize this potential sequel by regularly monitoring intake and output, plasma sodium level, and urine specific gravity.

The polymorphisms of protein-tyrosine phosphatase receptor-type delta gene and its association with pediatric asthma in the Taiwanese population

We previously reported an association between genetic differences of pediatric asthma subtypes and a short tandem repeat (STR) marker, D9S286. It has been known that the protein-tyrosine phosphatase receptor-type delta (PTPRD) gene is located downstream of D9S286 and that the physical distance between them is about 0.25 Mb. We selected and conducted genotyping on 76 single-nucleotide polymorphisms (SNPs) that encircle the genomic region of PTPRD in Taiwanese children with or without asthma. A total of 996 subjects were divided into testing group (674 subjects) and validation group (322 subjects). The results were further validated with the third subject group (611 subjects) recruited from different geographical regions. After Bonferroni correction, 3 out of 80 SNPs were found to be strongly significant (P<0.05/76=0.000658) in the allele frequency test. This association was confirmed by validation groups. The results indicate that polymorphisms of PTPRD are strongly associated with pediatric bronchial asthma in the Taiwanese population.

Neurogenic Diabetes Insipidus in a Child with Fatal Coxsackie Virus B1 Encephalitis

A 5 year-old boy presented with fever, sore throat, diarrhea, and general soreness which evolved into encephalitis. His cerebrospinal fluid showed a cell count of 3 mononuclear cells/microliters, protein 2800 mg/l, and growth of Coxsackie virus B1. Cardiorespiratory arrest was noted after a convulsion and infusion of diazepam. Although he was immediately resuscitated, he remained unconscious with a modified Glasgow coma score of 4 or 3. He developed neurogenic diabetes insipidus 169 hours after the convulsion and died the next day. We conclude that although Coxsackie virus infection is usually benign it may become overwhelming and be complicated with neurogenic diabetes insipidus. It is important to recognize this potential sequel by regularly monitoring weight, intake and output, plasma sodium level, and urine specific gravity.

De novo mutation in the BTK gene of atypical X-linked agammaglobulinemia in a patient with recurrent pyoderma

BACKGROUND X-linked agammaglobulinemia (XLA), characterized by a profound deficiency of all immunoglobulins and the absence of mature B cells, is caused by mutations in the gene encoding Bruton tyrosine kinase (BTK). Most patients have recurrent sinopulmonary infection. Infections usually occur in multiple locations across time, but single infection may be limited to one anatomic location. OBJECTIVES To report a case of atypical XLA with recurrent pyoderma and to observe the immunologic changes in the patient in 10 years. METHODS Immunologic investigations, skin wound culture, and molecular study with DNA sequencing were performed. RESULTS The patient was originally diagnosed as having common variable immunodeficiency disease because of the presence of circulating B cells (CD19+ B cells: 7%) at 11 years old. On further evaluation at the age of 20 years, flow cytometric analysis of lymphocytes showed only 0.4% B cells. The molecular study with DNA sequencing of the patient showed a point mutation in complementary DNA 1630 A>G(p.R544G) in the BTK gene, indicating that the patient has XLA. The mutation analysis of the BTK gene revealed a normal DNA sequence in the other family members. CONCLUSIONS This case is an important example of a possible presentation of XLA with a predominant skin manifestation, and it demonstrates that maintaining a high level of clinical suspicion is essential for the diagnosis of XLA in a child with recurrent pyoderma.

Clinical Features and Genetic Analysis of Taiwanese Patients With the Hyper Igm Syndrome Phenotype

Objectives: Hyper IgM syndrome (HIGM), characterized by recurrent infections, low serum IgG and IgA, normal or elevated IgM, defective class switch recombination and somatic hypermutation, are heterogeneous disorders with at least 6 distinct molecular defects, including the CD40 ligand (CD40L) and the nuclear factor &kgr;B essential modulator (NEMO, also known as IKK&ggr;) genes (both X-linked), the CD40, activation-induced cytidine deaminase (AICDA or AID), uracil-DNA glycosylase genes (autosomal recessive) and I&kgr;B&agr; (IKBA) (autosomal dominant). Our objective was to determine the molecular basis and clinical features of Taiwanese patients with the HIGM phenotype. Methods: Clinical manifestations and candidate genes were analyzed in a nationwide population-based study. Results: Among 14 patients (12 unrelated families) since 2003, 10 patents were identified (8 families) with CD40L mutations, including 2 novel deletions of “A” nucleotide (Del 347A and Del 366A), both frameshift and stop at the 127th location; 1 novel AID deletion mutation lack of the 37thAsp and 38th Ser; 1 ataxia–telangiectasia mutation; and 1 deletion of chromosome 1q42. An adult-onset patient with mutant (Thr254Met)CD40L had approximately 30% detectable affinity and therefore less severity. Memory B cells decreased in patients with CD40L and activation-induced cytidine deaminase mutations. Three mortalities encompassed renal cell carcinoma in 1 patient with (Tyr169Asn)CD40L, pneumothorax in 1 with (Tyr140Stop)CD40L and pneumonia after chemotherapy in an ataxia–telangiectasia patient. One patient without detectable genetic defects but normal lymphocyte proliferation resembled the mild form of common variable immune deficiency phenotype. Conclusions: In contrast to those with AICDA mutation, small chromosome 1 q42 deletion and unknown genetic defect, the majority (10/14; 71.4%) with CD40L mutations except (Thr254Met) and an ataxia–telangiectasia patient had the severe form of HIGM phenotype.

Juvenile Recurrent Parotitis

BACKGROUND Juvenile recurrent parotitis (JRP) is a rare, recurrent non-obstructive, nonsuppurative parotid inflammation in young children with a multifactorial etiology. METHODS The records of 12 children with recurrent parotitis were retrospectively reviewed. RESULTS The age of onset ranged from 3 to 8 years (mean, 5.1 years). Each attack lasted an average of 3.5 days. The major clinical manifestations included fever (75%), swelling (100%), and pain (100%). One girl also had xerostomia and keratoconjunctivitis sicca. Her biopsy specimen from a minor salivary gland was consistent with juvenile Sjiigrens syndrome. Six patients had positive antinuclear antibodies (4 with a speckled pattern and 2 each with a homogeneous or nucleolar pattern). Bilateral sialography was performed in 9 children. The results in 4 were normal, 2 had unilateral punctate sialectasis, and 3 had bilateral sialectasis. After sialography, the frequency of recurrences significantly decreased from 5.11 to 0.56 per year (P < 0.05). CONCLUSIONS Bilateral sialography is useful for the diagnosis of JRP, but it also appears to decrease the frequency of recurrences.