Characterization of Bruton's Tyrosine Kinase Genetic Mutations in One Korean X-linked Agammaglobulinemia Family

PURPOSE: X-linked agammaglobulinemia(XLA) is an immunodeficiency caused by abnormalities in Bruton's tyrosine kinase(Btk), and is characterized by a deficiency of peripheral blood B cells. We studied the cytoplasmic expression of Btk protein and analyzed the Btk gene in peripheral blood mononuclear cells from two siblings and one cousin with XLA, as well as additional family members. METHODS: Btk protein expression was analyzed by flow cytometry. Isolation of the coding sequence of the Btk gene was performed by amplification using the reverse transcription-polymerase chain reaction(RT-PCR) technique. Sequence alterations were screened by the single-stranded conformation polymorphism(SSCP) method and characterized by standard sequencing protocols. RESULTS: Cytoplasmic expression of Btk protein in monocytes was not detected in three patients with XLA. In addition, Btk protein analysis clearly showed cellular mosaicism in monocytes from four obligate carriers, findings further supported by SSCP. A single base pair mutation(T to C) in Btk-exon three, which encodes the PH domain, was identified in four XLA patients. A diagnostic sequencing analysis was established to detect heterozygotic pattern in 4 carrier females. Furthermore, we found significant clinical heterogeneity in individuals with the same gene mutation. CONCLUSION: The implicating genetic alteration provided valuable clues to the pathogenesis of XLA in Korea and the flow cytometric analysis was suggested as a useful tool for rapid detection of XLA patients and carriers. The present study has identified a genetic mutation in the Btk coding region and demonstrated heterogeneity in clinical manifestations among patients with the same mutation. A flow cytometric analysis was found to be informative in establishing a deficiency of Btk protein in both patients and carriers and is recommended as a frontline procedure in the molecular diagnosis and work-up of XLA.

A Case of Multiple Ectopic Thyroid Glands with Goiter and Compensated Hypothyroidism Diagnosed by Computerized Tomography / 대한소아내분비학회지

Ectopic thyroid is an uncommon embryological aberration characterized by the presence of thyroid tissue at a site other than in its usual pretracheal region. Usually it occurs along the path of descent of the developing thyroid primodium from the foramen cecum, commonest being lingual followed by sublingual and in the anterior midline of neck at, or below, the level of the hyoid bone. It is unusal for lingual thyroid to present simultaneously with another ectopic thyroid, so we report a case of 12-year-old girl who had multiple ectopic thyroid glands with goiter and compensated hypothyroidism diagnosed by computerized tomography in lingual and infrahyoid area.

Identification of a Novel Mutation of Bruton's Tyrosine Kinase(BTK)Gene in a X-linked Agammaglobulinemia(XLA) Family

X-linked agammaglobulinemia(XLA) is a heritable humoral immunodeficiency disease characterized by inefficient expansion of pre-B cells into later B cell stages or incomplete differentiation of B cell precursors to pre-B cells. The gene mutated in XLA was identified as a cytoplasmic tyrosine kinase, named Bruton's tyrosine kinase(BTK). In this report we investigated the characteristics of immune cells, the patterns of intracellular BTK protein expression by flow cytometry, and the genetic abnormality by direct sequencing in one Korean XLA family. Finally, we found that the serum immunoglobulins and the number of peripheral B cells were extremly low in the patient and his brother. The histogram of intracellular BTK staining in the patient and his brother showed typical case of XLA, whereas that of their mother showed a carrier pattern. We also identified a novel point mutation in the first intron of the BTK gene in the patient and his brother. The genomic DNA sequencing of mother and sister showed a G/A heterozygote pattern. These results will provide valuable clues to the pathogenesis of XLA, and suggest an approach useful for carrier detection.

A Case of Primary Mucinous Adenocarcinoma of the Colon in Children / 대한소아혈액종양학회지

Carcinomas are malignant neoplasms composed of epithelial cells and epithelial cancers are rare in the young. When it comes to colorectal carcinoma, the incidence of the large bowel has been noted with increasing frequency in the younger population, but this disease has remained very rare in children. Only 1% of all malignant growths of the large intestine arise in persons under 20 years of age. Inspite of these facts, the colon is the most common site of gastrointestinal carcinoma in children. While the prognosis is relatively acceptable in adults, it is very gloomy in children. Of all the histologic categories of colorectal cancer, the mucinous variety, which accounts for approximately 15% of adult colorectal carcinoma, is the predominant histologic variety in patients younger than 20 years of age at the time of diagnosis. Now, only two cases of carcinoma of the colon in children under 15 years of age have been reported in Korea. We report a case of mucinous adenocarcinoma of the colon in a 14-year-old boy with a brief review of the cases on record.