Brain MR Imaging Findings of Cardiac-Type Fabry Disease with an IVS4+919G>A Mutation.

BACKGROUND AND PURPOSE: A high incidence of cardiac-type Fabry disease with an α-galactosidase A mutation, IVS4 + 919 G>A, has been identified in the Taiwanese population. The neurologic manifestation has not been understood in this specific cardiac variant. This study aimed to investigate the typical imaging features of classic Fabry disease in patients with IVS4 Fabry disease. MATERIALS AND METHODS: Twenty-six patients with IVS4-type Fabry disease (20 men and 6 women; age range, 43-71 years; median age, 61 years) and 26 age- and sex-matched healthy controls (age range, 44-68 years; median age, 60 years) were analyzed for white matter hyperintensities, the pulvinar sign, and basilar artery diameter. The volumes of white matter hyperintensities were calculated by comparison with an in-house data base of 276 controls. RESULTS: Infarctions were found in 9 patients with IVS4 Fabry disease (35%) and in none of the healthy controls (P = .001). A pulvinar sign was found in 8 patients with IVS4 Fabry disease (30%) and in none of the healthy controls (P = .002). No significant difference was found in Fazekas scale scores for white matter hyperintensities; however, white matter hyperintensity volume in the deep white matter was higher in patients with IVS4 Fabry disease than in those from the healthy control data base (P = .004). CONCLUSIONS: Along with its involvement of the cardiac system, IVS4-type Fabry disease has features similar to those of classic Fabry disease and a higher frequency of deep white matter hyperintensities and a higher incidence of infarctions and pulvinar signs than in healthy controls.

A whole genome methylation analysis of systemic lupus erythematosus: hypomethylation of the IL10 and IL1R2 promoters is associated with disease activity.

The etiology of systemic lupus erythematosus (SLE) involves a complex interaction of genetic and environmental factors. Investigations have shown that environmentally driven epigenetic changes contribute to the etiology of SLE. Here, we hypothesize that aberrant DNA methylation may contribute to the activation of the immune machinery and trigger lupus disease activity. A whole genome methylation array was applied to investigate the DNA methylation changes between 12 pairs of active SLE patients and healthy controls. The results were further confirmed in 66 SLE patients, 102 healthy controls. The methylation statuses of the IL10 and IL1R2 genes were significantly reduced in the SLE patient samples relative to the healthy controls (age-adjusted odds ratios, 64.2 and 16.9, respectively, P<0.0001). There was a trend toward SLE patients having hypomethylated IL10 and IL1R2 genes accompanied by greater disease activity. We observed that the methylation degree of IL10 and IL1R2 genes were reduced in the rheumatoid arthritis (RA) patients as well but the hypomethylation change was more significant in IL1R2 genes than in the IL10 genes in RA patients. This study demonstrated that DNA hypomethylation might be associated with SLE. Hypomethylated IL10 and IL1R2 genes may provide potential epigenetic markers as clinical predictors for autoimmune diseases.

Contribution of genetic factors to neonatal transient hypothyroidism.

BACKGROUND: The causes of neonatal transient hypothyroidism (NTH) remain incompletely understood. Whether it is influenced by genetic background is rarely discussed and remains unproven. A defect in thyroid peroxidase is a common cause of dyshormonogenesis of the thyroid gland in Taiwanese, with a novel mutation (2268insT) present in nearly 90% of alleles studied. OBJECTIVE: To determine if the presence of this common mutation is associated with NTH in Taiwan. METHODS: A mismatched primer was designed and used for this specific 2268insT mutation to screen 1000 normal babies and 260 babies with confirmed NTH. RESULTS: The carrier rate for 2268insT in normal babies (1/200) was significantly lower than in babies with NTH (1/13; p<0.0001). CONCLUSIONS: The results strongly suggest that the presence of this thyroid peroxidase mutation contributes to the development of NTH. Likely pathogenetic explanations include the effect of the stress of extrauterine adaptation during labour on an immature pituitary-thyroid axis in genetically predisposed individuals, combined with environmental triggers such as iodine deficiency, perinatal iodine exposure, and/or goitrogen contamination.

Contributions of bone maturation measurements to the differential diagnosis of neonatal transient hypothyroidism versus dyshormonogenetic congenital hypothyroidism.

AIM: To a) evaluate the contribution of bone maturation in the diagnosis of neonatal transient hypothyroidism versus dyshormonogenetic congenital hypothyroidism in full-term newborns, and b) use bone maturation to test the hypothesis that neonatal transient hypothyroidism is perinatal in onset. MATERIALS AND METHODS: The study included 20 patients with dyshormonogenetic and 43 with transient hypothyroidism. Thyroid function and measurements of the distal femoral epiphysis area, obtained at the time of first confirmatory diagnosis, were compared between the two groups. The epiphysis area in two control groups with normal thyroid function was also measured and compared with that in patients with transient hypothyroidism, at age 1-3 d (control A), or at the age when normal thyroid function was confirmed (control B). RESULTS: Mean epiphysis area was 0.04 cm2 in patients with dyshormonogenetic versus 0.22 cm2 in patients with transient hypothyroidism (p < 0.0001). An area <0.05 cm2 was limited to patients with dyshormonogenetic hypothyroidism. Conversely, a normal area (>0.2 cm2) was only observed in patients with transient hypothyroidism. Mean epiphysis areas in control A (0.20 cm2) and in patients with transient hypothyroidism were similar (p = 0.37), consistent with perinatal onset of transient hypothyroidism. Mean epiphysis area in control B (0.31 cm2) was significantly greater than in patients with transient hypothyroidism (p < 0.01). CONCLUSIONS: A short duration of hypothyroidism can significantly delay bone maturation. Examination of bone maturation at initial confirmatory evaluation yields important information pertaining to congenital hypothyroidism, not only to predict intellectual development, but also to evaluate the risk of dyshormonogenetic hypothyroidism.

A pilot study of neonatal screening by electrospray ionization tandem mass spectrometry in Taiwan.

Amino acid and acylcarnitine profiling of dry blood specimens using electrospray tandem mass spectrometry (ESI/MS/MS) has been recognized as an useful tool for screening inherited metabolic defects of newborns. In this pilot study, we introduced this technology to screen 2100 newborns to establish the normal amino acid and acylcarnitine level. Based on the upper cutoff level (average + 4*SD), twenty-nine samples studied were considered as abnormal. After follow-up samples and urine GC/MS analysis, only two were confirmed as true inborn errors. One was identified as hyperphenylalaninemia, and the other as isovaleric acidemia. The positive rate of true inborn metabolic error was 0.09% (2/2100), and the false positive rate 1.28% (29/2100) in this study. ESI/MS/MS is proven to be an adequate tool for inborn metabolic error screening.

Diagnosis of congenital hypothyroidism from human anagen scalp hair by infrared microspectroscopy.

A highly efficient Fourier transform infrared (FT-IR) microscopy was used to determine the biophysical structure of anagen scalp hair roots of neonates suffering from congenital hypothyroidism (CH) due to ectopic thyroid. The present results indicate that the lower composition near 1,053 cm(-1) (also assigned to the aromatic iodide stretching band) in the infrared (IR) spectra of the hair roots for CH patients was directly associated with the lower serum level of T4 and fT4, and the elevated TSH levels determined by RIA method. This strongly implies the lower evidence of the aromatic iodide stretching band in the IR spectra of hair roots. These findings suggest that FT-IR microscopy has the potential to become a good diagnostic tool and that hair can be useful as a genetic marker.

Differentiation of hair growth cycle from scalp hair roots for the diagnosis of glucose-6-phosphate dehydrogenase deficiency in neonates.

Hair analysis can be used as a screening tool in the diagnosis of genetic diseases. The scalp hair roots of 67 normal neonates and 39 neonates with glucose-6-phosphate dehydrogenase (G6PD) deficiency were analysed using Fourier transform infrared (FT-IR) microspectroscopy to differentiate the stages of the hair growth cycle and to diagnose the genetic disorder on the basis of spectral differences. We have demonstrated that FT-IR microspectroscopy is a rapid and effective noninvasive diagnostic method to differentiate scalp hair roots of normal neonates into the anagen, catagen or telogen phases of the hair growth cycle, using IR spectral differences within the 3000-2800 cm(-1) region and the IR peak area ratio of 2854 cm(-1)/2873 cm(-1) or 1084 cm(-1)/amide II band (p<0.001). Moreover, G6PD-deficient neonates could be accurately diagnosed from telogen phase hair roots owing to significant differences in IR peak area ratios of 2854 cm(-1)/2873(-1) or 1084 cm(-1)/amide II band compared to normal values in healthy neonates. The result suggests that the application of FT-IR microspectroscopy may be capable not only of differentiating the hair growth cycle into anagen, categen or telogen phases but also of detecting G6PD deficiency. Hair root analysis promises to be a useful complement to serum and urine analysis in the diagnosis of genetic diseases.

Congenital hypothyroidism with multiple ovarian cysts.

UNLABELLED: A case of ectopic thyroid with congenital hypothyroidism presenting with bilateral multicystic ovaries without marked precocious puberty is reported. The cystic ovaries disappeared dramatically after thyroid hormone therapy. CONCLUSION: When ovarian cysts are found in prepubescent females, the possibility of associated hypothyroidism should be considered.

DiGeorge syndrome with microdeletion of chromosome 22q11.2: report of one case.

DiGeorge syndrome (DGS) is a congenital anomaly involving developmental defects of the third and fourth pharyngeal pouches. Thymic aplasia or hypoplasia, parathyroid aplasia or hypoplasia, cardiac malformations, and dysmorphic facies are characteristics features. We present a case which had thymic aplasia, hypocalcemia, facial dysmorphism (hypertelorism, low set ears, cleft of soft palate, fish-like mouth and micrognathia) and congenital heart disease (ventricular septal defect, perimembranous type). The T-cell immunologic functions as a percentage of T-cell and phytohemagglutinin stimulation test were within normal range matched with age. Molecular study showed microdeletion of chromosome 22q11.2 by genotype analysis, but chromosome study of high-resolution cytogenetic analysis by G-banding technique was normal. To our knowledge, about 90% of DiGeorge syndrome patients show chromosome abnormalities, most involving chromosome 22 (monosomy of 22q11.2). In the past, most cases were proven by high-resolution cytogenetic analysis or fluorescence in situ hybridization(FISH). We report a case of DGS in Taiwan with microdeletion of chromosome 22q11.2 detected by genotype analysis.

Chinese achondroplasia is also defined by recurrent G380R mutations of the fibroblast growth factor receptor-3 gene.

Achondroplasia is the most common form of dwarfism in humans. A recurrent glycine-to-arginine mutation at codon 380 (G380R) of the transmembrane domain of fibroblast growth factor receptor-3 (FGFR-3) was identified in the majority of Western and Japanese patients, which is uncommon in other autosomal dominant genetic diseases. To determine whether this mutation is also common in Chinese patients, we examined the G380R mutation in Chinese patients with achondroplasia. Of ten patients studied, including eight sporadic cases and one family with two affected members, all have the same G380R mutation with a G-to-A transition. Our results support the argument that the G380R mutation of FGFR-3 is the most frequent mutation causing achondroplasia across different populations.

Comparison of radioisotopic and ultrasonic scanning in the evaluation of neonatal hypothyroidism.

BACKGROUND: Technetium-99m pertechnetate (Tc-99m) scan is presently the best diagnostic modality to delineate the anatomy of the neonatal thyroid. Because several factors will inhibit Tc-99m uptake in a normal thyroid gland and the Tc-99m scan requires expensive equipment and sometimes raises fear of radiation in parents, the ultrasonography might be an important complementary method for neonatal thyroid disorders. We described our experience with ultrasonography of the thyroid in 52 infants with suspected congenital hypothyroidism to compare the results obtained by using Tc-99m imaging in the same infants. METHODS: From Dec. 1991 to May 1992, 52 neonates with suspected congenital hypothyroidism by newborn screening were referred to Veterans General Hospital-Taipei for confirmatory diagnoses. All of them were investigated with Tc-99m and ultrasonography of the thyroid gland. Results of Tc-99m scan and ultrasonography were compared and analyzed. RESULTS: The ultrasonography failed to identify any ectopic gland and all cases were misinterpreted as hypoplasia or hemiagenesis of thyroid gland, but it never misinterpreted them as normal thyroid glands. The ultrasound never misinterpreted normal thyroid gland, while the Tc-99m scan misguided a normal gland as an athyreotic gland. CONCLUSIONS: The ultrasonography may be adopted as the first line image examination for the babies with suspected congenital hypothyroidism. If sonography shows abnormal thyroid gland such as hypoplasia, hemiagenesis or agenesis, the isotopic scan may be a good complementary method to confirm the diagnosis.

[Maturation of ganglioneuroblastoma to ganglioneuroma: a case report].

A 1 year and 7 months old girl had suffered from chronic diarrhea for 6 weeks. A huge abdominal mass was found. She received subtotal resection of the tumor and the histological picture showed ganglioneuroblastoma. Then, 12 courses of chemotherapy (including cyclophosphamide, doxorubicin cisplatin and etoposide) were given for 8 months, but the residual tumor mass over the previous surgical area was still noted by CT scan. A second excision of the tumor was performed and histology showed a picture of ganglioneuroma incidentally. Chemotherapy was discontinued. The patient is still alive and well for more than one year.