Isolated 17,20-Lyase Deficiency in a CYB5A Mutated Female With Normal Sexual Development and Fertility.

Isolated 17,20-lyase deficiency may be caused by mutations in the CYP17A1 (coding for cytochrome P450c17), POR (coding for cytochrome P450 oxidoreductase) and CYB5A (coding for microsomal cytochrome b5) genes. Of these, mutations in the CYB5A gene have thus far only been described in genetic males who presented with methemoglobinemia and 46,XY disorders of sex development (DSD) due to 17,20-lyase deficiency. A 24-year-old Chinese woman presented to the hematology outpatient clinic with purplish discoloration of fingers, toes, and lips since childhood. Investigations confirmed methemoglobinemia. A homozygous c.105C>G (p.Tyr35Ter) nonsense mutation was detected in the CYB5A gene. Hormonal studies showed isolated 17,20-lyase deficiency. Interestingly, she had a completely normal female phenotype with no DSD, normal pubertal development, and spontaneous pregnancy giving birth uneventfully to a healthy female infant. The sex hormone-related features of genetic females with 17,20-lyase deficiency due to cytochrome b5 gene mutation appear to differ from that of females with 17,20-lyase deficiency caused by other genetic defects who presented with hypergonadotropic hypogonadism and infertility and differ from genetic males with the same mutation.

Salivary Cortisol and Cortisone After Low-Dose Corticotropin Stimulation in the Diagnosis of Adrenal Insufficiency.

CONTEXT: Basal and poststimulation salivary cortisol and cortisone levels can be useful in the diagnosis of adrenal insufficiency. However, little is known about the optimal cutoffs and performance characteristics of these tests. OBJECTIVE: To derive the cutoff values and study the performance characteristics of salivary cortisol and salivary cortisone in the diagnosis of adrenal insufficiency. DESIGN AND SETTING: Prospective study in a regional hospital in Hong Kong from January 2014 to September 2015. PARTICIPANTS: Fifty-six Chinese healthy volunteers and 171 patients suspected of having adrenal insufficiency. MAIN OUTCOME MEASURES: All participants underwent low-dose short Synacthen test (LDSST) with intravenous injection of 1 µg of tetracosactide (Synacthen 1-24). Serum cortisol, salivary cortisol and cortisone levels were measured at baseline and 30 and 60 minutes afterward. RESULTS: Using the reference cutoff (mean - 2 standard deviations of post-LDSST peak serum cortisol) derived from healthy volunteers as the gold standard, receiver operating characteristic analysis of patients' data revealed that both post-LDSST peak salivary cortisol and cortisone performed better than basal tests. The most optimal cutoff values for serum cortisol as measured by immunoassay and for salivary cortisol and salivary cortisone as measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) were 376, 8.6, and 33.5 nmol/L, respectively, for post-LDSST peak values, and 170, 1.7, and 12.5 nmol/L, respectively, for basal values. CONCLUSIONS: We established method-specific reference cutoffs for serum cortisol, salivary cortisol, and salivary cortisone during LDSST. Both post-LDSST peak salivary cortisol and cortisone performed well as diagnostic tests for adrenal insufficiency. Their measurements by LC-MS/MS can alleviate problems associated with serum cortisol immunoassays.

Declining Trends of Cardiovascular-Renal Complications and Mortality in Type 2 Diabetes: The Hong Kong Diabetes Database.

OBJECTIVE: Nationwide studies on secular trends of diabetes complications are not available in Asia. We examined changes in risk factor control and incidence of complications from diabetes and death in a large longitudinal cohort of Chinese adults with type 2 diabetes in Hong Kong. RESEARCH DESIGN AND METHODS: Between 1 January 2000 and 31 December 2012, 338,908 Chinese adults with type 2 diabetes underwent metabolic and complication assessment in 16 diabetes centers operated by Hong Kong Hospital Authority that provided care to a large majority of diagnosed patients. Patients were followed for incident acute myocardial infarction (AMI), stroke, end-stage renal disease (ESRD), and death until 31 December 2012. Risk factor levels between enrollment periods were compared. Incidence of clinical events, stratified by diabetes duration, was examined over time. RESULTS: Incidence of complications from diabetes and death declined over the observation period in patients at varying disease duration. Among the high-risk group with diabetes for at least 15 years, crude incidence of AMI decreased from 8.7 to 5.8, stroke from 13.5 to 10.1, ESRD from 25.8 to 22.5, and death from 29.0 to 26.6 per 1,000 person-year between the periods 2000 to 2002 and 2010 to 2012. Improvements in levels of metabolic risk factors were detected. Proportion of patients achieving HbA1c <7.0% (53 mmol/mol) was increased from 32.9 to 50.0%, blood pressure ≤130/80 mmHg from 24.7 to 30.7%, and LDL cholesterol <2.6 mmol/L from 25.8 to 38.1%. CONCLUSIONS: From this territory-wide Hong Kong Diabetes Database, we observed decreases in incidence of cardiovascular-renal complications and death and corresponding improvements in risk factor control over a 13-year period.

Genome-wide association study identifies a susceptibility locus for thyrotoxic periodic paralysis at 17q24.3.

Thyrotoxic periodic paralysis (TPP) is a potentially life-threatening complication of thyrotoxicosis. We conducted a genome-wide association study (GWAS) and a replication study with a total of 123 southern Chinese with TPP (cases) and 1,170 healthy controls and identified a susceptibility locus on chromosome 17q24.3 near KCNJ2 (rs312691: odds ratio (OR) = 3.3; P(meta-analysis) = 1.8 × 10(-14)). All subjects with TPP also had Graves' disease, and subsequent TPP versus Graves' disease comparison confirmed that the association at 17q24.3 was specific to TPP. The area under the curve (AUC) of rs312691 genotype for risk prediction of TPP in subjects with Graves' disease was 0.73. Expression quantitative trait locus (eQTL) analysis identified SNPs in the region flanking rs312691 (±10 kb) that could potentially affect KCNJ2 expression (P = 0.0001). Our study has identified a susceptibility locus associated with TPP and provides insight into the causes of TPP.

Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients.

In Caucasians, maturity-onset diabetes of the young (MODY) is mostly caused by mutations in the hepatocyte nuclear factor (HNF)-1alpha (MODY3) and glucokinase (MODY2) genes. Most Japanese MODY patients, however, are not linked to known MODY genes. In this study, we examined the genetic and clinical characteristics of Chinese subjects with MODY. The study included 146 unrelated families fulfilling the minimum criteria for MODY: two consecutive generations of type II diabetes with at least one member diagnosed under the age of 25. We screened for mutations in the HNF-4alpha (MODY1), MODY2 and MODY3 genes by direct sequencing. Antibody to glutamic acid decarboxylase (GAD-Ab) was measured in subjects with MODY of unknown cause (MODYX). Insulin resistance index and other clinical data were compared in sex-, age- and duration-matched MODY3 and MODYX patients. In all, 13 families had MODY3 mutations and two had MODY2 mutations. No MODY1 mutation was found. Four of the 12 different MODY3 mutations were newly identified novel mutations (Q243E, A311D, P379R and P488fsdelC). In subjects with MODYX, 3% were GAD-Ab positive and 60% were overweight. Compared to MODY3 patients, MODYX patients had higher body mass index (P<0.02), higher insulin resistance index (P=0.001) and triglyceride level (P<0.02), lower HDL level (P=0.001) and more hypertension (P<0.05), but no significant difference in the prevalence of diabetic complications. In conclusion, MODY3 and MODY2 account for only 9 and 1%, respectively, of Chinese MODY. A majority of Chinese MODY patients are due to defects in unknown genes and appear to be characterized by insulin resistance.

The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling.

Recent reviews recommended the use of the aldosterone/renin ratio (ARR) to screen for primary hyperaldosteronism. However, widely different cutoff levels have been proposed, and test characteristics of ARR under different conditions of sampling are not known. We conducted a retrospective review among 45 subjects with carefully validated diagnoses of primary hyperaldosteronism and 17 subjects with essential hypertension to study the utility of ARR. Sixty-two patients with 75 sets of plasma renin activity (PRA), aldosterone, and ARR values from a postural study and 48 sets of values from a saline suppression test were analyzed. Ninety-four percent of these subjects underwent investigations because of hypokalemic hypertension.ARR yielded larger areas under the curve in the receiver-operating-characteristics curve than PRA or aldosterone under all conditions of testing. Our results confirmed the superiority of ARR to either aldosterone or PRA alone as a diagnostic test for primary hyperaldosteronism.ARR cutoff levels were significantly affected by the condition of testing. Depending on posture and time of day, it varied from 13.1-35.0 ng/dl per ng/ml.h in our study population. When using ARR for screening primary hyperaldosteronism, posture and time of sampling should be standardized both within and between centers to minimize variability in cutoff levels.

Postprandial glucose response to Chinese foods in patients with type 2 diabetes.

The objective of this study is to examine the glycemic response to common Chinese foods in patients with type 2 diabetes. Twenty-four Chinese adults with type 2 diabetes participated. Subjects were allocated to eat a pair of test meals in random order. Test meals included plain porridge with lean pork (meal 1A), plain porridge and Shrimp Shao Mai (Doll Brand, Winner Food Products Limited, Hong Kong) (meal 1B), boiled rice with boiled egg white (meal 2A), fried rice with whole egg (meal 2B), plain noodles in clear soup (meal 3A), and Pickled Vegetable and Pork-flavored Instant Bowl Noodles (Doll Brand, Winner Food Products Limited) (meal 3B). Nutritional content of the meals was calculated from the nutritional label on the food package and the food composition table. Plasma glucose was checked before the meal and in 30-minute intervals for up to 4 hours after the meal. Significant differences in the area under the curve of glucose up to 2 hours after the meal were detected between meal 1A and 2A ( P =.044), 1A and 3A ( P =.001), and 3A and 3B ( P =.017). The results suggest that fat alone does not alter the glycemic response to rice or porridge. Porridge produces a higher glycemic response than rice and noodles despite similar carbohydrate contents, and different noodles lead to differences in glycemic excursion, suggesting that the glycemic index of common Chinese foods is affected by cooking methods and food processing.

Serum adiponectin is reduced in acromegaly and normalized after correction of growth hormone excess.

Adiponectin, an adipocyte-derived hormone, possesses insulin-sensitizing, antiinflammatory, and antiatherogenic properties. We hypothesized that hypoadiponectinemia was present in acromegaly, as in other conditions with increased insulin resistance and cardiovascular risk. Using an in-house RIA, serum adiponectin was determined in 35 patients with active acromegaly and 35 age-, sex-, and body mass index-matched healthy controls. Twenty-five patients were restudied after GH-lowering therapies. Serum adiponectin was significantly reduced in the acromegalic patients (4.3 +/- 1.8 vs. 6.7 +/- 1.8 microg/ml in controls; P < 0.001), but was increased after treatment with Sandostatin LAR, a long-acting somatostatin analog (5.8 +/- 2.6 vs. 3.8 +/- 1.6 microg/ml pretreatment; P < 0.001; n = 15) or transsphenoidal surgery (6.5 +/- 2.7 vs. 3.9 +/- 1.5 microg/ml preoperation; P < 0.01; n = 10). Fasting insulin was an independent determinant of serum adiponectin levels (P < 0.01) in control subjects, contributing to 11.7% of the variance in circulating adiponectin. In cultured 3T3-L1 adipocytes, adiponectin mRNA levels were decreased by insulin (1.5 microm; P < 0.005) or IGF-I (1 microg/ml; P < 0.05), but not by GH (1 microm) or somatostatin (1 microm). In conclusion, hypoadiponectinemia is present in active acromegaly, probably secondary to the inhibitory effect of high circulating insulin levels. Hypoadiponectinemia, reversible with GH-lowering therapies, may contribute to the increased insulin resistance and cardiovascular risk in patients with acromegaly.

Increased bone mineral density in patients with chronic hypoparathyroidism.

Bone mineral density (BMD) has been shown to be increased in postmenopausal females with postthyroidectomy hypoparathyroidism, but it is not known whether similar gains occur in patients with idiopathic hypoparathyroidism. In this study, we measured the BMD of lumbar spine and proximal femur in 14 patients, 8 with idiopathic hypoparathyroidism and 6 with postthyroidectomy hypoparathyroidism, using dual-energy x-ray absorptiometry. Their age ranged from 23-57 yr old, with a mean of 42.5 yr. The results showed that patients with hypoparathyroidism had a higher BMD than the normal age- and sex-matched population. This was particularly evident at the lumbar spine (L2-L4), with positive Z-score of 1.93 +/- 1.03, whereas Z-score at the femoral neck was 1.14 +/- 0.62 SD. Subgroup analysis showed that those with postthyroidectomy hypoparathyroidism had a mean lumbar spine BMD of 1.434 g/cm(2) and femoral neck BMD of 1.026 g/cm(2), compared with a mean BMD of 1.364 g/cm(2) and 1.022 g/cm(2) at spine and hip, respectively, for those with idiopathic hypoparathyroidism. Statistical analysis did not reveal any significant difference in the BMD, T-score, and Z-score of the bone, at these two sites, between the two groups. In conclusion, the state of chronic hypoparathyroidism is associated with increased BMD, especially at the lumbar spine. Those with idiopathic hypoparathyroidism have a similar degree of increase in BMD as those with postthyroidectomy hypoparathyroidism.

Development of the human cerebral cortex: a histochemical study.

In recent years, improvement in diagnostic techniques has led to better recognition of "disorders of cortical development". These disorders constitute a significant cause of epilepsy, mental retardation, developmental delay and neurological deficits in childhood, and may also contribute to the pathogenesis of psychological and neurodegenerative diseases in adults. Hitherto, however, few systematic studies of the human fetal cortex have been performed, and little is known about the ontogenetic processes of the neocortex in man. The aim of the study is to establish an understanding of the developmental events that occur in the second and third trimesters of gestation, by investigating the biochemical patterns of development of the human neocortex during this period. The temporal and spatial patterns of expression of the neuronal markers gamma-aminobutyric acid (GABA), choline acetyltransferase (ChAT), dopamine beta hydroxylase (DBH), dopamine receptor DR1 and synaptophysin, as well as the glial cell markers glial fibrillary acidic protein (GFAP), S100B and excitatory amino acid transporter protein GLT-1 are delineated in the fetal cortex using immunohistochemistry. Results of this study showed that different neuronal and glial cell proteins follow different developmental patterns and many show inter- or intra-regional variations in expression. Details of these patterns are described and discussed. The early expression of these proteins suggests that they play important roles in the developmental processes of cell proliferation, migration and differentiation. Both neurotransmitters and glial cell proteins probably function outside the confines of synapses in the fetal brain, as paracrine/autocrine factors. Early developmental events seem to be dictated by an innate programme, whereas late events may be more susceptible to extrinsic influences. It is hoped that knowledge of the normal developmental process can lead to better understanding of the causes and mechanisms of "disorders of cortical development", and to better treatments.

Proliferation and apoptosis in the developing human neocortex.

The cell kinetics of the developing central nervous system (CNS) is determined by both proliferation and apoptosis. In the human neocortex at week 6 of gestation, proliferation is confined to the ventricular zone, where mitotic figures and nuclear immunoreactivity for proliferating cell nuclear antigen (PCNA) are detectable. Cell division is symmetric, with both daughter cells reentering mitosis. At week 7, the subventricular zone, a secondary proliferative zone, appears. It mainly gives rise to local circuit neurons and glial cells. Around week 12, the ventricular and subventricular zones are thickest, and the nuclear PCNA label is strongest, indicating that proliferation peaks at this stage. Thereafter, asymmetric division becomes the predominant mode of proliferation, with one daughter cell reentering mitosis and the other one migrating out. Towards late gestation, the ventricular and subventricular zones almost completely disappear and proliferation shifts towards the intermediate and subplate zones, where mainly glial cells are generated. A remnant of the subventricular zone with proliferative activity persists into adulthood. In general, proliferation follows a latero-medial gradient in the neocortex lasting longer in its lateral parts. Apoptotic nuclei have been detected around week 5, occurring in low numbers in the ventricular zone at this stage. Apoptotic cell death increases around midgestation and then spreads throughout all cortical layers, with most dying cells located in the ventricular and subventricular zones. This spatial distribution of apoptosis extends into late gestation. During the early postnatal period, most apoptotic cells are still located in the subcortical layers. During early embryonic development, proliferation and apoptosis are closely related, and are probably regulated by common regulators. In the late fetal and early postnatal periods, when proliferation has considerably declined in all cortical layers, apoptosis may occur in neurons whose sprouting axons do not find their targets.