A novel mutation in the beta-subunit of the epithelial sodium channel gene (SCNN1B) in a Thai family with Liddle's syndrome.

Liddle's syndrome is a rare form of autosomal dominant hypertension with early penetrance and cardiovascular sequelae. It is caused by missense or frameshift mutations in the epithelial sodium channel (ENaC) gene resulting in excessive salt and water resorption from the distal nephron, volume expansion, and suppression of plasma renin activity and serum aldosterone secretion. Treatment with an antagonist of the amiloride-sensitive ENaC, amiloride or triamterine, can correct hypertension and biochemical abnormalities in Liddle's syndrome by closing the sodium channels. Missense and truncation mutations at the C-terminus of the ENaC gene have been found in two of the three genes encoding beta- and gamma-subunits of ENaC. We report here a Thai family with Liddle's syndrome caused by a novel P615H missense mutation in the proline-rich domain of the SCNN1B gene coding for the beta-subunit of ENaC. This mutation occurs within the conserved proline-rich (PY) motif at the C-terminal end and emphasizes the critical role of this motif in ENaC internalization. The presence of severe hypertension and/or a suggestive family history of hypertension with or without hypokalemia in young children should always raise a suspicion of Liddle's syndrome.

The etiologies of adrenal insufficiency in 73 Thai children: 20 years experience.

BACKGROUND: Adrenal insufficiency (AI) is an event caused by an inadequate secretion or action of adrenal hormones. It can be classified as primary (1 degree) and secondary (2 degree). AI may result in severe morbidity and mortality when undiagnosed or ineffectively treated. OBJECTIVE: To determine the etiologies of AI in Thai children. MATERIAL AND METHOD: Data of children with AI presented to the authors' pediatric endocrine service between 1982 and 2002 (20 years) were retrospectively collected and analyzed. RESULTS: AI was diagnosed by clinical and laboratory data in 73 children (31 boys and 42 girls). Sixty-two (84.9%) patients had 1degree AI while 11 (15.1%) had 2 degree AI. The majority of patients with 1 degree AI (87.1%) were diagnosed with congenital adrenal hyperplasia (CAH). Other causes of 1 degree AI were uncommon such as ACTH unresponsiveness (4.8%) and no definite diagnosis (8.1%). Most children with 1 degree AI presented with hyperpigmentation. Causes of 2 degree AI were as follows: panhypopituitarism (63.6%), isolated ACTH deficiency (9.1%), and low birth weight (27.3%). CONCLUSION: In the present study, CAH was the most common cause of 1 degree AI while panhypopituitarism was the most common cause of 2 degree AI. Other causes of AI were quite uncommon. Definite causes of AI have not yet been identified in some children. Further clinical observation and special tests including molecular studies in these children are warranted for diagnostic and prognostic importance.

Anterior pituitary hormone effects on hepatic functions in infants with congenital hypopituitarism.

BACKGROUND: Congenital hypopituitarism is an uncommon cause of neonatal cholestasis. Little is known about the effect of anterior pituitary hormone on hepatic functions. METHODS: A retrospective review of the medical charts of eight infants with congenital hypopituitarism and neonatal cholestasis was performed. The results of endocrinological investigations, eye examinations, and magnetic resonance imaging were used to classify these infants. RESULTS: Eight infants (4 male and 4 female; mean age, 1.7 weeks) who presented with cholestatic jaundice subsequently (mean age, 7.6 weeks) developed isolated or multiple anterior pituitary hormone deficiencies. Persistent hypoglycemia, ocular abnormalities, and microphallus were often clinical signs prompting further endocrinological and radiological investigations. Septo-optic dysplasia was prevalent, occurring in five cases. Cholestasis and hepatosplenomegaly resolved within a mean of 9.7 and 10 weeks, respectively, in the majority of cases after replacement of glucocorticoid and thyroid hormones. However, transaminase levels remained high after hormone replacement. Cortisol deficiency and hypoglycemia were noted in all cases, often following stress. Hyperlipidemia persisted in one case after the resolution of cholestasis and after corticosteroid and thyroid hormone replacement therapy. Growth hormone deficiency was not corrected due to the absence of hypoglycemia after corticosteroid hormone, an infant's age, and/or a lack of financial resources. CONCLUSIONS: In our series, it appears that glucocorticoid and thyroid hormones play a significant role in the resolution of cholestasis and hepatosplenomegaly. A persistently elevated transaminase level and hyperlipidemia after corticosteroid and thyroid hormone replacement may indicate the need for long-term follow-up and/or growth hormone therapy.

Treatment outcome of Graves' disease in Thai children.

BACKGROUND: Graves' disease is the most common cause of thyrotoxicosis in children. Treatment of Graves' disease consists of anti-thyroid drugs, radioactive iodide and thyroidectomy but the optimal treatment of GD in children is still controversial. OBJECTIVE: To review treatment outcome of Graves' disease in Thai children. MATERIAL AND METHOD: Retrospective review of 32 children with Graves' disease, diagnosed between Jan. 1994 and Dec. 2004, at the Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand was performed. RESULTS: All patients (median age 10.5 yrs, range 2.85-15 yrs) presented with goiter and increased serum T4 (median 18.4 mcg/dL, range 8.8-30 mcg/dL), serum T3 (median 443 ng/dL, range 206-800 ng/dL) and suppressed TSH levels (median 0.009 mU/L, range 0-0.18 mU/L). Anti-thyroglobulin and Anti-microsomal antibodies were positive in 70% and 82% respectively. All patients except two were initially treated with propylthiouracil (PTU). Two patients were initially treated with methimazole. Adverse reaction of PTU occurred in two patients (One girl had arthralgia, positive pANCA, nephritis and another girl had skin rash and arthralgia). Clinical course of 32 patients after treatment with anti-thyroid drugs mainly PTU for 3.4 (range 0.3-11.2) years is as follows: six (18.8%) underwent remission (cessation of PTU > 2 yrs), three (9.4%) relapsed, one (3.1%) underwent subtotal thyroidectomy, and seven (21.9%) had I131 treatment. All patients (6 of 7) who received I131 dose of 100 microCi/g of thyroid tissue required more than a single dose of I131 treatment. Further outcome in fifteen patients (46.9%) is yet to be followed. Among these patients PTU was just discontinued in four and eleven had never been off anti-thyroid drugs (four still had biochemical hyperthyroidism and seven were biochemically euthyroid). CONCLUSION: PTU was the most common first line therapy in the presented patients with Graves' disease. Remission rate was only 18.8% after an average 3.5 years of treatment with anti-thyroid drugs. I131 or thyroidectomy was used as second line therapy in the present study. They were offered to those who developed side effects, had poor compliance or failed medication. For those who received I131, higher dose (200 microCi/g of thyroid tissue) seemed to be more effective than the lower dose (100 microCi/g).

Tamoxifen improved final height prediction in a girl with McCune-Albright syndrome: patient report and literature review.

McCune-Albright syndrome (MAS) is characterized by gonadotropin-independent precocious puberty, café-au-lait spots on the skin and polyostotic fibrous dysplasia of bones. Treatment of precocious puberty (PP) in MAS should be considered in patients with poor predicted adult height (PAH). Treatment of gonadotropin-independent PP in MAS with ketoconazole, cyproterone acetate or testolactone, an aromatase inhibitor, does not appear to be always effective in slowing bon. maturation. We report here a Thai girl with MAS who received tamoxifen, one of the selective estrogen receptor modulators, for the management of advanced puberty and rapid bone maturation. Her pubertal progression, vaginal bleeding, growth rate and PAH improved during treatment with tamoxifen despite persistently elevated serum estradiol levels and an enlarged ovarian cyst.

Obese adolescent girls with polycystic ovary syndrome (PCOS) have more severe insulin resistance measured by HOMA-IR score than obese girls without PCOS.

UNLABELLED: The prevalence of obesity in Thai children is increasing. These individuals are at increased risks of metabolic syndrome that includes insulin resistance, type 2 diabetes mellitus (T2DM), polycystic ovary syndrome (PCOS), dyslipidemia and hypertension. PCOS has been known to be associated with insulin resistance. OBJECTIVES: To compare the insulin sensitivity between obese adolescent girls with PCOS and those without PCOS. MATERIAL AND METHOD: We reviewed demographic and hormonal data of 6 obese adolescent girls with PCOS and compared with 6 age, weight and BMI-matched non-PCOS controls. Each subject underwent an oral glucose tolerance test. RESULTS: Homeostasis model assessment of insulin resistance score (HOMA-IR score) in obese adolescent girls with PCOS was significantly higher than in girls without PCOS with median and range as follows (16.5 [3.8, 21.8] vs. 4.1 [3.3, 6.9], p = 0.04). Our study demonstrates that obese adolescent girls with PCOS have more severe insulin resistance measured by HOMA-IR score than girls without PCOS independent of the degree of obesity. Since insulin resistance is a metabolic precursor of future cardiovascular diseases, obese adolescent girls with PCOS might be at greater risk of developing cardiovascular disease in later adulthood than their non-PCOS counterparts.

Preliminary data of insulin glargine use among Thai adolescents and young adults with type 1 diabetes mellitus treated at Siriraj Hospital.

UNLABELLED: Insulin glargine is a new long-acting insulin analog with a duration of action of 24 hours and can be given once a day as the only basal insulin combined with short or rapid-acting insulin as bolus insulin for each meal. The goals of this study were to evaluate short term result of treatment with insulin glargine compared to NPH and to determine the initial dosage of insulin glargine in Thai adolescents with type 1 diabetes. We reviewed charts of 10 adolescents (median age 20.8 years, range 12.3-22.7 years) with type 1 diabetes who had received insulin glargine for > or = 4 months (median 16.5 months, range 4-25 months). Before switching to insulin glargine, all patients received NPH. Seventy percent of subjects had improvement of HbA1c from 10.4% (range 8.2-12.6) to 8% (range 6.7-10.6). The total amount of insulin dosage was significantly decreased from 1.2 (range 0.9-2.4) to 0.9 (range 0.4-1.5) units/kg/day as well as the percentage of basal insulin which was decreased from 70% (range 67-81) to 47% (range 38-56) of the total daily insulin. Insulin glargine did not cause severe hypoglycemia in this study. CONCLUSION: Insulin glargine is another promising therapy for adolescents with type 1 diabetes. We recommend the starting total daily insulin dosage to be decreased to 70-80% of previous dosage. Insulin glargine should be started at 50% of the new total daily insulin dosage.

Clinical pictures of type 2 diabetes in Thai children and adolescents is highly related to features of metabolic syndrome.

Prevalence of type 2 diabetes (T2DM) in children and adolescents has increased, parallelled to the increased prevalence of obesity around the world. The objectives of this study are (1) to identify the clinical presenting features of T2DM in Thai children and adolescents, and (2) to identify evidence of feature of metabolic syndrome in these affected. We analyzed 26 T2DM patients who were treated by Pediatric endocrinologists in our hospital. The study showed that their mean ages (+/- SD) at diagnosis was 12.1 +/- 2.3 years, all were obese and 96% had acanthosis nigricans. Fifty three percents (53%) presented with clinical signs and symptoms which included DKA (19.2%), clinical triad of polyuria, polydipsia and weight loss (15.4%), only polyuria, polydipsia (11.5%) and abnormal menstruation (7%). The rest of 46.2% had no clinical symptoms. The initial fasting or random plasma glucose found above diagnostic range in 84.5%, the rest of 15.5% were diagnosed by using oral glucose tolerance test. Dyslipidemia was found in 75%. Fifteen percents had no family history. Eighty percents had three or more than three features of metabolic syndrome. In conclusions, clinical picture of type 2 diabetes in Thai youth varied from asymptomatic to severe illness (DKA). Almost all had clinical features of metabolic syndrome. Childhood obesity has become epidemic in our population. Such clinical picture should alert all pediatricians to be aware of chronic diseases and for making an early diagnosis and preventing long-term complications in the future.

Improved glycemic control among Thai children and young adults with type 1 diabetes participating in the diabetes camp.

Diabetes Education Program, Faculty of Medicine Siriraj Hospital has provided summer camps for Thai children with type 1 diabetes since 1990. The objective of this study was to evaluate the effectiveness of the diabetes camp in glycemic control. Twenty male and forty-two female patients participated in the 5-day diabetes camp held in Karnchanaburi, Thailand in 2003. The mean age was 14.1 +/- 4.3 years and the mean duration of disease was 4.5 +/- 3.5 years. Fifty out of sixty-two patients returned for a 3-month-postcamp visit. The glycemic control improved significantly. The mean precamp and postcamp HbA1c levels were 10.0 +/- 3.1% and 9.0 +/- 2.6% (p = 0.008) respectively. The diabetes camp is a valuable program for patients to learn diabetes-self management skills, especially in countries where the diabetes education programs are not always available.

Spironolactone abolishes the relationship between aldosterone and plasminogen activator inhibitor-1 in humans.

Recent studies have defined a link between the renin-angiotensin-aldosterone system and fibrinolysis. The present study tests the hypothesis that endogenous aldosterone regulates plasminogen activator inhibitor-1 (PAI-1) production in humans. Hemodynamic parameters, PAI-1 and tissue-type plasminogen activator (t-PA) antigen, potassium, PRA, angiotensin II, and aldosterone were measured in nine male hypertensive subjects after a 3-wk washout, after 2 wk of hydrochlorothiazide (HCTZ; 25 mg plus 20 mmol KCl/d), and after 2 wk of spironolactone (100 mg/d plus KCl placebo). Spironolactone (P = 0.04), but not HCTZ (P = 0.57 vs. baseline; P = 0.1 vs. spironolactone), significantly lowered systolic blood pressure. Angiotensin II increased from baseline during both HCTZ (P = 0.02) and spironolactone (P = 0.02 vs. baseline; P = 0.19 vs. HCTZ) treatments. Although both HCTZ (P = 0.004) and spironolactone (P < 0.001 vs. baseline) increased aldosterone, the effect was greater with spironolactone (P < 0.001 vs. HCTZ). HCTZ increased PAI-1 antigen (P = 0.02), but did not alter t-PA antigen. In contrast, there was no effect of spironolactone on PAI-1 antigen (P = 0.28), whereas t-PA antigen was increased (P = 0.01). There was a significant correlation between PAI-1 antigen and serum aldosterone during both baseline and HCTZ study days (r(2) = 0.57; P = 0.0003); however, treatment with spironolactone abolished this correlation (r(2) = 0.13; P = 0.33). This study provides evidence that endogenous aldosterone influences PAI-1 production in humans.

Effect of combined AT1 receptor and aldosterone receptor antagonism on plasminogen activator inhibitor-1.

Aldosterone enhances angiotensin II (Ang II)-induced plasminogen activator inhibitor (PAI)-1 expression in vitro. This study tested the hypothesis that angiotensin II type 1 (AT(1)) and aldosterone receptor antagonism interact to decrease PAI-1 in humans. Effects of candesartan (16 mg/d), spironolactone (25 mg/d), or combined candesartan/spironolactone on mean arterial pressure (MAP), endocrine, and fibrinolytic variables were measured in 18 normotensive subjects [age 33.7 yr (95% confidence interval 29.3, 38.0), body mass index 26.6 (24.7, 28.4) kg/m(2)] in whom the renin-angiotensin-aldosterone system was activated by furosemide (20 mg/d). Candesartan [83.3 mm Hg (78.9, 87.7)], but not spironolactone [89.4 mm Hg (85.4, 93.5)], decreased MAP, compared with baseline [92.2 mm Hg (88.9, 95.5), P < 0.001] and furosemide alone [89.1 mm Hg (85.7, 92.4), P = 0.002]. Coadministration of spironolactone with candesartan did not further decrease MAP. Candesartan dramatically increased Ang II [177.9 pg/ml (113.3, 242.6)], compared with baseline [34.8 pg/ml (29.3, 40.4), P = 0.002] and furosemide alone [40.6 pg/ml (29.7, 51.5), P = 0.003]. Spironolactone increased Ang II [51.5 pg/ml (41.3, 61.7), P = 0.014 vs. baseline, P = 0.004 vs. candesartan]. There was no additive effect of candesartan and spironolactone on Ang II [197.6 pg/ml (134.2, 261.0)]. Aldosterone was lower during candesartan [8.9 ng/dl (7.3, 10.6), P = 0.007] than during furosemide alone [14.1 ng/dl (10.9, 17.3), P = 0.007], spironolactone [18.7 ng/dl (14.5, 22.9), P = 0.002], or combined candesartan/spironolactone [13.9 ng/dl (11.8, 15.9), P = 0.006]. Furosemide increased PAI-1 antigen [27.8 ng/ml (20.6, 35.0), P = 0.002 vs. 19.3 ng/ml (13.4, 25.2) baseline], even in the presence of candesartan [27.2 ng/ml (16.5, 37.8), P = 0.042 vs. baseline] or spironolactone [27.3 ng/ml (17.9, 36.8), P = 0.015 vs. baseline]. However, coadministration of AT(1) and aldosterone receptor antagonists prevented the furosemide-induced increase in PAI-1 [19.2 ng/ml (9.8, 28.6), P = 0.974 vs. baseline, P < 0.05 vs. candesartan, spironolactone or furosemide alone]. This study evidences an interactive effect of endogenous Ang II and aldosterone on PAI-1 production in humans.

Acute angiotensin II increases plasma F2-isoprostanes in salt-replete human hypertensives.

Angiotensin (Ang) II induces oxidative stress in vitro and in animal models of hypertension. We tested the hypothesis that Ang II increases oxidative stress in human hypertension, as assessed by plasma F2-isoprostane concentrations. Plasma F2-isoprostanes, hemodynamic and endocrine parameters were measured at baseline and following a 55 min infusion of 3 ng/kg/min Ang II in 13 normotensive and 13 hypertensive volunteers ingesting a high- (200 mmol/d) or low- (10 mmol/d) sodium diet. Mean arterial pressure (MAP) and body mass index were higher in hypertensive subjects. Ang II infusion increased MAP (p<.001) and plasma aldosterone concentrations (p<.001) and decreased plasma renin activity (p<.001) and renal plasma flow (p<.001) to a similar extent in both groups. Plasma F2-isoprostane concentrations were similar at baseline. There was no effect of Ang II on F2-isoprostane concentrations during low-salt intake in either group (normotensive 51.7 +/- 7.1 to 53.7 +/- 6.5 pg/ml and hypertensive 52.2 +/- 8.2 to 56.2 +/- 10.0 pg/ml; mean +/- SE). During high-salt intake, Ang II increased F2-isoprostane concentrations in the hypertensive group (52.3 +/- 7.2 to 63.2 +/- 10.4 pg/ml, p=0.010) but not in the normotensive group (54.2 +/- 4.4 to 58.9 +/- 6.6 pg/ml, p=0.83). Acute Ang II infusion increases oxidative stress in vivo in hypertensive humans. The renin-angiotensin system may contribute to oxidative stress in human cardiovascular disease.

Persistent hyperinsulinemic hypoglycemia of infancy: experience at Siriraj Hospital.

BACKGROUND: Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is the most common cause of recurrent or persistent hypoglycemia in early childhood. Conventionally, pancreatectomy (Px) has often been recommended to control hypoglycemia. However, PHHI can be managed successfully by intensive medical treatment to avoid pancreatectomy. METHOD: Data from 10 infants (8M, 2F) with PHHI were retrospectively analyzed. RESULTS: Eight patients (80%) developed symptoms within 72 hours after birth (early-onset). Six patients (60%) underwent 85 per cent-95 per cent Px due to failure of medical treatment. Two patients who underwent less than 95 per cent Px required second Px (97% and 99%). One patient developed permanent diabetes mellitus and malabsorption. Hypoglycemia could be successfully managed by medication alone in four patients (40%). Of these, three patients had early-onset neonatal hypoglycemia. Medication could be discontinued in three patients (75%). Three of ten patients (30%) had delayed development. Pancreatectomies and/or the diagnosis of PHHI were made late for these patients. One of these three children also developed epilepsy. CONCLUSIONS: Patients with PHHI frequently require pancreatectomy which commonly results in long-term complications especially diabetes mellitus and malabsorption. Our data suggest that PHHI can be managed successfully with an intensive medical regimen even in patients with early-onset hypoglycemia. Although medical management is very laborious for the family and physician, it should be applied until euglycemia is accomplished. Moreover, the early diagnosis of PHHI and the successful hypoglycemic control are very necessary to prevent permanent neurologic sequelae.

Ambiguous genitalia: an overview of 22 years experience and the diagnostic approach in the Pediatric Department, Siriraj Hospital.

The newborn with abnormal genital development presents a difficult diagnostic and treatment challenge for the pediatrician providing care. It is important that a definitive diagnosis be determined as quickly as possible so that the appropriate treatment plan can be established to minimize medical, psychological and social complications. The purpose of this study was to provide an extensive review of the clinical characteristics of a patient cohort with ambiguous genitalia, from 22 years' experience in the Division of Endocrinology and Metabolism, Department of Pediatrics, Siriraj Hospital, and to classify them into diagnostic categories. Moreover, a cascade of diagnostic tools in approaching sexual ambiguity in the authors' institution, starting with history and physical examination and leading to further radiographic and laboratory investigations is demonstrated and can be adopted as a guideline for the clinical management of these disorders. From 1979 to 2001, care was provided to a total of 109 patients with ambiguous genitalia, of whom 104 patients were reviewed. Among these individuals, 52 patients (50.0%) belonged to the diagnosis of female pseudohermaphroditism, 5 patients (4.8%) were in the true hermaphroditism group and the remaining 47 patients (45.2%) were in the male pseudohermaphroditism group. All female pseudohermaphrodites carried a diagnosis of congenital adrenal hyperplasia (CAH) and were reared as girls. 21 hydroxylase deficiency CAH accounted for all except one (98%) in this group. Among the 47 male pseudohermaphrodites, 9 (19.1%) had dysgenetic male pseudohermaphroditism, 7 (14.9%) had either testosterone biosynthetic defects or hCG unresponsiveness, 22 (46.8%) had either androgen insensitivity syndrome or 5 alpha-reductase deficiency, 4 (8.5%) had ambiguous genitalia in a 46,XY male associated with multiple anomalies and 5 (10.6%) had an unidentifiable cause. Sex reassignment occurred, not uncommonly, in 4 cases of female pseudohermaphrodites (7.7%) and at least 2 cases (3.9%) in the combined group of male pseudohermaphrodites and true hermaphrodites. The scope of the ambiguous genitalia problem is definitely not minor. An inappropriate approach to this problem poses an undue risk to the integrity of the physical and psychosexual health in the future for these children.

Cushing's syndrome caused by an ACTH-producing ovarian steroid cell tumor, NOS, in a prepubertal girl.

Ectopic ACTH syndrome is a very rare cause of pediatric Cushing's syndrome. And if present, bronchial or thymic carcinoids predominate as causes. We hereby demonstrate a first case report of ACTH-producing ovarian steroid cell tumor, NOS, causing ectopic ACTH syndrome in a prepubertal girl.