Sex-specific ranges and ratios for anogenital distance among Thai full-term newborns.

INTRODUCTION: Anogenital distance (AGD) is a marker of prenatal androgen exposure and a tool for assessment of differences of sex development. Data for AGD in newborns have been published, but these findings may not be applicable to Thai newborns. AIM: To provide the sex-specific ranges for AGD in Thai full-term newborns. METHODS: A cross-sectional study was conducted in term newborns in Thailand, during 2016-2018. AGD was measured from anus to anterior base of penis (AGDAP) and to perineoscrotal junction (AGDAS) in males and from anus to clitoris (AGDAC) and to posterior fourchette (AGDAF) in females. AGD ratio is defined as AGDAS divided by AGDAP in males and AGDAF divided by AGDAC in females. RESULTS: A total of 364 newborns were studied (male 51.4%). The mean AGDAS, AGDAP and AGD ratio in males were 25.20 ± 4.80, 52.60 ± 6.90 and 0.48 ± 0.08 mm, respectively. The mean AGDAF, AGDAC, and AGD ratio in females were 16.50 ± 3.90, 42.60 ± 6.20 and 0.39 ± 0.08 mm, respectively. There were significant differences between AGDAS and AGDAF, AGDAP and AGDAC, and AGD ratio between males and females (p < 0.001). The AGDAS, AGDAP, AGDAF, AGDAC were correlated with birth weight and length, but AGD ratio showed no correlation. CONCLUSION: The sex-specific ranges for AGD in Thai full-term newborns were determined. AGD ratio is a useful marker of prenatal androgen exposure since it differs between sexes, but constant between races and did not vary by body size.

Increased bisphenol A levels in Thai children and adolescents with type 1 diabetes mellitus.

BACKGROUND: The incidence of type 1 diabetes mellitus (T1DM) in children and adolescents continues to increase worldwide. The reason for this is unclear. In addition to the role of genetics, bisphenol A (BPA) has been investigated as a possible causal factor for T1DM. This study aimed to determine the correlation between urinary BPA levels and T1DM in Thai children and adolescents. METHODS: A cross-sectional study was conducted in T1DM patients who were followed at the endocrinology clinic at King Chulalongkorn Memorial Hospital from December 2018 to December 2019 and age-matched healthy controls. Urinary BPA levels were analyzed by high-performance liquid chromatography and adjusted by urine creatinine. Anthropometric data were measured in all participants and clinical data were collected for the T1DM patients. All participants completed a questionnaire regarding possible BPA exposures. Multivariate logistic regression analysis was used to estimate the adjusted odds ratio for T1DM. RESULTS: Seventy-five T1DM patients and 113 age-matched controls were included in the study. The mean age for T1DM and control groups were 14.8 ± 5.7 and 14.4 ± 6.2 years, respectively. The T1DM group had a significantly higher median (interquartile range) level of adjusted urinary BPA compared to the control (31.50 [7.87, 69.45] vs 10.1 [0, 54.01] µg/g creatinine, P = 0.02). Urinary BPA of 17 µg/g creatinine or more was significantly associated with TIDM, with adjusted odds ratio (95% Confident interval, CI) of 2.38 (1.27, 4.44), P = 0.006. CONCLUSIONS: Higher urinary BPA level is one of the possible risk factors for T1DM.

Adrenal insufficiency in non-transfusion-dependent α-thalassemia.

BACKGROUND: Very few studies about adrenal insufficiency (AI) have been published with regard to non-transfusion-dependent (NTD) thalassemia, and none of those studies involved α-thalassemia patients. The aim of this study was therefore to determine the prevalence of AI in patients with NTD α-thalassemia, and to identify factors that predict the development of AI in this thalassemia subpopulation. METHODS: This cross-sectional descriptive study was conducted in NTD α-thalassemic children at three referral hospitals in Thailand in 2015-2016. Preliminary screening for AI was done using the 1 µg adrenocorticotropic hormone (ACTH) stimulation test. Suspected AI was then confirmed on insulin tolerance test (ITT). AI was defined as peak cortisol <18 µg/dL. AI was categorized as either primary or secondary AI according to peak ACTH. RESULTS: Thirty patients with NTD α-thalassemia were included in this study. Ten of 25 patients (40%) had abnormal initial screening. Eight of nine (88.9%) who underwent ITT were confirmed as having AI. No patients diagnosed with AI had any clinical symptoms of AI. The percentage of primary and secondary AI (n = 8) was 25% and 75%, respectively. Mean age and mean hemoglobin level showed a trend toward being associated with AI (P = 0.98). CONCLUSION: The prevalence of biochemical AI in α-thalassemia patients was similar to rates previously reported for NTD ß-thalassemia. Annual screening for AI in α-thalassemia patients is recommended, and glucocorticoid replacement should be considered in NTD α-thalassemia patients with AI during critical illness.

Splicing analysis of CYP11B1 mutation in a family affected with 11ß-hydroxylase deficiency: case report.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to steroid 11ß-hydroxylase deficiency (11ß-OHD) is a rare form of CAH associated with low renin hypertension, hypokalemia, hyperandrogenemia and ambiguous genitalia in affected females. Herein we describe the clinical, hormonal and molecular characteristics of two Uzbekistan siblings with 11ß-OHD and analyze the effects of a splicing mutation. CASE PRESENTATION: A 46,XX girl presented with genital ambiguity and low renin hypertension; her 46,XY brother presented with precocious puberty. Hormonal studies suggested 11ß-OHD. Mutation analysis was performed by PCR followed by Sanger sequencing of the entire coding regions and their flanking introns of the CYP11B1 gene. Mutation analysis showed that both patients were compound heterozygous for IVS7 + 1G > A, and c.421C > T. Although the identified mutations have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. A minigene assay was used to determine the effects of the splicing mutation. The constructs containing either the wild-type or the splice-site mutant CYP11B1 genomic DNA of exons-introns 6-9 were transfected into COS-7 cells; subsequently, RNA splicing was assessed by reversed transcribed-PCR of CYP11B1 complementary DNA. The minigene assay revealed that the IVS7 + 1G > A mutation resulted in two shorter incorrectly spliced products; one skipping the exon 7 and the other skipping the exons 7-8. The c.421C > T mutation leads to the introduction of a premature stop codon at residue 141 (p.R141X). These mutations are expected to code non-functional proteins. CONCLUSION: Compound heterozygous mutations (IVS7 + 1G > A and p.R141X) in the CYP11B1 gene were found to cause 11ß-OHD. The IVS7 + 1G > A mutation causes aberrant splicing of CYP11B1 leading to exon skipping. This finding could facilitate the future novel therapies targeted on splicing modulation to treat human disease.

Growth Hormone (GH) Retesting and Final Adult Height in Childhood-Onset GH Deficiency (CO-GHD): Experiences from King Chulalongkorn Memorial Hospital, Thailand.

OBJECTIVE: Evaluate GHstatus in CO-GHD subjects after completion of linear growth, and report the auxological outcomes of rhGH treatment. MATERIAL AND METHOD: Twenty-four CO-GHD subjects (14 with IGHD and 10 with MPHD), treated with rhGH for a period of 6.6 ± 3.1 years were re-evaluated for their capacity of GH secretion by performing insulin tolerance test (ITT). Ht SDS at final height was compared with Ht SDS at the start of the treatment and MPH SDS. RESULTS: Thirty-eight percent (9 in 24) of CO-GHD subjects had normal GH secretion on retesting. All subjects were diagnosed as isolated GHD during childhood. In contrast, all MPHD subjects during childhood period had GH insufficiency on retesting. GH insufficient subjects had higher total cholesterol level than those with GH sufficiency (214 ± 51 vs. 1 74 ± 36 mg/mL, p = 0.03). rhGH treatment significantly increased Ht SDS of -2.0 ± 1.1 at the start of the treatment to -0.6 ± 1.3 at the end of the treatment (p < 0.01) and -0.8 ± 1.2 at GH retesting (p < 0.01). CONCLUSION: GH retesting is recommended in subjects with IGHD during the childhood period. However rhGH treatment can enhance the final height in both GH sufficient and insufficient subjects on retesting.

Kisspeptin and DLK1 levels for monitoring treatment of girls with central precocious puberty.

BACKGROUND: Kisspeptin and delta-like 1 homolog (DLK1) are neuropeptides that reportedly play an important role in pubertal timing by activating and inhibiting the hypothalamic-pituitary-gonadal axis, respectively. Consequently, serum kisspeptin and DLK1 levels may be novel biomarkers for differentiating between central precocious puberty (CPP) and premature thelarche (PT) in girls and used to monitor CPP treatment. PURPOSE: To compare baseline serum kisspeptin and DLK1 levels in girls with CPP at diagnosis and after treatment to age-matched girls with PT. METHODS: This prospective longitudinal study included girls with precocious puberty and girls with PT who experienced breast development before 8 years of age and peak luteinizing hormone levels of ≥6 versus <6 IU/L after a gonadotropin-releasing hormone (GnRH) stimulation test. Serum kisspeptin and DLK1 levels were determined in both groups at baseline and after 6 months of GnRH analog treatment in the CPP group and analyzed by enzyme-linked immunosorbent assay. RESULTS: The study divided a total of 48 girls into CPP (n=24; mean age, 7.7±0.7 years) and PT (n=24; mean age, 7.4±0.8 years) groups. The baseline median serum kisspeptin levels were 50.5 pg/mL (range, 38.2-77 pg/mL) and 49.5 pg/mL (range, 39.7-67.6 pg/mL), respectively (P=0.89), while the baseline median serum DLK1 levels were 6.5 ng/mL (range, 5.9-7.5 ng/mL) and 6 ng/mL (4.4-14.4 ng/mL), respectively (P=0.68). After 6 months of GnRH analog treatment in the CPP group, the median serum kisspeptin level was lower (46.4 ng/mL; range, 37.1-60 ng/mL) than that at baseline (P=0.002), while the median serum DLK1 level was higher (7 ng/mL; range, 6.7-8.9) than that at baseline (P=0.002). CONCLUSION: Our findings suggest that baseline serum kisspeptin and DLK1 levels are not reliable biomarkers for differentiating between CPP and PT. However, significant changes in serum kisspeptin and DLK1 levels may be used to monitor CPP treatment.

Effectiveness of leuprolide acetate administered monthly compared to three-monthly in the treatment of central precocious puberty: evaluation at the end of treatment.

Introduction: Gonadotropin-releasing hormone (GnRH) analogs are the standard treatment for central precocious puberty (CPP). Although there are numerous varieties of GnRH agonists, the effectiveness of 1-monthly compared with 3-monthly Leuprolide acetate is still restricted. The objective of this study was to evaluate the outcomes of CPP treatment with Leuprolide acetate at a 1-monthly dosage of 3.75 mg, in comparison to a dosage of 11.25 mg administered every 3 months. Method: This retrospective cohort study involved 143 girls diagnosed with CPP with 72 of them receiving the monthly treatment regimen and 71 receiving the 3-monthly treatment regimen. Anthropometric measurements were compared at the start and end of the therapy. The rates and level of LH suppression were assessed six months after therapy. Results: The regimen administered every 3 months showed more significant suppression of LH. The 3-monthly group showed lower actual height and degree of bone age advancement at the end of therapy. However, the predicted adult height (PAH) remained comparable in both groups. Conclusion: The 3-monthly treatment showed greater hormonal and growth suppression effects, but there was no significant difference in PAH between the two groups.

Preliminary study of renal hemodynamic alteration in early childhood diabetes mellitus.

Renal hemodynamic study was performed in eight patients associated with type 1, early childhood diabetes mellitus (DM) and seven patients associated with type 2, early childhood DM. The results in both types of DM revealed a significant reduction in peritubular capillary flow and a high value of glomerular filtration rate (GFR) in the presence of reduced renal perfusion characteristic of glomerular hyperfiltration. These findings imply that renal ischemia has already developed in both types of early stage childhood DM and GFR is overestimated in DM, which may mislead to improper interpretation of renal function.

Coexistence of Graves' disease with acute rheumatic fever treated as thyroid storm in young Thai patient.

OBJECTIVES: This report presents a case of acute onset of chorea, concurrent Graves' disease, and acute rheumatic fever in an 8-year-old female patient. CASE PRESENTATION: The child had intermittent involuntary movement of all extremities and both eyes for 4 days, with a previous history of increased appetite, weight lost, and heat intolerance over a period of two months. Physical examination revealed fever, tachycardia, exophthalmos, eyelid retraction, as well as diffused thyroid enlargement. Initial clinical features and thyroid function testing suggested a thyroid storm due to Graves' disease. Methimazole, propranolol, potassium iodide (SSKI), and dexamethasone were prescribed. Congestive heart failure developed after propranolol and cardiovascular re-evaluation and Revised Jones criteria suggested acute rheumatic fever. Chorea was successfully treated with pulse methylprednisolone. CONCLUSIONS: We reported Graves' disease patients with acute rheumatic fever simulating a thyroid storm. The underlying cardiac disease must be considered, especially where chorea and congestive heart failure are present.

The utilization of basal luteinizing hormone in combination with the basal luteinizing hormone and follicle-stimulating hormone ratio as a diagnostic tool for central precocious puberty in girls.

PURPOSE: Intravenous gonadotropin-releasing hormone (IV GnRH) testing is the gold standard for confirming a central precocious puberty (CPP) diagnosis. However, this test is not widely available commercially. Therefore, our study aim was to establish cutoff values for basal gonadotropin level and gonadotrophin responses to a 100-µg subcutaneous IV GnRH test that can distinguish between CPP and premature thelarche (PT) to discover a simple method to detect CPP. METHODS: Girls between the ages of 6 and 8 years who attended the pediatric endocrinology outpatient clinic at our tertiary hospital between 2019 and 2022 were included in this study. They were evaluated for breast development, and a subcutaneous 100-µg GnRH test was administered by measuring the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in blood samples at baseline and then 30, 60, 90, and 120 minutes after injection. CPP is characterized by increased height velocity, advanced bone age, and progression of breast development. The cutoff value for diagnosis of CPP was determined using a receiver operating characteristic (ROC) analysis. RESULTS: In 86 Thai girls (56 with CPP and 30 with PT), the ROC analysis showed 71.4% and 100% sensitivity and specificity, respectively, for basal LH (cutoff ≥ 0.2 IU/L) plus the basal LH/FSH ratio (cutoff ≥ 0.1). The optimal cutoff values for peak LH (cutoff ≥ 7 IU/L) demonstrated a sensitivity of 94.6% and a specificity of 100%, whereas the LH value at 30 and 60 minutes after injection (cutoff ≥ 6 IU/L) demonstrated sensitivities of 92.9% and 94.6% and a specificity of 100%, respectively. CONCLUSION: Combining the basal LH (cutoff: 0.2 IU/L) and the basal LH/FSH ratio (cutoff: 0.1) can easily and cost-effectively diagnose CPP in a girl in breast Tanner stage II.

Exposure to Bisphenol A and Its Analogs among Thai School-Age Children.

Bisphenol F (BPF) and bisphenol S (BPS) have become popular substitutes for bisphenol A (BPA) in the plastic industry due to concerns over BPA's adverse effects. However, there is limited information on children's exposure to these chemicals. This study aims to assess the extent of BPA, BPF, and BPS exposure and determine factors that influence such exposure. A group of Thai children (age 6-13 years, N = 358) were recruited between October 2019 and 2020. Two first-morning voids were collected one week apart. Demographic and exposure-related information was gathered. Urinary concentrations of bisphenols were analyzed by liquid chromatography and tandem mass spectrometry. Correlation between bisphenol concentrations with age, body weight, and sources of bisphenol exposure, was determined using generalized estimating equations with linear model. BPA, BPF, and BPS were detected at 79.6%, 31.0%, and 16.8%, with geometric mean (GM) concentrations of 1.41, 0.013, and 0.014 ng/mL, respectively. Younger children aged <10 years exhibited 1.3-1.6 times higher GM levels of all bisphenols compared to older children. Exposure to food stored in plastic containers was associated with higher levels of BPF and BPS. In conclusion, BPA was the most frequently detected bisphenol in urine samples from Thai children, followed by BPF and BPS.

Serum Cortisol as a Biomarker of Severe Dengue.

Dengue infection presents a wide range of clinical symptoms. Serum cortisol is known as a severity predictor of serious infection but is not yet clearly understood in dengue infection. We aimed to investigate the pattern of cortisol response after dengue infection and evaluate the possibility of using serum cortisol as the biomarker to predict the severity of dengue infection. This prospective study was conducted in Thailand during 2018. Serum cortisol and other laboratory tests were collected at four time points: day 1 at hospital admission, day 3, day of defervescence (DFV) (4-7 days post-fever onset), and day of discharge (DC). The study recruited 265 patients (median age (IQR) 17 (13, 27.5)). Approximately 10% presented severe dengue infection. Serum cortisol levels were highest on the day of admission and day 3. The best cut-off value of serum cortisol level for predicting severe dengue was 18.2 mcg/dL with an AUC of 0.62 (95% CI, 0.51, 0.74). The sensitivity, specificity, PPV and NPV were 65.4, 62.3, 16 and 94%, respectively. When we combined serum cortisol with persistent vomiting and day of fever, the AUC increased to 0.76. In summary, serum cortisol at day of admission was likely to be associated with dengue severity. Further studies may focus on the possibility of using serum cortisol as one of the biomarkers for dengue severity.

Novel CYP11B2 mutation causing aldosterone synthase (P450c11AS) deficiency.

UNLABELLED: Aldosterone synthase (P450c11AS) deficiency is a rare autosomal recessive disorder, presenting with severe salt-losing in early infancy. It is caused by inactivating mutations of the CYP11B2 gene. Here, we describe three unrelated Asian patients who have clinical and hormonal features compatible with aldosterone synthase deficiency and identify their CYP11B2 mutations. Patient 1 was a Thai female infant. Patient 2 was an Indian boy, and patient 3 was a Thai male infant. All subjects presented at the age of 1-2 months with diarrhea, failure to thrive, and severe dehydration. Their plasma electrolytes showed hyponatremia, hyperkalemia, and acidosis. All patients had normal cortisol response and had elevated plasma renin activity with low aldosterone levels. The entire coding regions of the CYP11B2 gene were amplified by polymerase chain reaction and sequenced. Patient 1 was homozygous for a previously described mutation, p.T318M. Patient 2 was homozygous for a novel c.666delC mutation inherited from both parents resulting in p.223F>Sfsx295. No CYP11B2 mutation was detected in patient 3. CONCLUSIONS: We report the first CYP11B2 defects in Southeast Asian families responsible for aldosterone synthase deficiency and identified a novel CYP11B2 mutation. However, the affected gene(s) responsible for primary hypoaldosteronism other than CYP11B2 remain to be determined.

Urinary phthalate concentrations are associated with total fat mass in Thai children.

OBJECTIVES: Phthalate is one of the endocrine-disrupting chemicals found in many daily consumer products. Chronic exposure to phthalate may associate with obesity and metabolic abnormalities. However, there is limited information showing a direct relationship between phthalate and body compositions. The aim of the study was to determine the association between urinary phthalate concentration and body composition measure among Thai children. METHODS: A cross-sectional analytic study on urinary phthalate concentrations and body composition in elementary school children, aged 6-13 years in Bangkok, was conducted during October 2019 to 2020. Urinary phthalate metabolites; (mono-methyl phthalate-MMP, mono-ethyl phthalate- MEP, mono-buthyl phthalate-MBP, and mono-ethylhexyl phthalate-MEHP), in early morning spot urine samples were measured by liquid chromatography tandem mass spectrometry (LC-MSMS) with a quantitation limit of 1 ng/mL. Phthalate exposures were identified through questionnaires. Body composition was measured by Tanita BC-418®. Multivariate logistic regression analysis was performed to determine significant associations. RESULTS: A total of 364 children were enrolled in the study (boy 51.4%). After adjusting for confounders (sex, caregiver educations, family income, BMI-SDS: Body mass index-standard deviation score, TV watching, and exercise frequency), total urinary phthalate concentrations were associated with fat mass 8.24 (0.94, 15.53), trunk percent fat 7.69 (3.26, 12.12), arm percent fat 3.69 (0.47, 6.91), arm fat mass 72.88 (1.08, 144.67), and leg fat mass 17.79 (2.37, 33.22). CONCLUSIONS: Higher urinary phthalate concentrations were significantly associated with elevated total fat mass among Thai school-aged children. These findings were not mediated through the degree of obesity defined by BMI. These finding emphasized to be careful when being use phthalate-containing products.

Late sequelae of drug reaction with eosinophilia and systemic symptoms (DRESS) cause thyroid dysfunction and thyroiditis: review of literature.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is one of the severe cutaneous adverse drug reactions (SCARs) with high mortality rate and variable long term sequelae, especially in thyroid dysfunction and thyroiditis. In this article, we review clinical course, culprit drugs, onset of diagnosis, and type of thyroid dysfunction in DRESS patients. There were a total of 51 cases including 12 children (aged less than 18 years old) and 39 adults from our review. The most common thyroid dysfunction was Hashimoto's thyroiditis (41/51=80.4%) including anti-thyroid antibody positive (29/51=56.9%), possible/compatible with Hashimoto's thyroiditis (12/51=23.5%) both in the children (n=12) and adult (n=39), Graves' disease/hyperthyroidism (7/51=13.7%) and non-specific hypothyroidism (3/51=5.9%), respectively. The most common culprit drugs and onset of thyroid dysfunction after DRESS diagnosis in children aged less than 18 years include antiepileptic drugs (phenytoin, phenobarbital, carbamazepine) (range 0-8 months, median 2 months) and sulfa groups (sulfasalazine, sulfamethoxazole, sulfonamide) (range 1-4 months, median 2 months). Data of prevalence, type, and clinical course of thyroid dysfunction from DRESS is important for clinicians to recognize for monitoring its sequelae and provide plans for treatment.

Novel Variants and Phenotypes in NEUROG3-Associated Syndrome.

CONTEXT: Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism. With only 17 reported cases, the clinical and mutational spectra of this disease are far from complete. OBJECTIVE: To identify the underlying genetic etiology in 3 unrelated Thai patients who presented with early-onset malabsorptive diarrhea, endocrine abnormalities, and renal defects and to determine the pathogenicity of the newly identified pathogenic variants using luciferase reporter assays and western blot. METHODS: Three unrelated patients with congenital diarrhea were recruited. Detailed clinical and endocrinological features were obtained. Exome sequencing was performed to identify mutations and in vitro functional experiments including luciferase reporter assay were studied to validate their pathogenicity. RESULTS: In addition to malabsorptive diarrhea due to enteric anendocrinosis, IDDM, short stature, and delayed puberty, our patients also exhibited pituitary gland hypoplasia with multiple pituitary hormone deficiencies (Patient 1, 2, 3) and proximal renal tubulopathy (Patient 2, 3) that have not previously reported. Exome sequencing revealed that Patient 1 was homozygous for c.371C > G (p.Thr124Arg) while the other 2 patients were homozygous for c.284G > C (p.Arg95Pro) in NEUROG3. Both variants have never been previously reported. Luciferase reporter assay demonstrated that these 2 variants impaired transcriptional activity of NEUROG3. CONCLUSIONS: This study reported pituitary gland hypoplasia with multiple pituitary hormone deficiencies and proximal renal tubulopathy and 2 newly identified NEUROG3 loss-of-function variants in the patients with NEUROG3-associated syndrome.

Obesity, metabolic syndrome, and insulin dynamics in children after craniopharyngioma surgery.

INTRODUCTION: Children after craniopharyngioma surgery often develop rapid weight gain and hyperphagia. We investigate the metabolic syndrome features, risk factors, and the insulin dynamics in these patients. MATERIALS AND METHODS: Standard oral glucose tolerance tests (OGTT) were performed in 12 subjects, aged 7.7-18.1 years, after surgical removal of craniopharyngioma and their healthy age-, sex-, body mass index-, and pubertal stage-matched controls. Blood samples were obtained for measurement of levels of plasma glucose, insulin, lipids, liver enzymes, baseline hormonal profiles with calculation of insulin secretion, and insulin sensitivity indices derived from OGTT. RESULTS AND DISCUSSION: Nine of 12 subjects were severely obese. All patients exhibited significant weight gain after surgery. The waist to hip ratio was higher in subjects compared to controls (P = 0.023). Subjects had higher fasting triglycerides (P = 0.019) and lower HDL/total cholesterol ratio (P = 0.012). Five of 12 subjects met the criteria for the metabolic syndrome, compared with one of 12 in controls. One patient had prediabetes and another patient had overt type 2 diabetes. Six of 12 subjects had nonalcoholic steatohepatitis. No significant risk factors were found between each group of patients with and without the metabolic syndrome. There were no differences of insulin secretion and insulin sensitivity indices between craniopharyngioma and control subjects. CONCLUSION: Children after craniopharyngioma surgery are at risk of rapid weight gain and the development of metabolic syndrome. Further studies to better understand the mechanism are required to design effective treatment and prevention.

A patient with combined pituitary hormone deficiency and osteogenesis imperfecta associated with mutations in LHX4 and COL1A2.

Genetic disorders have been shown to co-occur in individual patient. A Thai boy with features of osteogenesis imperfecta (OI) and combined pituitary hormone deficiency (CPHD) was identified. The causative mutations were investigated by whole exome and Sanger sequencing. Pathogenicity and pathomechanism of the variants were studied by luciferase assay. The proband was found to harbor a novel de novo heterozygous missense mutation, c.1531G > T (p.G511C), in COL1A2 leading to OI and a heterozygous missense variant, c.364C > T (p.R122W), in LHX4. The LHX4 p.R122W has never been reported to cause CPHD. The variant was predicted to be deleterious and found in the highly conserved LIM2 domain of LHX4. The luciferase assays revealed that the p.R122W was unable to activate POU1F1, GH1, and TSHB promoters, validating its pathogenic effect in CPHD. Moreover, the variant did not alter the function of wild-type LHX4, indicating its hypomorphic pathomechanism. In conclusion, the novel de novo heterozygous p.G511C mutation in COL1A2 and the heterozygous pathogenic p.R122W mutation in LHX4 were demonstrated in a patient with OI and CPHD. This study proposes that the mutations in two different genes should be sought in the patients with clinical features unable to be explained by a mutation in one gene.

Expanding clinical spectrum of non-autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene.

OBJECTIVE: To describe clinical and genetic features of a Thai family with non-autoimmune hyperthyroidism (NAH) caused by an activating germline mutation in the thyrotropin receptor (TSHR) gene. PATIENTS: Three affected individuals from the same family (a father and his two children) were studied. Clinical and imaging findings were reviewed and compared. GENETIC ANALYSIS: Genomic DNA was extracted from peripheral blood leukocytes and mutation analysis of the entire coding sequence of the TSHR gene was performed in both children and their parents by direct DNA sequencing. RESULTS: A heterozygous germline T to C transition in exon 10 of the TSHR gene (c.1358T-->C) resulting in the substitution of methionine (ATG) by threonine (ACG) at codon 453 (p.M453T) was identified in the father and his two children. They presented with different clinical severity and variable age of onset. In addition to hyperthyroidism, ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers were consistently found in all affected individuals. CONCLUSIONS: Ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers might be characteristic features of NAH because of an activating TSHR germline mutation. In addition, the shortening of the middle phalanges of the fifth fingers has never been previously described, expanding the phenotypic spectrum of the disease.