Thiti Snabboon

Identification of mutations in the SRD5A2 gene in Thai patients with male pseudohermaphroditism.

OBJECTIVE To describe two unrelated Thai patients with suspected 5alpha-reductase type 2 deficiency and perform mutation analysis of the SRD5A2 gene. DESIGN Case report. SETTING A pediatric endocrinology clinic at a university hospital. PATIENT(S) Two unrelated patients with 46,XY karyotype, born with ambiguous genitalia, were studied. One was reared as a boy and the other was reared as a girl. INTERVENTION(S) The entire coding regions of the SRD5A2 gene were assessed by polymerase chain reaction (PCR) and sequencing analysis. MAIN OUTCOME MEASURE(S) Molecular characterization of the SRD5A2 gene. RESULT(S) Four different pathogenic mutations (three missense and one nonsense) were identified. These were located at exon 1 (p.Q6X and p.L20P), exon 3 (p.G183S), and exon 4 (p.G203S). The T>C transition (c.59T>C) resulting in a leucine-to-proline substitution at codon 20 (p.L20P) has not been previously described and was not detected in 100 unaffected, ethnic-matched control chromosomes. In addition, p.G183S, previously identified only among patients from mixed African-European ancestry and in the Dominican Republic, was also detected in a Thai patient. CONCLUSION(S) This study demonstrates that the SRD5A2 gene is responsible for 5alpha-reductase type 2 deficiency across different populations and emphasizes the important role of genetic testing for the definite diagnosis and genetic counseling before gender assignment or any surgical intervention.

A Novel Germline Mutation, IVS4+1G>A, of the POU1F1 Gene Underlying Combined Pituitary Hormone Deficiency

Background: POU1F1 is a pituitary transcription factor that plays a pivotal role in pituitary development and expression of the GH, PRL and TSHβ genes. Therefore, abnormalities of the POU1F1 gene are known to be responsible for a phenotype causing combined pituitary hormone deficiency (CPHD) involving growth hormone, prolactin and thyrotropin. Methods: We described an 18-year-old Thai man, from a consanguineous family, who presented with short stature and cognitive deficit. He underwent endocrinological and molecular investigations. Results: Hormonal studies showed that the patient had GH deficiency and secondary hypothyroidism, consistent with CPHD. Direct DNA sequencing revealed a novel homozygous mutation at the splice site of exon 4, IVS4+1G>A. It is the first splice site mutation in the POU1F1 gene described to date. Of the 7 other family members studied for this mutation by restriction enzyme digestions, 5 were heterozygous. They were all unaffected, suggesting a recessive pattern of inheritance. Conclusions: We described a novel POU1F1 splice site mutation, IVS4+1G>A, the first of its kind, in a Thai patient with CPHD. Recessive inheritance is suggested. We also noted preventable morbidities which resulted from delay in diagnosis of concomitant pituitary hormone defects in newborns suspected of CPHD.

Asymptomatic bilateral giant adrenal myelolipomas: case report and review of literature.

OBJECTIVE To describe an unusual case of bilateral giant adrenal masses caused by a primary adrenal myelolipoma. METHODS We present the clinical, laboratory, and pathologic findings in a 32-year-old man with bilateral adrenal masses. The previous reports of bilateral myelolipomas also were reviewed. RESULTS During a routine examination, a 32-year-old Thai man was found to have an asymptomatic abdominal mass. A computed tomographic scan of the abdomen disclosed bilateral adrenal masses; the one on the left was approximately 27 by 24 by 12 cm, and the one on the right side was 9 by 5 by 5 cm. The computed tomographic scan characteristics showed that both masses consisted mainly of low-density tissues (-30 to -90 Hounsfield units), suggestive of fatty component. An endocrinologic evaluation revealed no evidence of adrenal cortical or medullary functional abnormalities. Bilateral adrenalectomy was performed because of the large size of the lesions and the inability to rule out malignant involvement. CONCLUSION Myelolipoma is a relatively rare benign tumor of the adrenal glands composed of adipose cells and mature hematopoietic elements. Most such lesions are small, asymptomatic, and unilateral; giant or bilateral myelolipomas are quite rare. To our knowledge, our current case may represent the largest bilateral lesions in the literature.

Psychosis as the first presentation of hyperthyroidism

A 40-year-old married woman was brought to the emergency department (ED) by her family members for agitation, paranoia and hallucinations. Before 6 months, she had gradually increasing appetite, thirst, loss of weight, insomnia and occasional nervousness without any apparent reason. Three months prior, she started having anxiety, was preoccupied, irritable and restless. Subsequent worsening led to additional features of psychomotor agitation, paranoid ideas and auditory hallucinations. She had otherwise been healthy, and did well on her job and with interpersonal relations. She had a history of Graves’ disease 5 years earlier, which was in remission after treatment with propylthiouracil (PTU) for 2 years. She denied any history of substance abuse. Physical examination revealed a normal temperature, tachycardia with a heart rate of 110 beats/min, moist skin, fine tremors and a lid lag with a facial appearance of staring. A diffusely enlarged thyroid gland with bruit was also noted. Relapse of the Graves’ disease was confirmed by elevated free thyroxine (2.75 ng/dl, normal level 0.8– 1.8), free triiodothyronine (10.77 pg/ml, normal level 1.6– 4.0) and low TSH (\0.005 lU/ml, normal level 0.3–4.1). Tests for thyroid microsomal antibody and thyroglobulin were also positive. Computerized tomography (CT) of the brain was normal. Electrolyte levels and blood counts were within normal limits. Thyroid crisis with acute psychosis was diagnosed. PTU 1,200 mg/day, saturated solution of potassium iodide (SSKI) 200 mg/day and dexamethasone 4 mg/day were administrated. Antipsychotic drugs including haloperidol (4–8 mg/day intravenously or oral) and lorazepam (1–2 mg/day oral) were also used. She showed dramatic improvement in all the symptoms over the next 3 days, and she felt well after 2 weeks except for occasional insomnia. After discharge, the patient remained in a euthyroid state with anti-thyroid drugs and refused I-131 therapy. Hyperthyroidism usually manifests with symptoms that include weight loss despite increased appetite, tremor, excessive perspiration, and palpitations. Various psychiatric disorders such as anxiety, emotional lability, insomnia, agitation, mania or depression are also found concurrently with hypermetabolic symptoms. Nevertheless, psychosis or an acute state of confusion is rare as a part of thyroid crisis [1]. The association of psychosis or delirium with hyperthyroidism has been reported in earlier times when less specific thyroid function tests and inadequate treatment of hyperthyroidism were the norm. With better control of thyroid dysfunction, there are fewer reports of severe manifestations and psychiatric illnesses such as mania, anxiety, depression and cognitive dysfunction [2]. Psychotic symptoms were formerly found especially with severe hyperthyroidism or thyroid storm. Nevertheless, atypical symptoms such as apathy, lethargy and severe depression (apathetic hyperthyroidism), may be seen in the elderly [1]. These psychiatric symptoms also parallel the medical illness and often remit with successful therapy of the hyperthyroid state. T. Snabboon A. Khemkha C. Chaiyaumporn V. Sridama Department of Internal Medicine, Chulalongkorn University, Bangkok, Thailand

Association between genetic polymorphisms and sites of cervicocerebral artery atherosclerosis.

Ischemic stroke is a multifactorial disease with strong genetic elements. The purpose of this case-control study was to find relationships between apolipoprotein E (APOE), angiotensin-converting enzyme (ACE), and methylenetetrahydrofolate reductase (MTHFR) genotypes and atherosclerosis of the extracranial internal carotid and intracranial arteries in the Thai population. Patients aged >45 years with significant intracranial stenosis (IC group) or extracranial carotid artery stenosis (EC group) diagnosed by duplex ultrasound and/or computed tomography angiography (CTA) or magnetic resonance angiography (MRA) were studied. The control group comprised volunteers with no history of stroke and no evidence of significant cervicocerebral artery stenosis by ultrasound. Genomic DNA was extracted and genotyped for APOE isoforms, ACE insertion/deletion (I/D) polymorphism, and MTHFR C677T polymorphisms. There were 141 cases (83 in the IC group and 58 in the EC group) and 167 controls. The APOE ε3/ε4 genotype and APOE ε4 allele were significantly associated with extracranial carotid artery stenosis (odds ratio, 2.55; 95% confidence interval, 1.07-6.05 and odds ratio, 2.85; 95% confidence interval, 1.35-5.99, respectively). These associations were not observed in patients with intracranial atherosclerosis. There was no significant association between ACE and MTHFR polymorphisms and stenosis at any site. In a multivariate model, sex, diabetes mellitus, hypertension, ischemic heart disease, and APOE ε4 allele remained predictive of extracranial atherosclerosis. In our Thai population, the ε4 allele in the APOE gene contributes to the genetic susceptibility of extracranial internal carotid atherosclerosis. The low prevalence of extracranial carotid stenosis in this population might result from low frequencies of the APOE ε4 allele.

Bilateral pheochromocytoma during the postpartum period

BackgroundPheochromocytoma manifesting during pregnancy is uncommon but it is responsible for a high maternal and fetal mortality rate, especially when unrecognized. Most cases of pheochromocytoma are sporadic but they can be part of hereditary autosomal dominant syndromes.CaseWe describe a case of bilateral pheochromocytoma in a term-pregnant patient with a previous history of medullary thyroid carcinoma (MTC). Her genetic study revealed a heterozygous mutation, c.1900T>C, in the RET proto-oncogene which confirmed the diagnosis of multiple endocrine neoplasia type 2A (MEN2A). Unrecognized, the tumors caused a crisis with fatal outcome in the mother during the postpartum period. This event might have been prevented if the tumor had been detected previously.ConclusionMEN2A affected pregnancy is an unusual condition. This syndrome should be suspected when a pregnant patient has a history of MTC. Early detection and appropriate management can prevent serious maternal and fetal complications. We also reviewed the literature of MEN2A-affected pregnancies.

Two common and three novel PDS mutations in Thai patients with Pendred syndrome

Pendred syndrome is an autosomal recessive disorder characterized by congenital sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the PDS gene. Most published mutation studies of Pendred syndrome have dealt with Western populations. In this study, we examined clinical and molecular characteristics of 16 affected individuals in 6 unrelated Thai families. Of all the affected, 100% (16/16) had bilateral deafness, 68.8% (11/16) goiters, and 25% (4/16) hypothyroidism. Follicular thyroid carcinoma and Hürthle cell adenoma were found in affected members of a family, raising the possibility of an increased risk of thyroid carcinoma in Pendred syndrome patients. Sequence analysis of the entire coding region of the PDS gene successfully identified all 12 mutant alleles in these 6 families. The 12 identified mutant alleles constituted 6 distinct mutations including 3 splice site mutations (IVS4-1G>A, IVS7-2A>G, IVS9-1G>A), one frame shift mutation (1548insC) and 2 missense mutations (T67S, H723R). Eight mutations out of 12 were constituted by IVS7-2A>G and 1548insC, each one being present in 4 distinct alleles in our studied group. The identification of these two frequent PDS mutations will facilitate the molecular diagnosis of Pendred syndrome in Thai populations. In addition, three newly identified mutations, T67S, IVS4-1G>A, and IVS9-1G>A, were not observed in 50 unrelated healthy Thai controls.

PTPRF is disrupted in a patient with syndromic amastia

BackgroundThe presence of mammary glands distinguishes mammals from other organisms. Despite significant advances in defining the signaling pathways responsible for mammary gland development in mice, our understanding of human mammary gland development remains rudimentary. Here, we identified a woman with bilateral amastia, ectodermal dysplasia and unilateral renal agenesis. She was found to have a chromosomal balanced translocation, 46,XX,t(1;20)(p34.1;q13.13). In addition to characterization of her clinical and cytogenetic features, we successfully identified the interrupted gene and studied its consequences.MethodsCharacterization of the breakpoints was performed by molecular cytogenetic techniques. The interrupted gene was further analyzed using quantitative real-time PCR and western blotting. Mutation analysis and high-density SNP array were carried out in order to find a pathogenic mutation. Allele segregations were obtained by haplotype analysis.ResultsWe enabled to identify its breakpoint on chromosome 1 interrupting the protein tyrosine receptor type F gene (PTPRF). While the patients mother and sisters also harbored the translocated chromosome, their non-translocated chromosomes 1 were different from that of the patient. Although a definite pathogenic mutation on the paternal allele could not be identified, PTPRFs RNA and protein of the patient were significantly less than those of her unaffected family members.ConclusionsAlthough ptprf has been shown to involve in murine mammary gland development, no evidence has incorporated PTPRF in human organ development. We, for the first time, demonstrated the possible association of PTPRF with syndromic amastia, making it a prime candidate to investigate for its spatial and temporal roles in human breast development.

Changes in Testosterone Levels and Sex Hormone-Binding Globulin Levels in Extremely Obese Men after Bariatric Surgery

Objective. Obesity is a risk factor for hypogonadotropic hypogonadism in men. Weight loss has been shown to improve hypogonadism in obese men. This study evaluated the early changes in sex hormones profile after bariatric surgery. Methods. This is a prospective study including 29 morbidly obese men. Main outcomes were changes in serum levels of total testosterone (TT), free testosterone (cFT), SHBG, estradiol, adiponectin, and leptin at 1 and 6 months after surgery. Results. The mean age of patients was 31 ± 8 years and the mean BMI was 56.8 ± 11.7 kg/m2. Fifteen patients underwent Roux-en-Y gastric bypass and 14 patients underwent sleeve gastrectomy. At baseline, 22 patients (75.9%) had either low TT levels (<10.4 nmol/L) or low cFT levels (<225 pmol/L). Total testosterone and SHBG levels increased significantly at 1 month after surgery (p ≤ 0.001). At 6 months after surgery, TT and cFT increased significantly (p ≤ 0.001) and 22 patients (75.9%) had normalized TT and cFT levels. There were no changes in estradiol levels at either 1 month or 6 months after surgery. Conclusions. Increases in TT and SHBG levels occurred early at 1 month after bariatric surgery while improvements in cFT levels were observed at 6 months after bariatric surgery.

Effectiveness of a low dose testosterone undecanoate to improve sexual function in postmenopausal women

BackgroundAdding testosterone to hormonal therapy could improve sexual function and general well-being among women during climacteric. We evaluated the effectiveness of testosterone undecanoate on sexual function in postmenopausal women utilizing the standardized questionnaire FSFI score.MethodsPostmenopausal women with sexual complaints and Female Sexual Function Index (FSFI) ≤ 26.5 were enrolled in to this randomized, double-blinded, placebo-controlled trial. Participants were randomly assigned to 8-week treatment with either oral testosterone undecanoate 40 mg or placebo twice weekly with daily oral estrogen. The FSFI scores before and after treatment were compared to assess any improvement of sexual function.ResultsSeventy women were recruited of which each group had 35 participants. The baseline characteristics and baseline FSFI scores were comparable between both groups. After 8 weeks of treatment, the FSFI scores significantly improved in both groups when compared to the baseline but the FSFI scores from the testosterone group were significantly higher than in the placebo group post-treatment (28.6 ± 3.6, 25.3 ± 6.7, respectively, p = 0.04). There was no difference in adverse effect between the two groupsConclusionsThe twice weekly addition of testosterone undecanoate to daily oral estrogen was associated with a significant improvement in sexual function among postmenopausal women than the use of the estrogen alone.Trial registrationClinicalTrials.gov Identifier NCT01724658 (February 17, 2012).