Apparent Mineralocorticoid Excess Caused by a Novel Mutation in 11-ß Hydroxysteroid Dehydrogenase Type 2 Enzyme: Its Genetics and Response to Therapy.

OBJECTIVE: To present a case of apparent mineralocorticoid excess (AME) due to a novel mutation in the HSD11B2 gene and describe the patient's response to therapy. METHODS: The clinical, biochemical, and genetic features of the proband and his family are presented. For the genetic study, DNA was extracted from peripheral leucocytes. The exons and exon-intron boundaries were polymerase chain reaction (PCR)-amplified and directly sequenced. RESULTS: A 10-year-old male presented with hypertension (HTN) and weakness and was found to have hypokalemia of 2.6 mmol/L. Plasma renin was undetectable, and plasma and urinary aldosterone were low. Serum cortisol and deoxycorticosterone were normal. Daily urinary excretion of cortisol was normal, but urinary and serum cortisone levels were undetectable. The patient was treated with spiranolactone with inadequate response. A small dose of dexamethasone was added and led to excellent control of HTN and hypokalemia. Genetic studies showed a novel missense biallelic mutation changing guanine to adenine in exon 3 (c.G526A) of the HSD11B2. This mutation changes the amino acid aspartic acid to asparagine at codon 176 (p.D176N). A monoallelic form of the same mutation was found in the parents and 3 of his 4 healthy siblings but not in a healthy sister or 100 normal subjects. CONCLUSIONS: A case of AME due to a novel mutation in HSD11B2 showed the usual features of AME but exhibited an inadequate response to spironolactone. A small dose of dexamethasone resulted in an excellent response.

Divergent gender identity in three siblings with 46XX karyotype and severely virilizing congenital adrenal hyperplasia caused by a novel CYP11B1 mutation.

OBJECTIVE: To describe conflicting gender identities in three karyotypically female siblings with congenital adrenal hyperplasia (CAH) caused by a novel mutation in the CYP11B1 gene, who were assigned as males at birth and followed up to adulthood. METHODS: We present 3 siblings (16, 14 and 10 years old) who were born with severe genital virilization and raised as males. Clinical examination showed Prader IV to V external genitalia with a stretched penile length of 7 to 11 cm. Adrenocorticotrophic hormone (ACTH) stimulation test showed a stimulated 11 deoxycortisol (11DOC) level of 12,300-18,700 µg/L (normal 0-5 µg/L). Their karyotypes were 46 XX, and they had normal-sized uterus and ovaries on pelvic ultrasound. DNA was isolated from peripheral leukocytes, and polymerase chain reaction (PCR) and direct sequencing revealed a novel CYP11B1 mutation. This mutation leads to a c.53_54 T insertion (c.53_54insT) with frameshift and truncation at c.115 (codon 39) of CYP11B1. RESULTS: Psychological evaluation of the oldest sibling suggested a female gender identity, and she declared herself as female, and female sex was re-assigned after 1 year of psychosocial adjustment. Psychological assessment for the 2 younger siblings and a fourth 46XY sibling with the same condition revealed male gender identities, and they continued their lives as males without significant difficulties. CONCLUSION: Divergent gender identity was observed in three severely masculinized 46XX siblings with CAH who carried the same CYP11B1 mutation and had comparable postnatal and probably prenatal androgen exposure and environmental circumstances. These cases suggest that the basis of gender identity is more complex than chromosomal, biochemical, and genetic constitution.

Uncommon TERT Promoter Mutations in Pediatric Thyroid Cancer.

PURPOSE: The aim of this study was to determine the rate and significance of TERT promoter mutations that have been recently described in adult thyroid cancer (TC) but not yet in the uncommonly occurring pediatric TC. Furthermore, the role of the BRAF(V600E) mutation in the clinical outcome of pediatric TC is unknown. METHOD: The study included 55 pediatric (median age 16 years, range 9-18 years; 46 females) and 210 adult TC patients (median age 40 years, range 20-75 years; 155 females) seen during the same time period. DNA was isolated from TC tissues and subjected to direct sequencing. Genetic-clinicopathological correlations were analyzed. RESULTS: Only one case of pediatric TC was found to harbor the C228T TERT promoter mutation (1.8%). The C250T mutation was not detected in any of the 55 pediatric TC. In contrast, there was a significantly higher rate of TERT promoter mutations in the adult patients (15.7%, 33/210) compared with the pediatric patients (p = 0.003). In addition, persistent/recurrent TC was seen in 8/12 (66.7%) pediatric patients harboring the BRAF(V600E) mutation versus 14/41 (34.1%) patients harboring the wild type BRAF (p = 0.05), and when only conventional papillary TC was examined, in 7/9 (77.8%) cases harboring BRAF(V600E) mutation versus 11/33 (33.3%) cases harboring wild type BRAF (p = 0.025). CONCLUSIONS: This is the first study on TERT promoter mutations in pediatric TC, which revealed an exceedingly low prevalence, suggesting a limited role of these mutations in pediatric TC. This study also for the first time demonstrates an association of the BRAF(V600E) mutation with TC recurrence in pediatric patients.

Absence of somatic mutations of the mTOR gene in differentiated thyroid cancer.

Thyroid cancer is the most common endocrine malignancy with increasing incidence. Mammalian target of rapamycin (mTOR) is an important downstream mediator of phosphatidylinositol 3-kinase (PI3K/Akt) signaling and regulates cell growth, apoptosis and metabolism. The mTOR gene is frequently mutated in human cancers. Although PI3K/Akt pathway and its component genes were extensively studied in thyroid cancer, it is not known whether mTOR gene is somatically mutated and play a role in differentiated thyroid cancer (DTC). To determine the status of mTOR mutations in 53 DTC, we extensively examined 19 selected exons of mTOR gene which were reported to be frequently mutated in other human cancers. Unlike in other human cancers, we did not find common somatic mutations in the mTOR gene in differentiated thyroid cancer, except for some synonymous single nucleotide polymorphisms. Our results suggest that mTOR mutation is very rare and may not play a significant role in DTC.

TERT promoter mutations in thyroid cancer: a report from a Middle Eastern population.

Telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have recently been described in follicular cell-derived thyroid cancer (TC) in patients from North America and Europe. In this study, we explored whether these findings could be replicated in patients from a different ethnic group. We screened 17 benign thyroid adenomas and 265 TC samples from patients in the Middle East for these mutations by PCR and direct sequencing using DNA isolated from paraffin-embedded tumor tissues. None of the 17 benign adenomas harbored TERT promoter mutations. Of 265 TC, 34 (12.8%) harbored TERT promoter mutations, including 10/153 (6.5%) conventional papillary TC (CPTC), 8/57 (14.0%) follicular variant PTC, 9/30 (30%) tall cell variant PTC, 1/3 (30%) Hurthle cell thyroid cancer (HTC), 1/5 (20%) follicular TC, and 5/13 (38.5%) poorly differentiated TC. C250T mutation was present in only 6/265 (2.3%) cases, while C228T mutation was present in a total of 28/265 (10.6%) cases. These two mutations were mutually exclusive. TERT promoter mutations were significantly more common in older (≥45 years) than younger patients and were associated with larger tumour size, vascular invasion, higher TNM stage (stage III and IV), BRAF(V600E) mutation and persistent/recurrent disease at 6-12 months after initial treatment and at the last follow up. These associations were stronger in non-CPTC. Thus, this study on a large cohort of TC patients from Middle East demonstrates that TERT promoter mutations are relatively common, especially in the non-CPTC, and are associated with more aggressive histopathological features, BRAF(V600E) mutation, and disease persistence/recurrence than the WT TERT.