Association of Free Thyroxine with Progression-Free Survival in Intermediate and High Risk Differentiated Thyroid Cancer.

CONTEXT: Supraphysiologic thyroxine (T4) doses are used in intermediate and high-risk patients with differentiated thyroid cancer (IR/HR-DTC) to suppress tumor progression by thyrotropin (TSH). However, preclinical data suggest that T4 can also act as a growth stimulus for cancer, but there is no clinical evidence supporting this claim. OBJECTIVE: We analyzed the association between free T4 (FT4) and progression-free survival (PFS) in patients with IR/HR-DTC. METHODS: This longitudinal cohort study, approved by multi-institutional review board, included patients with IR/HR-DTC treated uniformly with total thyroidectomy, radioiodine (RAI), and TSH suppression therapy, with at least three TSH and FT4 values available. Association between FT4 and PFS at landmarks 6, 12, and 18 months was assessed by Kaplan-Meier survival curves, while competing risks were assessed through Cox proportional hazards model. RESULTS: From 739 screened patients 382 met the inclusion criteria and were characterized by a median age of 46 (34-59) years, 64.1% women, treated with a median RAI dosage of 159 (110-410) mCi. During follow up of 7.1 (3.4-12.7) years 34.6% experienced disease progression.Elevated FT4, observed in 29.3% of patients, was not associated with worse PFS (HR 0.9, CI 0.54-1.5, p=0.69), while age (HR 1.02, CI 1.004-1.04, p=0.01), tumor size (HR 1.15, CI 1.04-1.28, p=0.01), and metastases to the lateral neck lymph nodes (HR 2.9, CI 1.7-4.74, p<0.001), bones (HR 4.87, CI 1.79-13.3, p=0.002), and brain (HR 5.56, CI 2.54-12.2, p<0.001) were associated with shorter PFS. CONCLUSIONS: Contrary to preclinical evidence, elevated FT4 levels do not affect PFS in patients with IR/HR-DTC.

A TNXB splice donor site variant as a cause of hypermobility type Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disease of steroidogenesis that affects 1 in 15,000. Approximately, 10% of the CAH population also suffer from CAH-X, a connective tissue dysplasia consistent with hypermobility type Ehlers-Danlos syndrome (EDS). Most patients with CAH-X carry a contiguous gene deletion involving CYP21A2 encoding 21-hydroxylase and TNXB encoding tenascin-X (TNX), but some are of unknown etiology. METHODS: We conducted clinical evaluation and medical history review of EDS-related manifestations in subjects from two unrelated CAH families who carry a heterozygous TNXB c.12463+2T>C variant that alters the splice donor site of intron 42. A next generation sequencing (NGS) based EDS panel composed of 45 genes was performed for index patients from each family. TNX expression in patient skin biopsy tissues and dermal fibroblasts was assessed by qRT-PCR and Sanger sequencing. RESULTS: All three evaluated CAH patients carrying the TNXB splice site variant had moderate EDS manifestations. An NGS panel excluded involvement of other known EDS-related variants. RNA assay on skin biopsies and dermal fibroblasts did not detect splicing errors in TNX mRNA; however, the removal of intron 42 was less efficient in the allele harboring the splice site variant as evidenced by the existence of a premature TNX RNA form, leading to an allele specific decrease in TNX mRNA. CONCLUSIONS: Carrying a TNXB c.12463+2T>C variant at the intron 42 splice donor site causes an allele specific decrease in TNX expression, which can be associated with moderate EDS in CAH patients.

Co-Occurrence of Familial Non-Medullary Thyroid Cancer (FNMTC) and Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Associated Tumors-A Cohort Study.

Familial non-medullary thyroid cancer (FNMTC) is a form of endocrine malignancy exhibiting an autosomal dominant mode of inheritance with largely unknown germline molecular mechanism. Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is another hereditary autosomal dominant cancer syndrome which, if proven to be caused by germline mutations in mismatch repair genes (MMR)-MLHL, MSH2, MSH6, PMS2, and EPCAM-is called Lynch syndrome (LS). LS results in hereditary predisposition to a number of cancers, especially colorectal and endometrial cancers. Tumors in LS are characterized by microsatellite instability (MSI) and/or loss of MMR protein expression in immunohistochemistry (IHC). MSI is a rare event in thyroid cancer (TC), although it is known to occur in up to 2.5% of sporadic follicular TC cases. There are limited data on the role of germline MMR variants FNMTC. The goal of this study was to analyze the potential clinical and molecular association between HNPCC and FNMTC. We performed a cohort study analyzing the demographic, clinical, and pathologic data of 43 kindreds encompassing 383 participants (104 affected, 279 unaffected), aged 43.5 [7-99] years with FNMTC, and performed high-throughput whole-exome sequencing (WES) of peripheral blood DNA samples of selected 168 participants (54 affected by FNMTC and 114 unaffected). Total affected by thyroid cancer members per family ranged between 2 and 9 patients. FNMTC was more prevalent in women (68.3%) and characterized by a median tumor size of 1.0 [0.2-5.0] cm, multifocal growth in 44%, and gross extrathyroidal extension in 11.3%. Central neck lymph node metastases were found in 40.3% of patients at presentation, 12.9% presented with lateral neck lymph node metastases, and none had distant metastases. Family history screening revealed one Caucasian family meeting the clinical criteria for FNMTC and HNPCC, with five members affected by FNMTC and at least eight individuals reportedly unaffected by HNPCC-associated tumors. In addition, two family members were affected by melanoma. Genome Analysis Tool Kit (GATK) pipeline was used in variant analysis. Among 168 sequenced participants, a heterozygous missense variant in the MSH2 gene (rs373226409; c.2120G>A; p.Cys707Tyr) was detected exclusively in FNMTC- HNPCC- kindred. In this family, the sequencing was performed in one member affected by FNMTC, HPNCC-associated tumors and melanoma, one member affected solely by HNPCC-associated tumor, and one member with FNMTC only, as well as seven unaffected family members. The variant was present in all three affected adults, and in two unaffected children of the affected member, under the age of 18 years, and was absent in non-affected adults. This variant is predicted to be damaging/pathogenic in 17/20 in-silico models. However, immunostaining performed on the thyroid tumor tissue of two affected by FNMTC family members revealed intact nuclear expression of MSH2, and microsatellite stable status in both tumors that were tested. Although the MSH2 p.Cys707Tyr variant is rare with a minor allele frequency (MAF) of 0.00006 in Caucasians; it is more common in the South Asian population at 0.003 MAF. Therefore, the MSH2 variant observed in this family is unlikely to be an etiologic factor of thyroid cancer and a common genetic association between FNMTC and HNPCC has not yet been identified. This is the first report known to us on the co-occurrence of FNMTC and HNPCC. The co-occurrence of FNMTC and HNPCC-associated tumors is a rare event and although presented in a single family in our large FNMTC cohort, a common genetic background between the two comorbidities could not be established.

Multidimensional Aspects of Female Sexual Function in Congenital Adrenal Hyperplasia: A Case-Control Study.

CONTEXT: 46,XX patients with classic congenital adrenal hyperplasia (CAH) are exposed to elevated androgens in utero causing varying levels of virilization. The majority undergo feminizing genitoplasty early in life, with potential impact on sexual function and health-related quality of life (HRQoL). OBJECTIVE: We aimed to determine how sexual and lower urinary tract function, body image, and global HRQoL differs between patients with classic CAH and controls and to characterize how gynecologic anatomy contributes to outcomes. METHODS: 36 patients with classic CAH and 27 control women who were matched for age, race, and marital status underwent standardized gynecological examination and validated questionnaires. The responses were analyzed in relation to gynecological measurements, genotype, and disease status. RESULTS: Compared with controls, patients with CAH were more likely to have sexual dysfunction (P = 0.009), dyspareunia (P = 0.007), and other pelvic pain (P = 0.007); were less likely to be heterosexual (P = 0.013) or ever have been sexually active (P = 0.003); had poorer body image independent of body mass index (P < 0.001); and had worse HRQoL in the areas of general health (P = 0.03) and pain (P = 0.009). The patients with CAH had smaller vaginal calibers and perineal body lengths and larger clitoral indexes when compared with controls (P < 0.001). A larger vaginal caliber in CAH patients was associated with better overall sexual function (P = 0.024), increased sexual satisfaction (P = 0.017), less pain (P < 0.001), and greater number of sexual partners (P = 0.02). CONCLUSIONS: 46,XX patients with CAH have increased rates of sexual dysfunction, poor body image, and poor HRQoL, which is mitigated by having a larger vaginal caliber. Management aimed at optimizing vaginal caliber might improve sexual function.

Individualizing Management of Infertility in Classic Congenital Adrenal Hyperplasia and Testicular Adrenal Rest Tumors.

Testicular adrenal rest tumors (TARTs) are a common cause of male infertility in patients with classic congenital adrenal hyperplasia (CAH). These tumors are located in the rete testis and can lead to impaired blood flow and functional impairment of seminiferous tubules. We describe restoration of fertility in a man with CAH and bilateral TARTs with use of lower-dose glucocorticoid therapy than previously described. A 28-year-old man with classic salt-wasting CAH presented with impaired fertility. Biochemical evaluation showed poor CAH control despite reported compliance with prednisone 5 mg every morning and fludrocortisone 50 µg twice daily. Semen analysis showed azoospermia. Testicular ultrasonography showed TARTs occupying 16% of total testicular volume. After 5 months of dexamethasone 250 µg at bedtime, total TART volume decreased 90%, biochemical control improved, and semen analysis showed a sperm count of 132 × 106 million per milliliter. The patient's wife was confirmed to be pregnant 9 months after the initial visit and delivered a healthy full-term baby girl. The patient's glucocorticoid therapy was changed to prednisone 3 mg twice daily, and 2 years later he continues to show adequate CAH control, stable TART volume, and normal semen analysis, and his wife is pregnant again. Management of CAH in men with TARTs needs to be individualized, and high-dose dexamethasone may not be indicated. The use of a long-acting glucocorticoid at typical recommended dosages can decrease TART size and reverse male infertility. Prednisone given once daily does not adequately control the ACTH-driven complications of CAH.

Longitudinal Assessment of Illnesses, Stress Dosing, and Illness Sequelae in Patients With Congenital Adrenal Hyperplasia.

Context: Patients with congenital adrenal hyperplasia (CAH) are at risk for life-threatening adrenal crises. Management of illness episodes aims to prevent adrenal crises. Objective: We evaluated rates of illnesses and associated factors in patients with CAH followed prospectively and receiving repeated glucocorticoid stress dosing education. Methods: Longitudinal analysis of 156 patients with CAH followed at the National Institutes of Health Clinical Center over 23 years was performed. The rates of illnesses and stress-dose days, emergency room (ER) visits, hospitalizations, and adrenal crises were analyzed in relation to phenotype, age, sex, treatment, and hormonal evaluations. Results: A total of 2298 visits were evaluated. Patients were followed for 9.3 ± 6.0 years. During childhood, there were more illness episodes and stress dosing than adulthood (P < 0.001); however, more ER visits and hospitalizations occurred during adulthood (P ≤ 0.03). The most robust predictors of stress dosing were young age, low hydrocortisone and high fludrocortisone dose during childhood, and female sex during adulthood. Gastrointestinal and upper respiratory tract infections (URIs) were the two most common precipitating events for adrenal crises and hospitalizations across all ages. Adrenal crisis with probable hypoglycemia occurred in 11 pediatric patients (ages 1.1 to 11.3 years). Undetectable epinephrine was associated with ER visits during childhood (P = 0.03) and illness episodes during adulthood (P = 0.03). Conclusions: Repeated stress-related glucocorticoid dosing teaching is essential, but revised age-appropriate guidelines for the management of infectious illnesses are needed for patients with adrenal insufficiency that aim to reduce adrenal crises and prevent hypoglycemia, particularly in children.