Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4). DESIGN: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries. PATIENTS: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry. MEASUREMENTS: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM). RESULTS: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1-9.2) were taking a median 11.3 mg/m2 /day (8.6-14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0-104.0). Median D4 under 12 years was 0 nmol/L (0-2.0) and above 12 years was 10.5 nmol/L (3.9-21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R2 = 0.29). In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p < 0.001, R2 = 0.08). Neither biomarker varied directly with dose or weight (p > 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m2 /day for every 1 point increase in weight standard deviation score. DISCUSSION: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain.

Gonadectomy in conditions affecting sex development: a registry-based cohort study.

OBJECTIVES: To determine trends in clinical practice for individuals with DSD requiring gonadectomy. DESIGN: Retrospective cohort study. METHODS: Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist centre; and location of centre from cases reported to the International DSD Registry and who were over 16 years old in January 2019. RESULTS: Data regarding gonadectomy were available in 668 (88%) individuals from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergone gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), respectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries. CONCLUSIONS: The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy.

Clinical but Not Histological Outcomes in Males With 45,X/46,XY Mosaicism Vary Depending on Reason for Diagnosis.

CONTEXT: Larger studies on outcomes in males with 45,X/46,XY mosaicism are rare. OBJECTIVE: To compare health outcomes in males with 45,X/46,XY diagnosed as a result of either genital abnormalities at birth or nongenital reasons later in life. DESIGN: A retrospective, multicenter study. SETTING: Sixteen tertiary centers. PATIENTS OR OTHER PARTICIPANTS: Sixty-three males older than 13 years with 45,X/46,XY mosaicism. MAIN OUTCOME MEASURES: Health outcomes, such as genital phenotype, gonadal function, growth, comorbidities, fertility, and gonadal histology, including risk of neoplasia. RESULTS: Thirty-five patients were in the genital group and 28 in the nongenital. Eighty percent of all patients experienced spontaneous pubertal onset, significantly more in the nongenital group (P = 0.023). Patients were significantly shorter in the genital group with median adult heights of 156.7 cm and 164.5 cm, respectively (P = 0.016). Twenty-seven percent of patients received recombinant human GH. Forty-four patients had gonadal histology evaluated. Germ cells were detected in 42%. Neoplasia in situ was found in five patients. Twenty-five percent had focal spermatogenesis, and another 25.0% had arrested spermatogenesis. Fourteen out of 17 (82%) with semen analyses were azoospermic; three had motile sperm. CONCLUSION: Patients diagnosed as a result of genital abnormalities have poorer health outcomes than those diagnosed as a result of nongenital reasons. Most patients, however, have relatively good endocrine gonadal function, but most are also short statured. Patients have a risk of gonadal neoplasia, and most are azoospermic, but almost one-half of patients has germ cells present histologically and up to one-quarter has focal spermatogenesis, providing hope for fertility treatment options.

Primary squamous cell carcinoma of the thyroid: a case report.

Primary squamous cell carcinoma of the thyroid is a very rare thyroid malignancy (less than 1% of thyroid cancers) with unfavorable clinical evolution and median survival less than one year, due to highly local tumor invasiveness with airway obstruction, metastases and treatment complications. We present a 62-year-old female patient with a fixed, rapidly increasing 5 cm right thyroid nodule, generating compressive signs and significant weight loss, resembling anaplastic thyroid carcinoma. Thyroid hormones, antithyroid antibodies and calcitonin were normal. Computed tomography (CT) scan revealed mediastinal extension of the tumor and excluded the presence of lymph nodes or other tumors (T3N0M0). Total thyroidectomy was performed and histopathological evaluation revealed squamous cell carcinoma, which was confirmed by immunohistochemistry, showing diffuse positivity for CK7, CK19, CK34ßE12, galectin-3, EGFR, focal positivity for p63 and negativity for TTF-1 and CD5. Subsequently, the patient underwent chemotherapy (Paclitaxel, Cisplatin, Epirubicin) and radiotherapy (40 Gy), but tumor recurrence was noticed one month after surgical resection and continued to grow despite treatment. Nodal and metastases status remained negative at regular follow-up. The patient died within one year after diagnosis. External radiotherapy and chemotherapy were not efficient in our case. New treatment options are needed to improve outcome in primary squamous cell carcinoma of the thyroid.

Thyroid regional metastasis from a giant cell malignant fibrous histiocytoma of the larynx in a patient with history of trichinellosis and tuberculosis.

Sarcomas represent less than 1% of malignant laryngeal tumors and giant cell malignant fibrous histiocytoma is exceptionally rare. Diagnosis is histologically based and immunohistochemistry allows differentiation from other fibro-histiocytic neoplasms. We present the case of a 53-year-old male patient with positive medical history for trichinellosis and tuberculosis, and a laryngeal tumor invading the thyroid and causing respiratory distress by airway obstruction. Total laryngectomy and thyroidectomy were performed followed by thyroxine replacement therapy and radiotherapy. Histologically, the tumor consisted of spindle shaped cells with prominent mitoses, and abundant, osteoclast-like, multinucleated giant cells. Similar lesions were identified in the thyroid, adipose and muscular tissues. Parasitic elements were present in muscles. Tumoral cells showed positive immunostaining for Ki67 (40-50%) and vimentin and negative for AE1/AE3, CD31, S100 and myoglobin; the giant multinucleated cells were CD68-positive. Chronic infection might have had a pathogenic significance.

The thyroid and autoimmunity.

Autoimmune thyroid diseases (Hashimoto thyroiditis, Graves' disease, postpartum thyroiditis, atrophic thyroiditis and drug induced thyroiditis) are prevalent disorders worldwide, especially in women (related to the millieu of sex steroids and X chromosome effects on the thyroid and the immune system). Disruption of thyroid self tolerance, usually induced by an infection, generates abnormal thyroid--immune interactions, implicating an array of cytokines and their receptors. Thyrocytes achieve antigen presenting cell properties which stimulate effector immune cells (Th1, Th2, Th17), in the context of defective immunomodulatory T regulatory cells, resulting in thyroid lymphocytic infiltration and activation of B cells, with production of antibodies against thyroid antigens, thyroid destruction or stimulation, depending on the Th1-Th2 balance. During pregnancy there is a Th2 predominance sustained by the increased glucocorticoid, estrogen and progesteron levels, which allows tolerance versus the histoincompatible fetoplacental unit. In the postpartum period, the return shift Th2 to Th1 favors the occurrence of postpartum thyroiditis. Altered thyroid hormone levels can influence the immune system, and, on the other side, some immune cells secrete TSH, which exerts endocrine and paracrine, cytokine-like effects. Understanding the complex pathogenesis of autoimmune thyroid disorders is crucial for prevention and management.

Holt-Oram syndrome.

The Holt-Oram syndrome or atriodigital dysplasia is an autosomal dominant disorder with near complete penetrance and variable expression, caused by mutations of the TBX5 gene (12q24.1), affecting one in 100 000 live births. 60% of cases are familial and 40% sporadic. We present the case of a 24 years old male patient with a personal history of bilateral coxa vara surgically corrected on the right at the age of 8 years, complicated by osteochondritis, short stature (160 cm), underweight (37 kg, BMI 14.45 kg/cm(2)), triangular face, micrognathia, down slanting palpebral fissures, hypertelorism, low set ears, scoliosis, narrow shoulders, shortened left arm, left thumb agenesia, limited supination, abnormal toes, hypoplastic muscles, atrial septal defect ostium secundum type, incomplete right bundle branch block, hypoacusia and normal intelligence.

Hypothyroidism in Turner syndrome.

Turner syndrome (TS) is characterized by an increased prevalence of hypothyroidism, the main etiology being autoimmunity. The aim of our study was to assess the prevalence of hypothyroidism in patients with Turner syndrome, to analyze the correlations with clinical, chromosomal, hormonal and metabolic features and to compare hypothyroid with euthyroid Turner subjects. We studied 28 patients with TS (mean age 24.68 +/- 9.59yr). 78.57% with 45,XO. 10.71% with 45,XO/46,XX and 10.71% with other karyotypes. Hypothyroidism was diagnosed in 10 patients (35.7%). TSH level was positively correlated with thyroid autoantibodies titer (p < 0.001), maternal age at conception (p< 0.01), the presence of spontaneous puberty (p < 0.05) and relative height (p < 0.05), and negatively correlated with FSH level (p < 0.001) which is an indicator of the estrogenic status, and was not correlated to karyotype. Hypothyroid Turner subjects had higher relative heights (p < 0.05) and lower FSH levels (p < 0.05) than euthyroid subjects, but cholesterol levels and BMI were not significantly different.

Ellis-van Creveld syndrome.

Ellis-van Creveld syndrome is a rare autosomal recessive disorder caused by mutations in the EVC and EVC2 gene (4p16), characterized by chondrodystrophy, postaxial polydactyly, ectodermal dysplasia and cardiac anomalies. We present the case of a 24 years old female patient with unaffected parents and an affected sister, with a personal history of surgically corrected postaxial polydactyly of both hands and atriventricular canal. Clinical features were: a marked acromesomelic short stature (135 cm height), narrow thorax, genu valgum, club feet, brachydactyly, malposed toes, hypoplastic nails and teeth, diffuse alopecia, atrioventricular canal, hypoplastic mammary glands and a small goiter. Radiologic evaluation revealed short metacarpals and phalanges, capitat and hamat fusion on the left, left ulnar epiphysis with areas of osteolysis and osteocondensation, genu valgum, short fibulae, narrow thorax, cardiac enlargement with hilar congestion. Echocardiogram showed absence of the atrial sept and the basal portion of the ventricular sept and electrochardiogram--right bundle branch block, left anterior fascicular block and left ventricular hypertrophy. Free thyroxine, TSH and usual laboratory parameters were in the normal range with exception of ionic calcium which was low (3.8 mg/dL).

46,XY hypergonadotropic hypogonadism and myasthenia gravis.

Both hypergonadotropic hypogonadism and myasthenia gravis can be parts of type II autoimmune polyendocrine syndrome and association between the two disorders has been reported in few cases. A 14 year old male patient with a personal history of bilateral cryptorchidism and ptosis was referred for delayed puberty. Clinical examination revealed eunuchoid habitus, small, soft testes, gynecomastia, ptosis, a myasthenic deficit score of 22.5 points and an IQ of 84 points. Decreased testosterone (0.064 ng/mL) and elevated LH (64.5 mUI/mL) were consistent with hypergonadotropic hypogonadism and karyotype was normal: 46,XY. Thyroid function, haematologic evaluation, BUN, electrolytes, and glycemia were in the normal range. Therapy consisted of anticholinesterase inhibitors, immunosuppressants, corticotherapy, testosterone; thoracoscopic thymectomy was performed showing thymic lymphoid hyperplasia on histopathologic examination. Myasthenic score improved (12.5 points), progressive virilization occurred, and a year later the patient presented with cushingoid features and obesity.

Erectile dysfunction in diabetes mellitus.

Erectile dysfunction (ED) is 2-3 times more frequent in men with diabetes mellitus than in men without such a history and might be an early marker of endothelial dysfunction. We studied a group of 310 unselected male patients within the Clinical Center of Diabetes and Metabolic Diseases of Dolj County, with ages ranging between 20-78 years (57.43 + 0.835) and a positive history of diabetes mellitus for 1-47 years (10.09 +/- 8.715). Erectile dysfunction, quantified using SHIM (Sexual Health Inventory for Men), was present in 196 patients (63.2%); severe in 52 patients (16.8%), moderate in 42 patients (13.5%) and mild in 102 patients (32.9%). Erectile dysfunction showed a positive correlation with age after 65 years, history of diabetes of more than 10 years, obesity, stroke, arteriopathy, retinopathy, neuropathy and the smoking habit and was not correlated to the type of diabetes mellitus, history of diabetes less than 10 years, diabetes therapy, hypertension, ischemic heart disease, nephropathy, dyslipidemia and alcohol consumption. Our results plead for a holistic approach of the diabetic patient, irrespective of age, in order to detect and to treat all the risk factors, keeping in mind that the appearance of erectile dysfunction might indicate the presence of occult chronic diabetes complications.