An ICET- A survey on Hypoparathyroidism in Patients with Thalassaemia Major and Intermedia: A preliminary report.

Hypoparathyroidism (HPT) is a rare disease with leading symptoms of hypocalcemia, associated with high serum phosphorus levels and absent or inappropriately low levels of parathyroid hormone (PTH). In patients with thalassemias it is mainly attributed to transfusional iron overload, and suboptimal iron chelation therapy. The main objectives of this survey were to provide data on the prevalence, demographic and clinical features of HPT in thalassemia major (TM) and intermedia (TI) patients living in different countries, and to assess its impact in clinical medical practice. A questionnaire was sent to all Thalassemia Centres participating to the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) Network.Seventeen centers, treating a total of 3023 TM and 739 TI patients, participated to the study. HPT was reported in 206 (6.8%) TM patients and 33 (4.4%) TI patients. In general, ages ranged from 10.5 to 57 years for the TM group and from 20 to 54 years for the TI group. Of the 206 TM patients and 33 TI patients with HPT, 117 (48.9%) had a serum ferritin level >2.500 ng/ml (54.3% TM and 15.1% TI patients) at the last observation. Hypocalcemia varied in its clinical presentation from an asymptomatic biochemical abnormality to a life-threatening condition, requiring hospitalization. Calcium and vitamin D metabolites are currently the cornerstone of therapy in HPT. In TM patients, HPT was preceded or followed by other endocrine and non-endocrine complications. Growth retardation and hypogonadism were the most common complications (53.3% and 67.4%, respectively). Although endocrine complications were more common in patients with TM, non-transfused or infrequently transfused patients with TI suffered a similar spectrum of complications but at a lower rate than their regularly transfused counterparts.In conclusion, although a large international registry would help to better define the prevalence, comorbidities and best treatment of HPT, through the result of this survey we hope to give a clearer understanding of the burden of this disease and its unmet needs. HPT requires lifelong therapy with vitamin D or metabolites and is often associated with complications and comorbidities.Therefore, it is important for endocrinologists and other physicians, who care for these patients, to be aware of recent advances of this disorder.

Cross-sectional observational study of nipple and areola changes during pubertal development and after menarche in 313 Italian girls.

UNLABELLED: Obiective: To describe the characteristics of nipple development during puberty in Italian females. In addition this is compared with Tanner criteria for breast and pubic hair development at different stages and correlated with body mass index (BMI) and the menstrual age. DESIGN: Cross-sectional observational study. SETTING: Italian children and adolescents consecutively assessed at the Endocrine and Adolescent Outpatient Clinic of Private Accredited Quisisana Hospital of Ferrara. Partecipants: Healthy females 2-20 years, belonging to Italian middle socio-economic class. Study duration: This study was conducted for a total period of 39 months from September 2012 to December 2015. METHODS: Demographic characteristics, age at menarche and menstrual duration, anthropometry (weight, height, BMI) and pubertal status (breast and pubic hair) were evaluated. The greatest diameters of the erect nipple and areola sizes were measured in all subjects in supine position using a plastic template with graduated circular cut-outs or a transparent graduated ruler. RESULTS: Significant increments in nipple diameter were noted between Tanner's stages B1, B2, B3, B4 and B5 but the differences between stages B1 vs B2, B3 vs B4, B4 were more significant (p<0.001) than the difference between B4 vs B5 (p<0.004).The same statistical pattern was documented between Tanner's stage PH1 and PH2, PH2 and PH3 and PH4 and PH5. The nipple diameter increased significantly in relation to BMI in all Tanner's stage groups (p: 0.021 for B1 vs B2; and p<0.001 for B3 vs B4 and B4 vs B5) but one (B2 vs B3=p: 0.518).A significant correlation was observed between duration of menses, nipple and areola sizes (r: 0.490; p=<0.001 and r: 0.252; p=0.012, respectively). CONCLUSIONS: The assessment of sexual maturation is important in population studies as well as for daily clinical encounter. In our subjects the mean age of onset of secondary sexual characteristics was 10.3±1.4 years and mean age at menarche was 12.02±1.5 years. The study provides the normative data for nipple and areola sizes in Italian girls. Change in nipple and areola sizes may represent an early marker for transition to puberty.

Endocrine profile of ß-thalassemia major patients followed from childhood to advanced adulthood in a tertiary care center.

AIM: Chronic iron overload resulting from frequent transfusions, poor compliance to efficient chelation therapy and chronic liver disease is basically responsible for the most severe complications of thalassemia major (TM). Before conventional treatment, TM was entirely childhood disease with a very short survival. Today, survival improved to 40-50 years and becomes a prevalent disease of adulthood and in the near future it will be one of senility. Furthermore, clinical phenotype of TM is changing with age and appearance of severe complications from the heart and endocrine glands that require special health care from well-informed specialists. OBJECTIVES: The aims of our study were to: (1) Imprint the clinical profile of long-lived TM patients; (2) evaluate retrospectively the cumulative incidence of endocrine diseases; (3) identify potential risk factors; and (4) orient the physicians in the modified clinical phenotype and the relative patients' health needs. DESIGN: A retrospective cross-sectional study followed from childhood to adulthood by the same physician in a tertiary thalassemia clinic. PARTICIPANTS: Forty-three long-lived TM patients (mean age: 50.3 ± 10.8 years; range: 45.8-59.5 years; 23 females) were studied. PATIENTS AND METHODS: An extensive medical history, with detailed clinical and laboratory data, endocrine complications, and current treatments, was obtained. RESULTS: The data indicate that 88.4% of adult TM patients suffered from at least one endocrine complication. The majority of patients developed endocrine complications in the second decade of life when serum ferritin level was very high (12/23 TM female and 8/20 TM male patients, the serum ferritin levels at the diagnosis were above 5.000 ng/ml). CONCLUSIONS: These data underline that endocrine and bone complications in adult TM patients are highly prevalent and necessitate close monitoring, treatment, and follow-up. Physicians' strategies to optimize chelation therapy include identifying patients who are at risk for developing organ damage, developing chelation plans, promoting compliance, and educating patients. Several clinical aspects remain to be elucidated such as growth and impairment of glucose tolerance in relation to hepatitis C virus infection. Furthermore, affordable worldwide-established long-term treatment protocols for hypogonadism and osteoporosis are needed.

Clinical and Biochemical Data of Adult Thalassemia Major patients (TM) with Multiple Endocrine Complications (MEC) versus TM Patients with Normal Endocrine Functions: A long-term Retrospective Study (40 years) in a Tertiary Care Center in Italy.

INTRODUCTION: It is well known that the older generation of adult TM patients has a higher incidence of morbidities and co-morbidities. At present, little information is available on adult TM patients with multiple endocrine complications (MEC). The main objectives of this longitudinal retrospective survey were: 1) to establish the incidence and progression of MEC (3 or more) in TM patients; 2) to compare the clinical, laboratory and imaging data to a sex and age-matched group of TM patients without MEC; 3) to assess the influence of iron overload represented by serum ferritin (peak and mean annual value at the last endocrine observation). PATIENTS AND METHODS: The study was started in January 1974 and was completed by the same physician at the end of December 2015. The registry database of the regularly followed TM patients from diagnosis included 145 adults (> 18 years). All TM patients were of Italian ethnic origin. Eleven out of 145 patients (7.5 %) developed MEC. Twenty-four other patients (12 females and 12 males) had a normal endocrine function (16.5 %) and served as controls. RESULTS: In our survey, four important, relevant aspects emerged in the MEC group. These included the late age at the start of chelation therapy with desferrioxamine mesylate (DFO); the higher serum ferritin peak (8521.8 ± 5958.9 vs 3575.2 ± 1801.4 ng/ml); the upper proportion of splenectomized (81.8 % vs. 28.5%) patients and poor compliance registered mainly during the peripubertal and pubertal age (72.7 % vs.16.6 %) in TM patients developing MEC versus those without endocrine complications. Furthermore, a negative correlation was observed in all TM patients between LIC and final height (r: -0.424; p = 0.031). CONCLUSIONS: Our study supports the view that simultaneous involvement of more than one endocrine gland is not uncommon (7.5 %). It mainly occurred in TM patients who started chelation therapy with DFO late in life and who had irregular/poor compliance to treatment. Therefore, prevention of the endocrine complications through adopting early and regular chelation therapy appears mandatory for improving the quality of life and psychological outcome of these patients. When diagnosing and managing patients with MEC, it is of paramount importance that the multidisciplinary team have excellent knowledge relating to these complications. In ideal circumstances an endocrinologist with experience of TM will form part of the regular multidisciplinary team caring for such patients.

Acquired Hypogonadotropic Hypogonadism (AHH) in Thalassaemia Major Patients: An Underdiagnosed Condition?

INTRODUCTION: In males, acquired hypogonadotropic hypogonadism (AHH) includes all disorders that damage or alter the function of gonadotropin-releasing hormone (GnRH) neurons and/or pituitary gonadotroph cells. The clinical characteristics of AHH are androgen deficiency and lack, delay or halt of pubertal sexual maturation. AHH lead to decreased libido, impaired erectile function, and strength, a worsened sense of well-being and degraded quality of life (QOL). PATIENTS AND METHODS: We studied 11 adult men with thalassemia major (TM) aged between 26 to 54 years (mean ± SD: 34.3 ± 8.8 years) with AHH. Twelve age- and sex-matched TM patients with normal pubertal development were used as a control group. All patients were on regular transfusions and iron chelation therapy. Fasting venous blood samples were collected two weeks after transfusion to measure serum concentrations of IGF-1, free thyroxine (FT4), thyrotropin (TSH), cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (TT), prolactin and estradiol (E2), glucose, urea, creatinine and electrolytes (including calcium and phosphate). Liver functions and screening for hepatitis C virus seropositivity (HCVab and HCV-RNA) were performed. Iron status was assessed by measuring serum ferritin levels, and evaluation of iron concentrations in the liver (LIC) and heart using MRI- T2*. Bone mineral density was measured at the lumbar spine (L1-L4) for all patients with AHH by dual energy X-ray absorptiometry (DXA) using Hologic QDR 4000 machine. RESULTS: The mean basal serum LH and FSH concentrations in AHH patients were 2.4 ± 2.2 IU/L and 1.2 ± 0.9 IU/L respectively; these, values were significantly lower compared to the control group. Semen analysis in 5 patients with AHH showed azoospermia in 3 and oligoasthenozoospermia in 2. The percentage of patients with serum ferritin level >2000 ng/ml (severe iron load) was significantly higher in AHH patients compared to controls, 5/11 (45.4 %) versus1/12 (8.3%), p=0.043. Heart iron concentrations (T2* values) were significantly lower in AHH patients compared to controls (p=0.004). Magnetic resonance imaging in the 3 azoospermic patients revealed volume loss and reduction of pituitary signal intensity. Heart T2* values were significantly reduced in the AHH group vs. the controls (p=0.004). On the other hand, liver iron concentration (mg/g dry weight) was not different between the two groups of TM patients. Using DXA, 63.6 % (7/11) of patients with AHH were osteoporotic, and 36.3 % (4/11) were osteopenic. CONCLUSIONS: In this cohort of thalassemic patients iron overload and chronic liver disease appear to play a role in the development of AHH. Treatment of AHH in TM patients is a vital and dynamic field for improving their health and QOL. Early identification and management of AHH are very crucial to avoid long-term morbidity, including sexual dysfunction and infertility. Therapy aims to restore serum testosterone levels to the mid-normal range. Many exciting opportunities remain for further research and therapeutic development.

Methods for Rating Sexual Development in Girls.

Sexual maturity rating (SMR) is important in population studies and in clinical care. Pubertal staging allows doctors to assess the maturation of adolescents to correlate several pubertal phenomena such as age at menarche, growth spurt and final height, to advise and manage patients appropriately and to have sensitive "sensors" of the effects of environmental exposure on human populations. The commonly used markers of the timing of female puberty are thelarche and menarche. Appearance of the breast bud is the first indicator of puberty onset in 90% of girls. Assessment of thelarche may be performed by a physician with expertise in adolescents or by self-assessment, in which the adolescent identifies her stage of maturation based on Tanner's photographs/illustrations. The assessment of Tanner stages by professionals provides more reliable information than self-assessment but may involve variations between observers. Tanner self-assessment has been proposed as an alternative in various studies. Some studies have found reasonable agreement between self-assessment and examination by a physician whereas others found discrepancies. Measuring nipple and areola diameters is feasible for sexual maturation staging. Both sizes show a significant increase during pubertal development and after menarche. However, the ratings using nipple/areola method need to be analyzed to establish their degree of concordance with standard techniques and other markers of development in girls.