Manifestations of HbSE sickle cell disease: a systematic review.

BACKGROUND: Sickle cell disease (SCD) is commonly encountered in Africa and Middle Eastern countries. The causative mutation in the gene encoding the hemoglobin subunit ß (HBB) leads to various genotypic variants of the disease. This results in varied phenotypes, with a spectrum of complications, from benign to fatal. Hemoglobin SS (HBSS) genotype is associated with most of these complications; hence, it is a severe form of SCD. On the other hand, rare genotypes such as hemoglobin SE (HBSE) are considered benign. There is limited literature about the clinical manifestations and characteristics of patients with HBSE. We pooled all available data describing the phenotypic manifestations of HBSE heterozygote worldwide to perform a systematic review. METHODS: We performed a systematic review according to PRISMA guidelines using PubMed, SCOPUS, and Google Scholar databases. Two independent reviewers (FA and IK) evaluated studies for eligibility and extracted data. We synthesized data on demographics, manifestations, and management of HBSE disease. PROSPERO Registration Number: CRD42021229877. RESULTS: We found 68 HBSE patients reported in the literature. 24 cases were extracted from case reports whereas 44 cases from case series and retrospective studies. Turkey reported the highest number of patients (n = 22). 32 (47%) of the patients were males. The mean age was 20.9 ± 18.26 years. The mean HBS and HBE percentages were 61.1% ± 7.25% and 32.3% ± 5.06%, respectively, whereas the mean hemoglobin was 11.64 ± 1.73 g/dl. Reported manifestations of HBSE disease included acute vaso-occlusive pain crisis (n = 22, 32.3%), splenomegaly (n = 11, 16.1%), hemolytic anemia (n = 10, 14.7%), infections (n = 8. 11.7%), bone infarction (n = 4, 5.8%), gallstones (n = 3, 4.4%), venous thromboembolism (VTE) (n = 2, 2.9%) and stroke (n = 2, 2.9%), and hematuria (n = 2, 2.9%). Death due to HBSE complications was reported in three patients. CONCLUSION: HBSE is a rare genotypic variant of SCD. It has been considered a benign form; however, there are multiple reports of severe complications. Severe complications observed in HBSE disease include vaso-occlusive crisis, acute chest syndrome, stroke, bone marrow embolism, and death.

The Prevalence of Hypothyroidism among Patients With ß-Thalassemia: A Systematic Review and Meta-Analysis of Cross-Sectional Studies.

As a cause of chronic blood transfusions, iron overload is an important issue in ß-thalassemia (ß-thal) patients that leads to multiple organ dysfunctions. This is an updated meta-analysis conducted to summarize the existing evidence of the prevalence of hypothyroidism (HT) among patients with transfusion-dependent (TDT) and non transfusion-dependent ß-thal (NTDT) and for the first time we meta-analyzed the relationship between ferritin level and HT. This systematic review and meta-analysis were done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. We searched databases including Web of Science (ISI), Scopus, PubMed, Embase, and Scholar. The quality of the included studies was assessed based on the Newcastle-Ottawa scale (NOS) checklist. Meta-analysis was done using Stata statistical software. The pooled prevalence of total HT, subclinical HT, and overt HT among ß-thal patients was 13.25 [95% confidence interval (95% CI): 10.29-16.21; 11.84, 95% CI: 8.43-15.25 and 12.46, 95% CI: 1.05-23.87], respectively. The prevalence of total HT was 16.22% (95% CI: 12.36-20.08) in TDT and 7.22% (95% CI: 3.66-10.78) in NTDT patients. Serum ferritin (SF) levels were significantly lower in euthyroid compared to hypothyroid patients [standard mean difference (SMD) -2.15 (95% CI: -3.08, -1.21, p value <0.001]. The prevalence of HT was higher in TDT compared to NTDT patients. Moreover, our results showed a significant association of high serum ferritin (SF) levels with hypothyroidism in ß-thal patients. Both of these findings highlight the importance of prevention measures and timely diagnosis and management of iron overload in ß-thal patients.

For Debate: Assessment of HbA1c in Transfusion Dependent Thalassemia Patients.

At present, assessment of haemoglobin A1c (HbA1c) is widely used for the diagnosis and monitoring of treatment in diabetes mellitus (DM). However, the HbA1c level is affected by many factors such as those influencing the lifespan of red blood cells and the structure, function and amount of normal HbA. Therefore, the clinical significance of HbA1c assessment in thalassemia patients needs careful consideration, especially in transfusion dependent thalassemia patients (TDT) in whom circulating Hb is that of blood donors. Preliminary reports have documented that HbA1c estimation in efficiently transfused patients seems valuable in diagnosis and monitoring of treatment in DM and other glucose disturbances in TDT patients. Herein, a short review of HbA1c measurement in anemias, blood transfusions and hemoglobinopathies, and the debate of the credibility of Hb A1c assessment in TDT patients is reported.

For Debate: Testicular Volume Development along Ages: Evaluation by Different Methods.

In the last five decades an increasing number of studies and clinical reports demonstrated the importance of testicular volume assessment in pediatric and adolescent population. Reliable and accurate determination of testicular volume (TV) through infancy and adolescence is of great importance for assessing normal pubertal development to diagnose disturbances in development and to suspect certain genetic and endocrine diseases. Various approaches are available for the assessment of TV, including orchidometry, rulers, callipers, and ultrasonography (USG). Our report focuses on the importance of the evolution of TV from birth to adulthood and debates the main factors influencing the accuracy of different TV measurements. We endorse that any method for the evaluation of TV must satisfy certain criteria: a. be applicable to persons of all ages from pre-adolescence, through the pubertal spurt to full maturity, b. be simple to use, c. be free from observer error as possible, and d. have a high degree of correlation with other observable developmental characteristics.

Meeting Report: The Equality Project on Endocrine Complications in Thalassemia: Selected Highlights from the First Turkish Congress, Antalya, 10th-11th December 2018.

Major difficulties reported by endocrinologists /pediatricians/ hematologists in the care of thalassemic patients with endocrine complications were: lack of facilities, correct interpretation of tests, unfamiliarity with medical treatment and the cost of diagnostics and therapeutics. Therefore, there is a felt need to educate and train more endocrinologists/pediatricians/hematologists in this field in order to optimise growth and prevent endocrine complications. To achieve this goal, in 2015, a project called Equality was submitted by three countries (Turkey, Spain and Italy) and approved by the European Union (EU) with the aim to train doctors and nurses, taking care of youth and young adults TM patients, in the prevention, diagnosis, and management of endocrine disorders. The selected highlights of the First Turkish Congress held in Antalya (10th-11th December 2018) are reported. Overall the conference provided a wide coverage of conventional treatment of thalassemias and endocrine complications in patients with ß-thalassemia major. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended.

The Management of Permanent Primary Hypoparathyroidism in Children and Adolescents: A Complex Task.

Management of hypoparathyroidism (hypoPT), depends on the etiology and the severity of hypocalcemia. Treatment goals include control of hypocalcemic symptoms preserving serum calcium in the low-normal range and phosphate in the high normal range. While correction of serum calcium to low-normal range does not fully correct mineral and bone metabolism it may be associated with increased risk of complications such as nephrolithiasis, nephrocalcinosis and soft tissue calcifications. Therefore, it is imperative to find out ways to individualize treatment of patients with hypoPT to achieve the best prognosis while minimizing complications. Replacement therapy with recombinant human PTH (rhPTH) was recently tested for optimizing treatment of hypoPT in a small number of patients. For children and adolescents, further studies are needed to evaluate the long-term effects and safety of rhPTH. In this short review we summarize current knowledge on the management of hypoPT and debate our gaps on the long-term management of children and adolescents with hypoPT.

For Debate: Should We Worry about Hematospermia in Adolescents and Young Men? A Report of Six Cases and Review of the Literature.

Hematospermia or hemospermia is defined as the presence of blood in ejaculate. The true prevalence of the condition is unknown because many cases escape the patient's notice, and remain unrecognized and unreported. There are two main aims in the patient evaluation: first, to ensure that there is no specific condition that is treatable; second, to reassure the patient's parents that no causative factor is present. Many physicians are unfamiliar with this disorder and this forms the basis for our current review. We performed an essentially English language search (Medline since 1966 to present and reference list of articles) for "hematospermia", or "hemospermia" in combination with "adolescents", "young adults", "genital diseases", "management" and "review". The authors' personal experience with 6 adolescents and young men (up to the age of 20 years) is also reported. Several anatomical structures contributing to the ejaculate may be the source of the hematospermia: seminal vesicles, prostate, testis and epididymis. Hematospermia is a generally benign and self-limited condition that is infrequently associated with significant underlying pathology. Once the diagnosis is clear, it is important to reassure the adolescent about the benign nature and self-limiting course of the condition and to provide appropriate treatment to help ensure the adolescent's normal sexual development.

Is the Second to Fourth Digit Ratio (2D:4D) a Biomarker of Sex-Steroids Activity?

The second-to-fourth digit ratio (2D:4D) has been used as an indirect method to investigate the putative effects of prenatal exposure to androgens, and has been reported to be smaller in males than in females. This gender difference in digit length ratios has been linked with the in utero balance of androgens to oestrogen. This sexual dimorphism in 2D:4D ratios is apparent by 2 years of age and seems to be established early in life, possibly by the 14th week of gestation. Digits in females attain their maximum length at about 2.2 years (dextral subjects) or 5.1 years (sinistral subjects) earlier than those in males and increase slightly with age. It has also been reported that the 2D:4D ratio is correlated negatively with prenatal testosterone levels. This tentative theory is partially supported by lower 2D:4D in girls with congenital adrenal hyperplasia (CAH), higher 2D:4D in individuals with complete androgen insensitivity syndrome (CAIS) and a relationship between 2D:4D and polymorphisms in the androgen receptor. In contrast, individuals with Klinefelter syndrome (KS), who have reduced testosterone secretion throughout life, have a mean 2D:4D value similar to those found in female population norms. Nevertheless, its validity has not yet been conclusively demonstrated and is currently debated. In this context, our aim was to review and debate the relationship between 2D:4D ratio and sex-steroids activity in children, adolescents and young adults.

Thyroid Hemiagenesis from Childhood to Adulthood: Review of Literature and Personal Experience.

Thyroid hemiagenesis (TH) is a rare congenital abnormality of the thyroid gland, characterised by the absence of one lobe. The true prevalence of this congenital abnormality is not known because the absence of one thyroid lobe usually does not cause clinical symptoms by itself. Between 1970 and 2010, 329 cases of TH have been reported. It is interesting to note that most cases have an agenesis of the left lobe (80% of cases) followed by the isthmus (44-50% of cases). Although the female to male ratio was 1:1.4 in 24,032 unselected 11-to 14-yr-old schoolchildren from South-eastern Sicily, several other reports have documented a higher prevalence in women, which may indicate a possible gender association. Most cases of TH are diagnosed when patients present a lesion in the functioning lobe. The functioning lobe of the thyroid gland can be a site of pathological changes similar to a normally developed gland and may present a spectrum of diseases like multinodular goiter, colloid goiter, follicular adenoma, thyroiditis, hypothyroidism and hyperthyroidism. In three of our patients, TH was associated with Hashimoto thyroiditis (n = 1) and with subclinical hypothyroidism (n = 2). The frequency of thyroid abnormalities in patients with TH varies with age, due to the longer exposure of the hemi-agenetic gland to TSH overstimulation in older patients. This could explain the controversy about the benign character of this anomaly. Other extrathyroidal lesions, such as parathyroid adenoma or hyperplasia, cervical thymic cysts, ectopic sublingual thyroid gland and thyroglossal duct cyst have been reported with TH. Therefore, systematic follow-up of all identified cases is recommended.

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.

Incidence of testicular microlithiasis in patients with ß-thalassemia major.

We assessed the prevalence of testicular microlithiasis by scrotal ultrasonography in ß-thalassemia major patients older than 10 years and evaluated the association with serum ferritin levels, calcium (Ca), phosphate (Ph), and parathyroid hormone levels (PTH). In this cross-sectional study, 132 male ß-thalassemia major patients from 300 male patients older than 10 years old were randomly evaluated by scrotal ultrasonography. Parathyroid hormone, calcium, phosphate, and serum ferritin levels were also evaluated. All of the patients were urologically asymptomatic. One hundred healthy age-matched subjects were selected as control group. Testicular microlithiasis was found in 16 patients and 1 individual in control group (12.1 vs 1 %; p = 0.003). Testicular microlithiasis was associated with age and high serum ferritin levels, but there was no association between Ca, Ph, and PTH levels; blood transfusion; and oral or subcutaneous iron chelation therapy. Also, there was no significant correlation between hyperparathyroidism, history of viral hepatitis, and splenectomy with testicular microlithiasis. The frequency of testicular microlithiasis in ß-thalassemia major patients was higher than previously reported. A correlation was found between testicular microlithiasis with age and serum ferritin levels, so regular and adequate iron chelator therapy (at least 10-12 h per day for 5-6 days a week) is recommended. We suggest a close observation and treatment with iron-chelating agents of these patients. Since testicular microlithiasis is occasionally associated with germ cell tumors, clinical and sonographic follow-up is recommended.

Cortisol levels in central adrenal insufficiency: light and shade.

Evaluating children or adolescents with central adrenal insufficiency (CAI) is a difficult task in clinical practice, especially in subjects with hypothalamic-pituitary diseases and partial ACTH deficiency, or in those with recent pituitary surgery or brain irradiation when the adrenal cortex may still be responsive to stress. In 2008, a meta-analysis reported a three-step approach for evaluating patients at risk for CAI with no acute illness. In particular, the authors recommended the evaluation of morning cortisol, a low dose ACTH test (LDST) and the "gold standard" insulin tolerance test or metyrapone test if the low LDCT was not diagnostic. Cortisol and ACTH secretion exhibit significant fluctuation throughout the day. The reference ranges supplied by labs are so wide that they only flag up extremely low cortisol levels. Interpreting the results correctly can be difficult for a physician without an experience in adrenal dysfunctions. The lack of uniformity in these cut-off levels could in part be attributed to differences in study populations, variability of dynainic tests, the use of different serum cortisol assays and dissimilar cut-off peak serum cortisol response indicative of a normal axis response and the difference in the clinical context in which the studies were done. Therefore, Laboratories have to advertise the need to establish reference values for given populations, both for basal or stimulated hormone levels. Failure to apply this rule may elicit false-positive and more critically, false-negative results. LDST (1 pg synthetic ACTH as iv bolus with measurement of serum cortisol) has been proposed as a sensitive test for the diagnosis of CAl. However, the advantage of LDST compared with the high dose test may be offset by the technical difficulties inherent to dilution of 250 pg ampoules. Clinical judgment remains imperative especially regarding the use of glucocorticoid supplementation during extreme stress.

Precocious Puberty Following Traumatic Brain Injury in Early Childhood: A Review of the Literature.

AIMS OF THE REVIEW: The intent of the current manuscript is to review the cases of central precocious puberty (CPP) in early childhood following traumatic brain injury (TBI). SEARCH OF THE LITERATURE: The MEDLINE database was accessed through PubMed in April 2015. Results were not restricted to the date and language of the articles. For the first search we utilized MeSH terms "precocious puberty" in conjunction with "traumatic brain injury" and with "endocrine consequences". Reference lists were reviewed and relevant papers were also consulted to find additional studies and data. In selected cases the corresponding author was contacted by email. RESULTS: In our systematic review, only a few case reports or small case series have highlighted a link between TBI and hypothalamic-pituitary hormone abnormalities. Fourteen reported children were females and 8 were males. The majority of patients reported had severe TBI, assessed by Glasgow Coma Scale or structural injury (skull fractures, intracranial hemorrhage or cerebral injury) reported on computerized tomography or magnetic resonance imaging scans. The pathogenic mechanism of precocious puberty has not yet been determined. An increased pressure on the hypothalamic-pituitary area with loss of normal childhood hypothalamic inhibition of pituitary gonadotropins could be one of the factors responsible for CPP after TBI. CONCLUSIONS: The current review highlights the importance of close clinical follow-up to evaluate the rate of linear growth and pubertal development after TBI. Although, precocious puberty appears to be rare after TBI, prevalence should ideally be assessed by longitudinal follow-up of a large population. Therefore, further multicenter and multidisciplinary studies are required to explore in detail the true incidence and the possible mechanisms of CPP after TBI. Because precocious puberty can be detected on clinical assessment during childhood, a pragmatic approach would be for family physicians to monitor growth and development in children after TBI. Inasmuch as precocity is mediated through the hypothalamic-pituitary pathways, use of LH-RH analogue therapy should be effective in arresting pubertal progression.

Primary Dysmenorrhea in Adolescents: Prevalence, Impact and Recent Knowledge.

BACKGROUND AND OBJECTIVES: Dysmenorrhea is commonly categorized into two types; primary and secondary. Primary dysmenorrhea (PD) is the focus of this review. PD is defined as painful menses with cramping sensation in the lower abdomen that is often accompanied by other symptoms, such as sweating, headache, nausea, vomiting, diarrhea, and tremulousness. All these symptoms occur just before or during the menses in women with normal pelvic anatomy. In adolescents the prevalence of PD varies between 16% and 93%, with severe pain perceived in 2% to 29% of the studied girls. Several studies suggest that severe menstrual pain is associated with absenteeism from school or work and limitation of other daily activities. One-third to one-half of females with PD are missing school or work at least once per cycle, and more frequently in 5% to 14% of them. The wide variation in the prevalence rates may be attributed to the use of selected groups of subjects. Many risk factors are associated with increased severity of dysmenorrhea including earlier age at menarche, long menstrual periods, heavy menstrual flow, smoking and positive family history. Young women using oral contraceptive pills (OCP) report less severe dysmenorrhea. The considerably high prevalence of dysmenorrhea among adolescents verified that this condition is a significant public health problem that requires great attention. SUMMARY OF MAIN RESULTS: Many methodological problems are encountered during quantifying and grading severity of pain related to dysmenorrhea. Quantifying and assessment tools depend on women's self-reporting with potential bias. There is a scarcity of longitudinal studies on the natural history of dysmenorrhea as well as the possible effects of many modifiable risk factors. In addition, the duration of follow-up in the available studies is relatively short. Therefore, several aspects are still open for research. Medical treatment for dysmenorrhea includes anti-inflammatory drugs (NSAIDs), OCP or surgical intervention. The efficacy of conventional treatments using NSAIDs and OCP is high. However, failure rate may reach up to 20% to 25%, besides the occurrence of drug-associated adverse effects. Only 6% of adolescents receive medical advice to treat dysmenorrhea while 70% practice self-management. Unfortunately, some girls even abuse these medications (non-therapeutic high doses) for quick pain relief. The persistence of dysmenorrhea despite the use of OCP and/or NSAIDs drugs is a strong indicator of an organic pelvic disease. This condition mandates an appropriate referral to a gynecologist with proper laparoscopic diagnosis of endometriosis and/or other pelvic diseases. CONCLUSIONS: Dysmenorrhea is an important health problem for adolescents, school and occupational as well as practitioners that adversely affects the daily activities and quality of life for adolescent women. The accurate prevalence of dysmenorrhea is difficult to establish due to the variety of diagnostic criteria and the subjective nature of the symptoms. In adolescents, moderate to severe dysmenorrhea that affects lifestyle and does not respond to medical treatment requires professional attention and proper diagnosis of possible underlying pelvic disease. Therefore, adolescent care providers should be more knowledgeable and actively involved in the care of dysmenorrhea.

Selected highlights of the VIII International Symposium of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) on Growth, Puberty and Endocrine Complications in Thalassaemia. Auditorium of the Sultan Qaboos University (SQU) Muscat (Sultanate of Oman), 20th of December 2014.

The VIII ICET-A International Symposium was held in Muscat (Sultanate of Oman) on the 20th of December, 2014. The symposium included four sessions on a wide range of topics covering growth disorders and endocrine complications in thalassaemia. Despite the fact that endocrine complications are very common in multi-transfused thalassaemia patients a recent survey conducted by the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) in 2014 in Acitrezza (Catania, Italy) showed that the major difficulties reported by hematologists or pediatricians experienced in thalassaemias or thalassaemia syndromes in following endocrine complications included: Lack of familiarity with medical treatment of endocrine complications, interpretation of endocrine tests, lack of collaboration and on-time consultation between thalassaemic centres supervised by haematologists and endocrinologists. Endocrine monitoring of growth, pubertal development, reproductive ability and endocrine function in general are essential to achieve a good quality of life as well as controlling the pain which results from the defects of bone structure, all of which increase with the age of patients. Such comprehensive care is best provided by coordinated, multidisciplinary teams working in expert centres. The multidisciplinary team must include an endocrinologist, preferably someone experienced in the management of hormonal deficiencies caused early in life by transfusion-induced iron overload.

Guidelines for diagnosis and management of Beta-thalassemia intermedia.

Beta-thalassemia intermedia (ß-TI) is a genetic variant of beta-thalassemias with a clinical disorder whose severity falls between thalassemia minor and thalassemia major. Different genetic defects are involved in this disorder and, based on severity of disease, clinical complications like skeletal deformities and growth retardation, splenomegaly, extramedullary hematopoiesis, heart failure, and endocrine disorders may be present in untreated patients. Precise diagnosis and management are essential in these patients for prevention of later clinical complications. Diagnosis of TI is based on clinical and laboratory data. There are some treatment strategies like modulation of gamma-globulin chain production with hydroxyurea or other drugs, transfusion, splenectomy, and stem cell transplantation. Iron chelation therapy is also needed in many of these patients even if they are not transfused. The aim of this manuscript is to review the clinical manifestations, complications, genetic defects, and unmet treatments needs in TI.

Macroorchidism in childhood and adolescence: an update.

In the last 30 years, scientific literature has been enriched with studies which demonstrate the importance of evaluating testis volume to recognize certain genetic and endocrine diseases. Macroorchidism is defined as an increase of testicular volume at least twice the norm for age. In clinical practice, when macroorchidism is suspected, the testicular volume may be evaluated with the Prader orchidometer and/or US, calculated by this formula: L x W x H x 0.71 and the resulting value should be compared with a table of percentiles for each age. Macroorchidism is a relatively uncommon sign; however, when present, it almost always has clinical relevance. Five groups of conditions are reviewed: genetic, endocrine, idiopathic and secondary to neoplasm or testicular torsions. An X-linked mental retardation syndrome must be suspected in all patients with macrorchidism, phenotypic abnormalities, and mental retardation. Furthermore, it is important to identify other males affected in the same family to confirm the X-linked transmission. In these cases, the patient must be referred to specialized cytogenetic centres for determination of fragile sites. Other possible etiologies of macroorchidism are long-standing primary hypothyroidism, adrenal remnants in congenital adrenal hyperplasia, follicle stimulating hormone (FSH)-secreting pituitary macroadenomas, local tumors, lymphomas, and aromatase deficiency. Early diagnosis is important in order to identify and reduce the incidence of X-linked mental retardation in affected families and to begin treatment in endocrinologic, tumoral and surgical disorders.

Are the new automated methods for bone age estimation advantageous over the manual approaches?

Bone Age Assessment (BAA) is performed worldwide for the evaluation of endocrine, genetic and chronic diseases, to monitor response to medical therapy and to determine the growth potential of children and adolescents. It is also used for consultation in planning orthopedic procedures, for determination of chronological age for adopted children, youth sports participation and in forensic settings. The main clinical methods for skeletal bone age estimation are the Greulich and Pyle (GP) and the Tanner and Whitehouse (TW) methods. Seventy six per cent (76%) of radiologists or pediatricians usually use the method of GP, 20% that of TW and 4% other methods. The advantages of using the TW method, as opposed to the GP method, are that it overcomes the subjectivity problem and results are more reproducible. However, it is complex and time consuming; for this reason its usage is just about 20% on a world-wide scale. Moreover, there are some evidences that bone age assignments by different physicians can differ significantly. Computerized and Quantitative Ultrasound Technologies (QUS) for assessing skeletal maturity have been developed with the aim of reducing many of the inconsistencies associated with radiographic investigations. In spite of the fact that the volume of automated methods for BAA has increased, the majotity of them are still in an early phase of development. QUS is comparable to the GP based method, but there is not enough established data yet for the healthy population. The Authors wish to stimulate the attention on the accuracy, reliability and consistency of BAA and to initiate a debate on manual versus automated approaches to enhance our assessment for skeletal matutation in children and adolescents.

Is priming with sex steroids useful for defining patients who will benefit from GH treatment?

Classic criteria for diagnosing GHD include: short stature (height below the third percentile), slow growth velocity, delayed bone age and failure to produce growth hormone in response to two provocative tests. While provocation tests can diagnose complete GHD, debate still exists about of what constitutes a normal or a subnormal GH response in subjects with "idiopathic" short stature or constitutional delay of growth and puberty. It has been suggested that in children with intermediate GH responses to pharmacologic stimuli, a pre-treatment with sex steroids priming may be of value in enhancing the GH response and in helping to clarify the diagnosis, particularly in children with delayed onset of puberty. Nevertheless, the use of priming with sex steroids prior to GH stimulation test in the peripubertal period is still controversial because it is considered an "unphysiologic method" and may mask children with transient GHD. Further studies and uniform guidelines are needed before solving this intriguing puzzle.

Can we Predict Incipient Diabetes Mellitus in Patients with Transfusion Dependent ß-Thalassemia (ß-TDT) Referred with a History of Prediabetes?

Background: Prediabetes and diabetes mellitus (DM) are complications in adult patients with transfusion-dependent ß-thalassemia (ß-TDT), with their incidence increasing with age. Objective: This retrospective observational study describes the glycemic trajectories and evaluates predictive indices of ß-cell function and insulin sensitivity/resistance in ß-TDT patients with prediabetes, both in a steady state and during 3-h oral glucose tolerance test (OGTT), in order to identify patients at high risk for incipient diabetes. Setting: The study was mainly conducted at the Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara (Italy), in collaboration with thalassemia referring centers across Italy. Patients: The study included 11 ß-TDT (aged 15.11-31.10 years) with prediabetes. Methods: The ADA criteria for the diagnosis of glucose dysregulation were adopted. Investigations included evaluating plasma glucose levels and insulin secretion, analyzing glycemic trajectories and indices of ß-cell function, and insulin sensitivity/resistance assessed in steady state and during OGTT. Results: The duration of progression from prediabetes to DM, expressed in years, showed a positive direct correlation with corrected insulin response (CIR-30 = r: 0.7606, P: 0.0065), insulinogenic index (IGI 0-120 = r: 0.6121, P:0.045), oral disposition index (oDI = r: 0.7119, P:0.013), insulin growth factor-1 (IGF-1= r: 0.6246, P: 0.039) and an inverse linear correlation with serum ferritin (SF = r: -0.7197, P: 0.012). The number of patients with 1-hour post-load PG value ≥ 155 mg/dL ( ≥ 8.6 mmol/L) was at -4 years: 4/9 (44.4%); -3 years: 8/9 (88.8%); - 2 years: 7/10 (70 %) and at -1 year: 11/11 (100%) (PG range:162-217 mg/dL). Conclusions: A progressive increase in 1-hour PG in response to OGTT is associated with progressive ß-cell failure, peripheral resistance to insulin action, and reduced oDI and may be considered a relevant marker for incipient DM in ß-TDT patients with prediabetes.