Vitamin D and growth hormone in children: a review of the current scientific knowledge.

BACKGROUND: Human growth is a complex mechanism that depends on genetic, environmental, nutritional and hormonal factors. The main hormone involved in growth at each stage of development is growth hormone (GH) and its mediator, insulin-like growth factor 1 (IGF-1). In contrast, vitamin D is involved in the processes of bone growth and mineralization through the regulation of calcium and phosphorus metabolism. Nevertheless, no scientific study has yet elucidated how they interact with one another, especially as a dysfunction in which one influences the other, even if numerous biochemical and clinical studies confirm the presence of a close relationship. MAIN BODY: We reviewed and analyzed the clinical studies that have considered the relationship between vitamin D and the GH/IGF-1 axis in pediatric populations. We found two main areas of interest: the vitamin D deficiency status in patients affected by GH deficit (GHD) and the relationship between serum vitamin D metabolites and IGF-1. Although limited by some bias, from the analysis of the studies presented in the scientific literature, it is possible to hypothesize a greater frequency of hypovitaminosis D in the subjects affected by GHD, a reduced possibility of its correction with only substitution treatment with recombinant growth hormone (rGH) and an improvement of IGF-1 levels after supplementation treatment with vitamin D. CONCLUSIONS: These results could be followed by preventive interventions aimed at reducing the vitamin D deficit in pediatric age. In addition, further research is needed to fully understand how vitamin D and growth are intertwined.

Approach to Neonates and Young Infants with Fever without a Source Who Are at Risk for Severe Bacterial Infection.

INTRODUCTION: Among neonates and infants <3 months of age with fever without a source (FWS), 5% to 15% of cases are patients with fever caused by a serious bacterial infection (SBI). To favour the differentiation between low- and high-risk infants, several algorithms based on analytical and clinical parameters have been developed. The aim of this review is to describe the management of young infants with FWS and to discuss the impact of recent knowledge regarding FWS management on clinical practice. MATERIALS AND METHODS: PubMed was used to search for all of the studies published over the last 35 years using the keywords: "fever without source" or "fever of unknown origin" or "meningitis" or "sepsis" or "urinary tract infection" and "neonate" or "newborn" or "infant <90 days of life" or "infant <3 months". RESULTS AND DISCUSSION: The selection of neonates and young infants who are <3 months old with FWS who are at risk for SBI remains a problem without a definitive solution. The old Rochester criteria remain effective for identifying young infants between 29 and 60 days old who do not have severe bacterial infections (SBIs). However, the addition of laboratory tests such as C-reactive protein (CRP) and procalcitonin (PCT) can significantly improve the identification of children with SBI. The approach in evaluating neonates is significantly more complicated, as their risk of SBIs, including bacteremia and meningitis, remains relevant and none of the suggested approaches can reduce the risk of dramatic mistakes. In both groups, the best antibiotic must be carefully selected considering the clinical findings, the laboratory data, the changing epidemiology, and increasing antibiotic resistance of the most common infectious bacteria.

Role of Small Intestinal Bacterial Overgrowth (SIBO) and Inflammation in Obese Children.

Knowledge of the real incidence of small intestinal bacterial overgrowth (SIBO) in obese children and its role in obesity development seems essential for a more effective approach to the treatment of this condition. In this prospective, single-blind study, presence of SIBO was evaluated in a group of children with overweight/obesity. A blood sample for evaluation of cytokine profile was collected to establish the potential relationship with inflammatory condition and lactulose breath test (LBT) to diagnose SIBO was performed. A total of 36 patients with excess of adipose tissue were recruited. Among them, 16 (44.4%) were overweight and 20 (45.6%) were obese. Overall, 26 (72.2%) children had a positive LBT and were considered suffering from SIBO, 12 (75.0%) among those overweight and 14 (70.0%) among those obese. Measurement of cytokines (IL-1α, IL-1ß, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12p40, IL-12p70, IL-17, IFN-α2, IFN-γ, TNF-α), cytokine antagonists (IL-1ra), chemokines (IP10, MCP-1, MIP1α, MIP1ß), and growth factors (EGF, G-CSF, GM-CSF, and VEGF) secreted in culture supernatants by PHA activated-PBMCs revealed that in the study population proinflammatory cytokines IL-1, IL-6, IL-8, IL-12, IFN-γ, IL-18, and TNF-α were high, whereas anti-inflammatory mediators IL-4 and IL-10 were low. However, no significance difference between children with SIBO and those without were evidenced. Evaluation of relationship of severity of SIBO showed a significant positive relationship between EGF or IFN-α2 and H2 but not CH4 levels and an inverse significant relationship with CH4 but not H2. Despite its limitations and further studies are needed, this study seems to indicate that SIBO is extremely common in overweight and obese children and can be demonstrated not only in severely obese subjects but also in moderately overweight patients. The inflammatory state seems to precede obesity development and SIBO does not seem to have relevance in obesity development, with no relationship found between severity of SIBO and inflammatory state.

The Bones of Children With Obesity.

Excess adiposity in childhood may affect bone development, ultimately leading to bone frailty. Previous reports showing an increased rate of extremity fractures in children with obesity support this fear. On the other hand, there is also evidence suggesting that bone mineral content is higher in obese children than in normal weight peers. Both adipocytes and osteoblasts derive from multipotent mesenchymal stem cells (MSCs) and obesity drives the differentiation of MSCs toward adipocytes at the expense of osteoblast differentiation. Furthermore, adipocytes in bone marrow microenvironment release a number of pro-inflammatory and immunomodulatory molecules that up-regulate formation and activation of osteoclasts, thus favoring bone frailty. On the other hand, body adiposity represents a mechanical load, which is beneficial for bone accrual. In this frame, bone quality, and structure result from the balance of inflammatory and mechanical stimuli. Diet, physical activity and the hormonal milieu at puberty play a pivotal role on this balance. In this review, we will address the question whether the bone of obese children and adolescents is unhealthy in comparison with normal-weight peers and discuss mechanisms underlying the differences in bone quality and structure. We anticipate that many biases and confounders affect the clinical studies conducted so far and preclude us from achieving robust conclusions. Sample-size, lack of adequate controls, heterogeneity of study designs are the major drawbacks of the existing reports. Due to the increased body size of children with obesity, dual energy absorptiometry might overestimate bone mineral density in these individuals. Magnetic resonance imaging, peripheral quantitative CT (pQCT) scanning and high-resolution pQCT are promising techniques for the accurate estimate of bone mineral content in obese children. Moreover, no longitudinal study on the risk of incident osteoporosis in early adulthood of children and adolescents with obesity is available. Finally, we will address emerging dietary issues (i.e., the likely benefits for the bone health of polyunsaturated fatty acids and polyphenols) since an healthy diet (i.e., the Mediterranean diet) with balanced intake of certain nutrients associated with physical activity remain the cornerstones for achieving an adequate bone accrual in young individuals regardless of their adiposity degree.

Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS).

Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive genetic disorder resulting from maternally inherited or de novo mutations involving the androgen receptor gene, situated in the Xq11-q12 region. The diagnosis is based on the presence of female external genitalia in a 46, XY human individual, with normally developed but undescended testes and complete unresponsiveness of target tissues to androgens. Subsequently, pelvic ultrasound or magnetic resonance imaging (MRI) could be helpful in confirming the absence of Mullerian structures, revealing the presence of a blind-ending vagina and identifying testes. CAIS management still represents a unique challenge throughout childhood and adolescence, particularly regarding timing of gonadectomy, type of hormonal therapy, and psychological concerns. Indeed this condition is associated with an increased risk of testicular germ cell tumour (TGCT), although TGCT results less frequently than in other disorders of sex development (DSD). Furthermore, the majority of detected tumoral lesions are non-invasive and with a low probability of progression into aggressive forms. Therefore, histological, epidemiological, and prognostic features of testicular cancer in CAIS allow postponing of the gonadectomy until after pubertal age in order to guarantee the initial spontaneous pubertal development and avoid the necessity of hormonal replacement therapy (HRT) induction. However, HRT is necessary after gonadectomy in order to prevent symptoms of hypoestrogenism and to maintain secondary sexual features. This article presents differential clinical presentations and management in patients with CAIS to emphasize the continued importance of standardizing the clinical and surgical approach to this disorder.

Corticosteroids in Moderate-To-Severe Graves' Ophthalmopathy: Oral or Intravenous Therapy?

BACKGROUND: Ophthalmopathy is a rare extra-thyroid manifestation of Graves' disease, in paediatrics. Intravenous corticosteroids are the main treatment of moderate-to-severe Graves' orbitopathy. In this paper, we describe a moderate-to-severe active Graves' ophthalmopathy in a child and the response to oral therapy with prednisone. CASE PRESENTATION: A nine-year-old male child suffering for a few months, from palpitations, tremors, and paresthesia was hospitalized in our Pediatric Clinic. At admission, the thyroid function laboratory tests showed hyperthyroidism with elevated free thyroxine (FT4) and free triiodothyronine (FT3) levels and suppressed thyroid-stimulating hormone (TSH) levels. These findings, combined with the clinical conditions-an ophthalmologic evaluation (that showed the presence of exophthalmos without lagophthalmos and visual acuity deficiency), thyroid ultrasound, and TSH receptor antibody positivity-led to a diagnosis of Graves' disease. Therefore, methimazole was administered at a dose of 0.4 mg/kg/day. After 4 months, thyroid function was clearly improved, with normal FT3 and FT4 values and increasing TSH values, without adverse effects. Nevertheless, an eye examination showed ophthalmopathy with signs of activity, an increase in the exophthalmos of the right eye with palpebral retraction, soft tissue involvement (succulent and oedematous eyelids, caruncle and conjunctival hyperaemia and oedema) and keratopathy, resulting from exposure. We began steroid therapy with oral administration of prednisone (1 mg/kg/day) for four weeks, followed by gradual tapering. After one week of therapy with prednisone, an eye assessment showed reduced retraction of the upper eyelid of the right eye, improvement of right eye exophthalmometry and reduction of conjunctival hyperaemia. After four weeks of therapy with prednisone, an eye assessment showed reduction of the right palpebral retraction without conjunctival hyperaemia and no other signs of inflammation of the anterior segment; after twelve weeks, an eye assessment showed a notable decrease in the right palpebral retraction and the absence of keratitis, despite persisting moderate conjunctival hyperaemia. No adverse event associated with steroid use was observed during the treatment period and no problem in compliance was reported. CONCLUSION: Prednisone seems a better choice than intravenous corticosteroids, for treating moderate-to-severe and active Graves' ophthalmopathy, keeping in mind the importance of quality of life in pediatric patients.

Growth Hormone (GH) Therapy During the Transition Period: Should We Think About Early Retesting in Patients with Idiopathic and Isolated GH Deficiency?

To investigate growth hormone (GH) secretion at the transition age, retesting of all subjects who have undergone GH replacement therapy is recommended when linear growth and pubertal development are complete to distinguish between transitional and persistent GH deficiency (GHD). Early retesting of children with idiopathic and isolated GHD (i.e., before the achievement of final height and/or the adult pubertal stage) can avoid possible over-treatment. Here, we report data from our population with idiopathic and isolated GHD to encourage changes in the management and timing of retesting. We recruited 31 patients (19 males) with idiopathic GHD who received recombinant GH (rGH) for at least 2 years. All of the patients were retested at the transition age at least 3 months after rGH discontinuation. Permanent GHD was defined as a GH peak of <19 ng/mL after administration of growth hormone⁻releasing hormone (GHRH) + arginine as a provocative test. Permanent GHD was confirmed in only five of 31 patients (16.13%). None of these patients presented low serum insulin-like growth factor (IGF)-1 levels (<-2 standard deviation score (SDS)). Only one male patient with an IGF-1 serum level lower than -2 SDS showed a normal GH stimulation response, with a GH peak of 44.99 ng/mL. Few patients with idiopathic and isolated GHD demonstrated persistence of the deficit when retested at the transition age, suggesting that the timing of retesting should be anticipated to avoid overtreatment.

Hashimoto's Disease and Thyroid Cancer in Children: Are They Associated?

Hashimoto's thyroiditis (HT) is the most common cause of thyroid disease in children and adolescents. Along with significant modifications of thyroid function, HT in pediatric age can be accompanied by relevant thyroid structural alterations. Over time, benign thyroid nodules, carcinoma and, rarely, primary non-Hodgkin lymphoma can develop. However, the relationships between HT and neoplasms are poorly defined. The main aim of this paper is to discuss what is presently known regarding the coexistence of HT and thyroid tumors. Moreover, we attempt to define the pathogenesis of cancer development in children with HT. Literature analysis showed that despite its rarity and relatively promising prognosis, thyroid cancer is associated with HT. Although not all reasons for the coexistence of these diseases are clearly defined, children with HT should be considered at higher risk for thyroid cancer development. Strict correlations between high levels of serum TSH and anti-thyroid antibodies with cancer must be remembered. The same is true for the presence of nodules, especially if multiple nodules are present and ultrasonography and thyroid fine needle aspiration cytology should be promptly used in uncertain cases.

Up-To-Date Review About Minipuberty and Overview on Hypothalamic-Pituitary-Gonadal Axis Activation in Fetal and Neonatal Life.

Minipuberty consists of activation of the hypothalamic-pituitary-gonadal (HPG) axis during the neonatal period, resulting in high gonadotropin and sex steroid levels, and occurs mainly in the first 3-6 months of life in both sexes. The rise in the levels of these hormones allows for the maturation of the sexual organs. In boys, the peak testosterone level is associated with penile and testicular growth and the proliferation of gonadic cells. In girls, the oestradiol levels stimulate breast tissue, but exhibit considerable fluctuations that probably reflect the cycles of maturation and atrophy of the ovarian follicles. Minipuberty allows for the development of the genital organs and creates the basis for future fertility, but further studies are necessary to understand its exact role, especially in girls. Nevertheless, no scientific study has yet elucidated how the HPG axis turns itself off and remains dormant until puberty. Additional future studies may identify clinical implications of minipuberty in selected cohorts of patients, such as premature and small for gestational age infants. Finally, minipuberty provides a fundamental 6-month window of the possibility of making early diagnoses in patients with suspected sexual reproductive disorders to enable the prompt initiation of treatment rather than delaying treatment until pubertal failure.

Rhabdomyolysis in a Young Girl with Van Wyk-Grumbach Syndrome due to Severe Hashimoto Thyroiditis.

Background: Autoimmune hypothyroidism (Hashimoto thyroiditis; HT) is the most common postnatal thyroid disease. Clinical manifestations of HT vary according to disease severity. Due to the pleiotropic effects of thyroid hormone, less common signs and symptoms of HT can occur, leading to a delay in diagnosis. Case presentation: A 9-year-old girl of Indian origin was admitted for a one-week history of widespread myalgia, fatigue, muscle weakness, difficulty walking, and a significant increase in weight (approximately 2 kg) without any changes in daily habits. The only relevant medical history was several intermittent vaginal bleeding episodes since four years of age. Breast development was consistent with Tanner stage 2 without pubic or axillary hair; while height and weight were at the 10th percentile and the 38th percentile; respectively. Bone age from a left wrist X-ray was delayed 1 year. Pelvic ultrasonography revealed a uterine body/neck ratio of >1 (pubertal stage) and multifollicular ovaries. Her external genitalia had a childlike appearance. Laboratory examinations showed an increased thyroid-stimulating hormone, decreased free thyroxine, and positive anti-thyroglobulin antibody titres, as well as elevation of creatine phosphokinase, myoglobin, lactate dehydrogenase, serum aspartate aminotransferase, hypercholesterolemia, and a basal serum prolactin near the upper limit of normal. Follicle stimulating hormone and estradiol were slightly and significantly elevated, respectively. Thyroid ultrasound showed an increased gland size with irregular echostructures and high vascularization. Levothyroxine replacement therapy led to complete normalization of clinical and laboratory findings, including rhabdomyolysis indices. No further vaginal bleeding episodes were reported. Conclusion: This case report highlights how various can be the clinical picture of HT in children, and how rare clinical manifestations can be the only signs of disease at presentation leading to delayed diagnosis and treatment. In this girl, a never-described association of Van Wyk-Grumbach syndrome and acute rhabdomyolysis in a young girl with previously unrecognized HT is described. The importance of recognizing the signs and symptoms of rare complications of HT in order to begin appropriate therapy is stressed.

Inhibin B in healthy and cryptorchid boys.

BACKGROUND: Cryptorchidism, the most common male genital abnormality observed in paediatrics, might often be associated with long-term functional consequences and can even reoccur after a successful orchidopexy. Serum markers that identify cryptorchid boys with gonadal dysfunction early should be useful in a decision-making process. Inhibin B, produced during all of childhood but altered in cryptorchid subjects, appears strictly related to Sertoli cells, and its levels directly reflect the status of the testis germinative epithelium. Unfortunately, its precise roles in bilateral and unilateral cryptorchidism are still debated and being unravelled. Herein, we report the most current knowledge about inhibin B in both healthy boys and those with cryptorchidism to discuss and clarify its potential clinical applications. DISCUSSION: Inhibin B represents a simple and repeatable serum marker and it seems to well asses the presence and function of the testicular tissue. Testicular tissue in prepubertal age is largely made up of Sertoli cells; inhibin B, coming from working Sertoli cells, allows to indirectly evaluate their function. Besides, inhibin B is produced throughout childhood, even before puberty, in contrast with central hormones, and it is not influenced by androgens during puberty, in contrast with other testicular hormones. Although further studies are needed, low levels of inhibin B have been related with low testicular score and/or with consistent alterations of testicular parameters at histological examination. This means that inhibin B could be an indirect marker of testicular functions that could even replace testicular biopsies, but current data are inconsistent to confirm this potential role of inhibin B in cryptorchidism. CONCLUSION: Inhibin B represents an effective candidate for early identification of testicular dysfunction after orchidopexy for cryptorchidism. Unfortunately, current data cannot exactly clarify the real role of inhibin B as a predictor of future testicular function in cryptorchidism and future long-term follow-up studies, with repeated inhibin B checks both in cryptorchid and in formerly cryptorchid children and adolescents, will permit to assess if previous normal levels of inhibin B would match with future normal pubertal development and fertility potential.

Report of a Novel SHOX Missense Variant in a Boy With Short Stature and His Mother With Leri-Weill Dyschondrosteosis.

Heterozygous mutations in the SHOX gene or in the upstream and downstream enhancer elements are associated with 2-22% of cases of idiopathic short stature (OMIM #300582) and with 60% of cases of Leri-Weill dyschondrosteosis (OMIM #127300) with which female subjects are generally more severely affected. Approximately 80-90% of SHOX pathogenic variants are deletions or duplications, and the remaining 10-20% are point mutations that primarily give rise to missense variants. The clinical interpretation of novel variants, particularly missense variants, can be challenging and can remain of uncertain significance. Here, we describe a novel missense variant (c.1044 G>T, p.Arg118Met) in a Moroccan boy with a disproportionately short stature and without any radiological traits or bone deformities and in his mother, who had a disproportionately short stature and a Madelung deformity. This variant has not been reported to date in the updated SHOX allelic variant or Human Gene Mutation Databases nor is it listed as a polymorphism in the ExAC browser, dbSNP, or 1000G. This mutation was predicted to be deleterious by three different bioinformatics tools since it modifies an amino acid in a highly conserved DNA-binding domain of the SHOX protein. Based on this evidence, the patient was treated with recombinant human growth hormone.

Pericardial Effusion as a Presenting Symptom of Hashimoto Thyroiditis: A Case Report.

Background: Hashimoto thyroiditis (HT) is the most frequent cause of acquired hypothyroidism in paediatrics. HT is usually diagnosed in older children and adolescents, mainly in females and is rare in infants and toddlers with cardiac involvement, including pericardial effusion, that can be found in 10% to 30% of adult HT cases. In this paper, a child with HT and pericardial effusion as the most important sign of HT is described. Case presentation: A four-year-old male child suffering for a few months from recurrent abdominal pain sometimes associated with vomiting underwent an abdominal ultrasound scan outside the hospital. This led to the identification of a significant pericardial effusion. At admission, his family history revealed that both his mother and maternal grandmother suffered from HT and that both were treated with l-thyroxine (LT4). The clinical examination did not reveal any pathological signs other than a palpable thyroid. His weight was 21 kg (78th percentile), his height was 101.8 cm (12th percentile) and his body max index (BMI) was 20.26 (96th percentile). On a chest radiograph, his heart had a globular appearance and the lung fields were normal. An echocardiography confirmed and determined the effusion amount (max, 23 mm; 600 mL) with light impairment of the heart kinetics. The ECG showed sinus bradycardia with a normal ST tract. Based on the blood test results, an infectious cause of the pericardial fluid excess was considered unlikely. Thyroid function testing revealed very high thyrotropin (TSH, 487 µIU/mL; normal range, 0.340-5.600 µIU/mL) and low serum-free thyroxine (fT4, 0.04 ng/dL; normal range, 0.54-1.24 ng/dL) levels. High thyroid peroxidase antibody titres in the blood were evidenced (>1500 UI/L; normal values, 0.0-9.0 UI/L). The thyroid ultrasound was consistent with thyroiditis. HT was diagnosed, and LT4 replacement therapy with levothyroxine sodium 1.78 µg/kg/die was initiated, with a gradual increase of the administered dose. The treatment was successful because a complete regression of the effusion after one month was evidenced, with a substantial modification towards normality of the thyroid function tests. One year later, the substitutive therapy led to complete normalization of the thyroid function indexes. A slight reduction of weight (BMI, 17.60 for age) and an increase of the velocity of height growth were evidenced. Conclusions: When fluid is identified in the pericardial space and pericarditis of unknown origin is diagnosed, the thyroid function should be immediately evaluated to prescribe substitutive hormonal therapy if necessary and thereby avoid overt hypothyroidism development and the risk of cardiac tamponade.

The Effect of Bisphenol A on Puberty: A Critical Review of the Medical Literature.

Many scientific studies have revealed a trend towards an earlier onset of puberty and have disclosed an increasing number of children that display precocious puberty. As an explanation, some authors have considered the global socio-economic improvement across different populations, and other authors have considered the action of endocrine disrupting chemicals (EDCs). Among these, bisphenol A (BPA), an aromatic compound largely used worldwide as a precursor of some plastics and chemical additives, is well known for its molecular oestrogen-like and obesogenic actions. We reviewed the medical literature of the previous 20 years that examined associations between BPA exposure and the age of puberty in humans, considering only those referring to clinical or epidemiological data. Of 19 studies, only 7 showed a correlation between BPA and puberty. In particular, the possible disruptive role of BPA on puberty may be seen in those with central precocious puberty or isolated premature breast development aged 2 months to 4 years old, even if the mechanism is undefined. Some studies also found a close relationship between urinary BPA, body weight, and early puberty, which can be explained by the obesogenic effect of BPA itself. The currently available data do not allow establishment of a clear role for BPA in pubertal development because of the conflicting results among all clinical and epidemiological studies examined. Further research is needed to fully understand the potential role of exposure to EDCs and their adverse endocrine health outcomes.

Valproic Acid Metabolism and its Consequences on Sexual Functions.

BACKGROUND: Valproic acid (VPA) is a broad spectrum antiepileptic drug (AED) that is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalised epilepsies. Available data suggest that menstrual disorders and certain endocrine manifestations of reproductive system disorders may be more common in women treated with VPA than in those treated with other AEDs. METHODS: A PubMed search for MEDLINE was undertaken to look for studies using the terms "VPA metabolism", "VPA and sexual functions in men", "VPA and sexual functions in women" and "VPA metabolism and endocrine disorders" as key words. The period covered was approximately 20 years. RESULTS: In women, VPA medication is associated with hyperandrogenism, polycystic ovary/polycystic ovarian syndrome, menstrual disorders and ovulatory failure. Men on VPA therapy show abnormalities in androgens blood levels, sperm motility and erectile dysfunctions. VPA negatively affects the release of luteinizing hormone, follicle stimulating hormone and prolactin but also the drug interferes in peripheral endocrine hormones. Its broad inhibitory action on cytochrome and glucuronidation systems can lead to high serum concentration of testosterone, androstenedione and dehydroepiandrosterone sulfate. VPA-dependent obesity and hyperinsulinemia can further contribute to an increase in sexual dysfunctions. CONCLUSIONS: VPA interferes with the endocrine system at multiples levels causing several reproductive and sexual dysfunctions in women and men with epilepsy, especially when administered in pubertal age. Since VPA is a first line AED both in children and adult with epilepsy and long-term medication with this drug is sometimes necessary, it is very important for physicians to implement strict monitoring of patients taking VPA in order to identify these kinds of side effects at an early stage.