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Introduction: A recent review from 14 Mediterranean and Middle East countries (n =4477, mean age = 16.5 years) showed that the pooled prevalence of delayed puberty / hypogonadism in patients with BTM was 45.6%. Studying the consequences of hypogonadism and the potential benefits versus unwanted side effects of sex-steroid hormone replacement therapy (HRT) in children and adolescents with Beta Thalassemia Major (BTM) represent an important issue for these patients. Objectives: We reviewed the literature (Pubmed, Google scholar, Scopus, Research gate) (1995: 2022) on the consequences of hypogonadism and benefits versus side effects of using sex Steroid therapy (HRT) in hypogonadal adolescents with BTM. Thirty-five papers were included and analyzed. Results: HRT had a variable but significant beneficial effect on improving bone mineral density (BMD), pubertal growth spurt, development of secondary sexual characteristics and subsequently improved quality of life (QOL) in children and adolescents with BTM. Increased side effects of HRT in these patients may occur due to their state of hypercoagulability especially in splenectomized patients and those with cardiomyopathy, chronic hepatitis, and dysglycemia. Gynecomastia and local pain in the site of injection confirmed in a considerable number of males on testosterone therapy. Local reaction to sex steroid patches appeared in around 30% of patients. Based on this review recommendations for using HRT in these patients were updated. Conclusion: Proper and wise use of sex steroid therapy in patients with BTM can significantly improve many consequences of hypogonadism.

Introduction: The placenta expresses significant amounts of insulin and IGF1 receptors at distinct locations on both fetal and maternal surfaces. This makes the IGF1 and the insulin receptor accessible to fetal and/or maternal insulin, IGF1 and IGF2. IGFs are involved in the receptor-mediated regulation of placental growth and transport, and placental angiogenesis. Maternal obesity during gestation mediates significant changes in the metabolism of mothers, placentas as well as fetal growth. Objectives: In obese women. the role of the insulin like growth factor system IGFs, IGF receptors, IGF-binding proteins (IGFBPs) and IGFBP proteases during gestation, and their effect on placental growth and fetal anthropometric changes need further clarification. In this update we reviewed the literature on the detected changes in the maternal and fetal IGFs in relation to placental growth and function and to fetal growth and newborn size in pregnant obese mothers. Eighteen research articles fitted the criteria of this update. Results: Twenty-three research papers were including 2817 pregnant obese and non-obese women (controls) and their babies were selected and reviewed. Results showed that obesity and excessive nutrient intake during gestation increase maternal IGF1and decreases IGBP1. Increased maternal IGF1 and/or its availability due to decreased IGFBP1 can increase the size (weight) and development of the placenta, stimulate mTOR signaling which stimulates protein synthesis, mitochondrial function, and upregulate specific placental amino acid transporter isoforms (amino acids transport), GLUT-1, (glucose transport) and possibly lipid transport to the fetus which can induce fetal IGF1 secretion and lead to overgrowth. Conclusions: In obese women during pregnancy, increased level of IGF1 and/or its availability due to decreased IGFBP1 can increase the size (weight) and development of the placenta, stimulate mTOR signaling which stimulates protein synthesis, mitochondrial function, and upregulate placental transport of amino acids, glucose and possibly fatty acids.

We evaluated the growth patterns in a cohort of infants (n = 120) born large-for-gestational-age (LGA) [birth weight (Bwt)4 kg] from birth to age 3 years of age in comparison with normal age and sex-matched children (WHO).LGA infants had high weight for age Z score (WAZ) at birth that decreased significantly during the first 6 months of life (by a mean of - 0.67 SD) that was followed by significant gain during the following 6 months of life (around + 0.4 SD). These children grew on a higher centile of WAZ with no significant change during the second and third years of life. The prevalence of obesity (WAZ2) increased markedly from 24% at the end of their first year to 34% and 36% at the end of their second and third years of life, respectively. The mean length for age Z score (LAZ) decreased significantly during the first 6 months (by a mean of -0.9 SD) but was maintained at high centile (1 SD) during the second and 3rd years. The weight for length SDS (WLZ) increased significantly during the first 18 months of life and decreases gradually during the second half of the 2nd year and the 3rd year. Their head circumference SDS decreased significantly in the first 6 months and then sustained around the 70th centiles (+1 SD) in the following 18 months.Our study showed that in LGA babies obesity increased progressively after the first year of life to reach 36% at the end of the third year. Therefore, it is important to apply the early nutritional intervention to decrease the occurrence of obesity and reduce later cardiometabolic risks.

Malnutrition may be classified as acute or chronic and by severity into mild, moderate, and severe forms. Features of chronic malnutrition include diminished weight gain, stunted growth, mental apa...

Objectives Some idiopathic short stature (ISS) patients may have varying degrees of insulin-like growth factor 1 (IGFI) deficiency. Others with growth hormone deficiency (GHD) (peak GH Methods We studied the effect of GH therapy (0.035–0.06 mg/kg/day) on linear growth and weight gain per day (WGPD) in children with ISS (n=13) and those with GHD (n=10) who have low pretreatment IGFISDS (IGF SDS Results At presentation, the height standard deviation score (HtSDS) of children with ISS who had low pretreatment IGFISDS was significantly lower compared to the normal IGFI group. The age, body mass index (BMI), BMISDS, peak GH response to clonidine provocation and bone age did not differ between the two study groups. After 1 year of treatment with rhGH (0.035–0.06 mg/kg/day) IGFISDS increased significantly in both groups (p Conclusions IGFI deficiency represents a low anabolic state. Correction of IGFI level (through rhGH and/or improved nutrition) in short children (ISS and GHD) was associated with increased linear growth and WGPD denoting significant effect on bone growth and muscle protein accretion.

Steroids are the main drugs used for the treatment of nephrotic syndrome (NS) in children. We investigated the steroid effect on linear growth and weight gain as well as the prevalence of different metabolic components and dysglycemia in children with NS with multiple relapses for 5 years in relation to the cumulative dose of steroids. Study population and sample size: Data of 30 children with NS were analyzed retrospectively. They received prednisolone treatment as advised by international guidelines. The cumulative dose of prednisolone (CDP) over the 5 years was calculated for each child. Their growth and different metabolic criteria, including impaired fasting glucose (IFG), high LDL and cholesterol, lower HDL, and high blood pressure studied over this period and compared with the data for 66 age-matched obese non-nephrotic children. The mean CDP was 100 ± 63 mg /kg/yr given over an average duration of 5 years. The height-SDS was not affected after 3 years but decreased by -0.4 SD after 5 years. The body mass index-SDS increased from 0.65 to 0.97 and 1.1 after 3 and 5 years, respectively. Obesity and overweight increased from 25% pre-treatment to 59.2% after 5 years of treatment. After 5 years of treatment, IFG was detected in 35 %, hypertension in 40%, high LDL in 77%, and high cholesterol in 80%.In children with frequently relapsing NS, long-term steroid therapy was associated with a higher rate of obesity, short stature as well as the occurrence of different metabolic syndrome (MetS.

The conventional treatment of β-thalassemia (β-TM) patients is based on the correction of anemia through regular blood transfusions and iron chelation therapy. However, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only currently available technique that has curative potential. Variable frequency and severity of long-term growth and endocrine changes after conventional treatment as well as after HSCT have been reported by different centers. The goal of this mini-review is to summarize and update knowledge about long-term growth and endocrine changes after HSCT in patients with β-TM in comparison to those occurring in β-TM patients on conventional treatment. Regular surveillance, early diagnosis, treatment, and follow-up in a multi-disciplinary specialized setting are suggested to optimize the patient's quality of life (www.actabiomedica.it).

Nutrition is one of the most important factors affecting pubertal development. Increasing demands for energy proteins and micronutrients are necessary to cope with the rapid linear pubertal growth and development, change in body composition, and increased physical activity. Adequate nutrition is a key permissive factor for the normal timing and tempo of pubertal development. Severe primary or secondary malnutrition also can adversely delay the onset and progression of puberty. The higher incidence of anorexia nervosa and bulimia in adolescents imposes a nutritional risk on pubertal development. Here we provide an overview of nutritional requirements (macronutrients and micronutrients) necessary to cope with these changes. In addition, we discuss possible nutritional interventions trials and their effects on several aspects of growth and development in undernourished and stunted adolescents, in low- and middle-income countries (LMIC), who require nutritional rehabilitation. This mini-review sums up some important findings in this important complex that links between nutrition, nutritional interventions, and pubertal development.

In Qatar, the prevalence of metabolic syndrome (MetS) in children and adults is increasing in parallel with the markedly increasing trends in obesity rates.The aim of our study was to assess the prevalence of different components of MetS, measure plasma atherogenic indexes (AIP), and to evaluate linear growth in young obese nondiabetic children (5 years) in comparison to older obese children (6-12 years). Methods: We analysed the anthropometric and biochemical profile of 135 random sample obese children who attended to the Paediatric Clinic of Hamad Medical Centre (HGH) in Doha (Qatar) from January 2018 to December 2019.A large proportion of children presented with obesity, around the age of 5 years, were obese at the end of their first year of life (63.8%) and more were obese at the 2 years of age (82.6%). Significantly rapid gain in weight and linear growth occurred during the first 6 months of postnatal life. Moreover, some metabolic risk factors and high AIP occurred more frequently in older obese children compared to young obese children.This study documented the early occurrence of different components of the MetS in young obese children and the progressive increase of their prevalence in older prepubertal children. Most of obese children who presented at or below 5 years of age had significant obesity and rapid linear growth during the first two years (infancy). These two findings pointed out to the necessity to impose early detection and preventive measures on a national scale.

Background: Individuals with Down syndrome (DS) are at an increased risk of developing thyroid disease, primarily autoimmune, with a lifetime prevalence ranging from 13% to 63%. Unfortunately, there are few studies systematically examining the frequency of thyroid disease in very young children. Aim of the study: The aim of the present study was to investigate the prevalence of different thyroid dysfunctions (TD) in a cohort of infants and children with DS and the growth parameters in subjects with normal versus abnormal thyroid function, followed for 3 years. Patients and methods: All children (n = 102; 48 males and 54 females, aged 2.3±3 years) with the diagnosis of DS who were seen at the General Pediatric Clinic of Hamad General Hospital in Doha (Qatar) from 2014 to 2018 were enrolled in our study. We recorded thyroid function and linear growth parameters [BMI, length/height SDS (Ht-SDS) and weight gain/day] and divided them into 3 groups according to their thyroid function. Group 1: (n = 36 subjects) with normal free T4 (FT4) and TSH; Group 2 (n = 44 subjects) with high TSH >5 and 12 mIU/L and/or FT4 1 year; n=55; mean age: 5.5±3.3 years) primary HT was detected in 7/55 (12.7%). Subclinical HT was diagnosed in 20/55 (36.4%) and positive thyroid antibodies were found in 26/55 (47.3%). Before treatment with L-thyroxine, using the CDC growth charts for DS, we found that the groups with high TSH (Groups 2 and 3) were significantly shorter and heavier compared to the group with normal TSH (Group 1). After treatment with L-thyroxine, the Ht-SDS and Wt-SDS did not differ between the two groups. The linear growth of those diagnosed early during the first year of life was compared to growth parameters of children who were diagnosed with thyroid dysfunction later in life. Conclusion: Our data provided more evidence to support the findings that L- thyroxine treatment can improve growth of infants and young DS children with high TSH (>5 mIU/L), especially in those with TSH >12 mIU/L. (www.actabiomedica.it)

Letter to Editor.

Sickle cell disease (SCD) is traditionally associated with growth failure and delayed puberty. Wasting and stunting are still prevalent in children and adolescents with SCD, especially in developing countries. In addition, sperm abnormalities are frequent in males with SCD, with high rates of low sperm density, low sperm counts, poor motility, and increased abnormal morphology. Severe anaemia, vaso-occlusive attacks with ischemic injury to different organs including the pituitary gland and testis, and nutritional factors are incriminated in the pathogenesis of defective growth, puberty, and spermatogenesis. There is great phenotypic variability among patients with SCD. The variability in the clinical severity of SCD can partly be explained by genetic modifiers, including HbF level and co-inheritance of α-thalassaemia. In the past, severe disease led to early mortality. Advancements in treatment have allowed patients with SCD to have a longer and better quality of life. For most patients, the mainstays of treatment are preventive and supportive. For those with severe SCD, three major therapeutic options are currently available: erythrocyte transfusion or exchange, hydroxyurea and hematopoietic stem cell transplantation. In this mini review the authors tried to recognize, delineate, and update knowledge on abnormalities due to SCD from those created by the use of different treatment modalities. (www.actabiomedica.it)

Background: The term double diabetes or “Hybrid Diabetes (HD)” describes diabetes with combined features of type 1 and type 2 diabetes (T2DM). Typically, HD is characterized by insulin resistance, obesity, and the presence of markers of β-cell autoimmunity. Differentiating HD from other forms of diabetes is important for a better understanding of the disease process and course, as well as for an appropriate management plan to prevent future complications. Patients and Methods: We report the clinical and biochemical characteristics of 7 children with HD and the course of their disease including the response to treatment. The data were compared to 59 children with a diagnosis of T2DM. Variables examined included age, height, weight, body mass index (BMI), triglycerides (Tg), high-density lipoprotein (HDL), and blood pressure. The Weiss criteria were used to diagnose metabolic syndrome (MetS). The atherogenic index of plasma (AIP) was calculated from the standard lipid profile. Four autoantibodies against pancreatic β-cell were measured in all patients. Results: Significant clinical and biochemical differences were detected among children with HD versus T2DM. The mean BMI of children with T2DM was significantly higher than for the HD group. At presentation, the mean C peptide level was significantly lower in HD versus T2DM group and 28% presented with diabetic ketoacidosis (DKA). The percentage of those with full criteria of MetS was significantly higher in T2DM versus HD group as well as the percentage of children with high atherogenic index. After a mean duration of 2.3 months from diagnosis, 4/7 of HD patients stopped insulin therapy and 3 patients had a marked reduction in the insulin requirement. During the follow-up (after 15 ±5 months), 5/7 HD patients required an increase in their insulin dose, one was controlled on a markedly low dose of basal insulin and the last patient did not require any insulin therapy for 40 months. Conclusion: Classifying a clinical condition is very important in disease diagnosis and treatment as it can guide clinicians to translate scientific understanding to clinical practice. Appropriate assessment of HD is necessary for early and correct diagnosis. Increasing awareness of HD among the general population and primary care practitioners is necessary for successfully and properly treating this complex disease. (www.actabiomedica.it)

Juvenile ovarian granulosa cell tumors (JGCTs) are described infrequently in pediatrics, and their finding in infants is exceptional. We highlight the presenting symptoms, radiologic images, operative management, and histopathologic findings of a 9-month-old female with isosexual pseudo-puberty. An updated revision of literature in infants below the age of 12 months is also reported. (www.actabiomedica.it)

Introduction: Hyperinsulinemic Hypoglycaemia (HH) is the most common cause of recurrent and persistent hypoglycemia in the neonatal period. Cortisol and GH play an important role as a counterregulatory hormone during hypoglycemia. Both antagonize the peripheral effects of insulin and directly influence glucose metabolism Patients and Methods: We studied cortisol and GH secretion in newborn infants with HH during spontaneous hypoglycemia. In addition, their basal ACTH level was measured and cortisol response to a standard dose ACTH test was performed. Results: Nine newborns with HH were studied during the first 2 weeks of life. During HH, their mean glucose concentration was 1.42 ± 0.7 mmol/L, mean beta hydroxybutyrate level was 0.08 ± 0.04 mmol/L, and mean serum insulin level was 17.78 ± 9.7 μU/mL. Their cortisol and GH levels at the time of spontaneous hypoglycemia were 94.7 ± 83.1 nmol/L and 82.4 ± 29 m IU/L respectively. They had relatively low level of ACTH (range: 14 :72 pg/ml, mean: 39.4 ± 20 pg/mL) during hypoglycemia. All infants had GH concentration > 20 mIU/L at the time of hypoglycemia. All infants underwent ACTH test. Their basal serum cortisol levels did not differ compared to cortisol levels during hypoglycemia, and all had a normal peak cortisol response (> 500 nmol/L) in response to i.v. ACTH stimulation test. Conclusion: Infants with HH have low cortisol response to spontaneous hypoglycemia with normal response to exogenous standard-dose ACTH. Checking hypothalamic-pituitary axis (HPA) axis later in infancy using low dose ACTH may be useful to diagnose persistent HPA abnormalities in these infants. All HH infants had appropriate elevation of GH during hypoglycemia. (www.actabiomedica.it)

Introduction: There is a high prevalence of childhood and adolescent overweight and obesity in Qatar (28 % of females and 24 % of males) with an increasing incidence of type 2 DM in children. We describe the anthropometric and biochemical profile of 100 randomly selected children and prepubertal non-diabetic adolescents with attending the Pediatric clinic of HGH from 2017: 2019. …

Linear growth failure (stunting) in childhood is the most prevalent form of undernutrition globally. The debate continues as to whether children who become stunted before age 24 months can catch up in growth and cognitive functions later in their lives. The potentially irreparable physical and neurocognitive damage that accompanies stunted growth is a major obstacle to human development. This review aims at evaluation and summarizing the published research covering the different aspects of stunting from childhood to adulthood. (www.actabiomedica.it)

Early puberty (EP) in girls is defined as the onset of thelarche that begins after 6 years and before 8 years and/or acceleration in the tempo of pubertal development. The stage of puberty and the ovarian volume at presentation and the effect of treatment with GnRH analogue (GnRHa) on final adult height are still debated.We analyzed the data of 22 girls, who presented early and fast puberty (FEP). The clinical stage of puberty, hormonal levels and the ovarian volume (OV) (measured by ovarian ultra-sonography) at presentation were studied. We recorded the effects of 3 years treatment with GnRHa on their growth in relation to their mid parental height, pubertal progression, and bone maturation.GnRHa therapy decreased the fast progress of puberty, skeletal maturation, and GV/year. It was successful in increasing the predicted final adult height comparable to or surpassing their mid-parenteral height. A larger OV at presentation was associated with reduced Ht-SDS after 3 years of GnRHa treatment. Clearly, a definitive evaluation of the efficacy of GnRHa as treatment for EFP in girls will require expanded and concerted studies.

Metformin is a widely used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The global increase in the prevalence of obesity among children and adolescents is accompanied by the appearance and increasing prevalence of insulin resistance, prediabetes, and type 2 diabetes mellitus (T2DM). In addition, children, and adolescents with premature pubarche and polycystic ovary have considerable degree of insulin resistance. The insulin sensitizing actions of metformin encouraged many investigators and physician to use it as the key drug in these conditions for both prevention and treatment. However, long term-controlled studies are still required to assess the degree and duration of effectiveness and safety of using metformin. This review tries to update physicians about the main and the new therapeutic perspectives of this drug. (www.actabiomedica.it)

Type 1 diabetes mellitus (T1DM) is rare in infants and toddlers and is usually associated with a relatively high mortality when complicated with diabetic ketoacidosis (DKA). In infants, the classical symptoms of DKA are atypical and therefore many infants with DKA are mistreated for infections. We report a case of DKA precipitated by COVID-19 in an 8-month-old infant with newly diagnosed diabetes mellitus. This case is reported in view of its rarity and originality. The relation between T1DM and COVID19 infection is discussed. (www.actabiomedica.it)

Arthrogryposis multiplex congenital, the occurrence of multiple joint contractures at birth, can in some cases be accompanied by insufficient myelination of peripheral nerves, muscular hypotonia, reduced tendon reflexes, and respiratory insufficiency. Recently mutations in the CASPR/CNTN1 complex have been associated with similar severe phenotypes and CNTNAP1 gene mutations, causing loss of the CASPR protein, were shown to cause severe, prenatal onset arthrogryposis multiplex congenita in four unrelated families. Here we report a consanguineous Arab family from Qatar with three children having an early lethal form of arthrogryposis multiplex congenita and a novel frameshift mutation in CNTNAP1. We further expand the existing CNTNAP1-associated phenotype to include profound cerebral and cerebellar atrophy.