Delayed puberty is defined as the lack of development of secondary sex characteristics in childhood. Based on a review of the literature, delayed puberty can be divided into three main categories: (i) hypergonadotropic hypogonadism (congenital and acquired); (ii) permanent hypogonadotropic hypogonadism (congenital and acquired); and (iii) transient hypogonadotropic hypogonadism [constitutional delay of growth and puberty (CDGP) and functional hypogonadotropic hypogonadism]. CDGP is the most common cause of hypogonadism in both males and females, accounting for 60% and 30% respectively. Testosterone is the primary treatment for male hypogonadism, while estrogen and progesterone are used for female hypogonadism. However, in recent years, physiological induction therapy protocols such as human chorionic gonadotropin (hCG) monotherapy, hCG + follicle-stimulating hormone combined therapy, and gonadotropin-releasing hormone infusion have been recommended for the treatment of hypogonadotropic hypogonadism to increase long-term fertility success. There is no clear consensus on treatment protocols for physiological induction treatment and its effect on fertility. This review will discuss the clinical approach to hypogonadism, as well as traditional and physiological induction protocols.

Disorders of sex development (DSD) are a clinically and genetically highly heterogeneous group of congenital disorders. The most accurate and rapid diagnosis may be possible with a complementary multidisciplinary diagnostic approach, including comprehensive clinical, hormonal, and genetic investigations. Rapid and accurate diagnosis of DSD requires urgency in terms of gender selection and management of the case. Despite the genetic tests performed in current daily practice, the genetic cause is still not elucidated in a significant proportion of cases. Karyotype analysis can be used as a standard for sex chromosome identification. In addition, quantitative fluorescent-polymerase chain reaction or fluorescence in situ hybridization analysis can be used for faster and more cost-effective detection of the sex chromosome and SRY gene. Multiplex ligation-dependent probe amplification, single-gene sequence analysis, next-generation sequence analysis (NGSA), targeted NGSA, whole-exome sequencing, and whole-genome sequencing analyses can be performed according to preliminary diagnoses. Microarray analysis, including array comparative genomic hybridization and single nucleotide polymorphism array, should be performed in cases with syndromic findings and if no pathology is detected with other tests. In DSD cases, the use of optical genome mapping and techniques, which will probably be in daily practice in the near future, may be considered. In conclusion, the clinical and genetic diagnosis of DSD is difficult, and molecular genetic diagnosis is often not available. This has psychosocial and health implications for patients and their families. New genetic techniques, especially those targeting the whole genome, may provide a better understanding of DSD through the identification of little-known genetic causes. This review focuses on conventional genetic and next-generation genetic techniques used in the genetic diagnosis of DSD, as well as possible genetic diagnostic techniques and approaches that may be used in routine practice in the near future.

INTRODUCTION: Previous reports indicate that diabetic ketoacidosis (DKA) rates in Malaysian children with type 1 diabetes mellitus (T1DM) range between 54-75%, which is higher than most European nations. Knowledge of trends and predictors of DKA can be helpful to inform measures to lower the rates of DKA. However, this data is lacking in Malaysian children. Hence, the aim of this study was to determine the predictors and trends of DKA in Malaysian children at the initial diagnosis of T1DM.
METHODS: This cross-sectional study examined demographic, clinical and biochemical data of all newly diagnosed Malaysian children aged 0-18 years with T1DM over 11 years from a single centre. Regression analyses were used to determine predictors and trends.
RESULTS: The overall DKA rate was 73.2%, 54.9% of the DKA cases were severe. Age ≥5 years [odds ratio (OR): 12.29, 95% confidence interval (CI): 1.58, 95.58, p=0.017] and misdiagnosis (OR: 3.73, 95% CI: 1.36, 10.24 p=0.01) were significant predictors of a DKA presentation. No significant trends in the annual rates of DKA, severe DKA nor children <5 years presenting with DKA were found during study period.
DISCUSSION AND CONCLUSION: DKA rates at initial diagnosis of T1DM in Malaysian children are high and severe DKA accounts for a notable proportion of these. Though misdiagnosis and age ≥5 years are predictors of DKA, misdiagnosis can be reduced through better awareness and education. The lack of downward trends in DKA and severe DKA highlights the urgency to develop measures to curb its rates.

INTRODUCTION: The frequency of obesity and poor sleep quality among adolescents is increasing and causes many chronic problems. The objective was to investigate the correlation between body mass index (BMI), sleep quality, sleep duration and social jet lag (SJL) among adolescents.
METHODS: This study was cross-sectional. A cohort of 416 adolescents, ranging in age from 12 to 18 years participated in the study. Adolescents were divided into three groups according to BMI standard deviation score (SDS): adolescents with normal weight, adolescents with overweight and adolescents with obesity. The Pittsburgh Sleep Quality Index (PSQI) questionnaire was used to determine the sleep quality of the adolescents. The calculation of SJL and sleep-corrected SJL was performed.
RESULTS: The mean age of the adolescents was 15.0±2.9 years. There were 222 males (53.4%). SJL and PSQI scores were significantly higher in the adolescents with obesity compared to the adolescents with normal weight and overweight (p<0.001). An analysis of the relationship between the PSQI and BMI SDS revealed a significant positive correlation (r=0.667; p<0.001).
DISCUSSION AND CONCLUSION: Adolescents with obesity have poorer sleep quality and a longer duration of SJL compared to adolescents with normalweight. Moreover, increased SJL was linked to an increase in BMI. Maintaining good sleep quality and reducing SJL may help reduce the risk of obesity.

INTRODUCTION: Central precocious puberty (CPP) is treated with long-acting gonadotropin releasing hormone (GnRH) analogues (GnRHa). Some adult patients undergoing GnRHa treatment experienced prolonged QT syndrome, which is associated with an increased risk of serious cardiac events, such as myocardial infarction, stroke, arrhythmias, and sudden cardiac death.
METHODS: Seventy-four patients, aged between 5 and 11 years and diagnosed with CPP but with no other concomitant disease or medication use, underwent electrocardiogram (ECG) assessment. They had been receiving 3.75 mg leuprolide acetate (Lucrin® Depot) injections every 28 days for at least three months.
RESULTS: The ECGs of all patients showed a corrected QT (QTc) interval within normal limits, consistent with the data for healthy Turkish children of the same age and gender. No other pathological physical examination or ECG findings were observed. Furthermore, there was no significant difference in QTc interval when adjusted for age, anthropometric data, or the duration or cumulative dose of the treatment.
DISCUSSION AND CONCLUSION: The study found no correlation between QTc interval values and age, treatment duration, total cumulative dose, and anthropometric data. These findings suggest that cardiovascular adverse events associated with GnRHa treatment may be related to age and other underlying physiopathological conditions in adults rather than being directly due to the drug.

INTRODUCTION: Osteogenesis imperfecta (OI) consists of a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. The aim was to investigate the molecular genetic etiology and determine the relationship between genotype and phenotype in OI patients using targeted next-generation sequencing (NGS).
METHODS: A targeted NGS analysis panel (Illumina TruSight One) containing genes involved in collagen/bone synthesis was performed on the Illumina Nextseq550 platform in patients with a confirmed diagnosis of OI.
RESULTS: Fifty-six patients (female/male: 25/31) from 46 different families were included. Consanguinity was noted in 15 (32.6%) families. Based on Sillence classification 18 (33.1%) were type 1 OI, 1 (1.7%) type 2, 26 (46.4%) type 3 and 11 (19.6%) type 4. Median body weight was -1.1 (-6.8, - 2.5) standard deviation scores (SDS), and height was -2.3 (-7.6, - 1.2) SDS. Bone deformity affected 30 (53.5%), while 31 (55.4%) were evaluated as mobile. Thirty-six (60.7%) had blue sclera, 13 (23.2%) had scoliosis, 12 (21.4%) had dentinogenesis imperfecta (DI), and 2 (3.6%) had hearing loss. Disease-causing variants in COL1A1 and COL1A2 were found in 24 (52.1%) and 6 (13%) families, respectively. In 8 (17.3%) of the remaining 16 (34.7%) families, the NGS panel revealed disease-causing variants in three different genes (FKBP10, SERPINF1, and P3H1). Nine (23.6%) of the variants detected by NGS panel had not previously been reported and were also classified as pathogenic based on American College of Medical Genetics guidelines pathogenity scores. In ten (21.7%) families, a disease-related variant was not found in any of the 13 OI genes on the panel.
DISCUSSION AND CONCLUSION: Genetic etiology was found in 38 (82.6%) of 46 families by targeted NGS analysis. Furthermore, nine new variants were identified in known OI genes which were classified as pathogenic by standard guidelines.

INTRODUCTION: Hyperglycemia in preterm infants is usually treated with adjustment of glucose intake and, if persistent, with continuous insulin infusion. However, hypoglycemia is a well-known complication of intravenous (iv) insulin treatment. The aim of this study was to evaluate the feasibility of continuous subcutaneous insulin infusion (CSII) in extremely preterm infants.
METHODS: Clinical data from extremely premature infants (<28 weeks of gestation) undergoing CSII treatment for severe hyperglycemia in the neonatal intensive care unit were included. Blood glucose levels during CSII, as well as the nutritional intake and insulin intake were recorded. Data were analyzed and compared to a control group of very preterm infants receiving iv insulin therapy.
RESULTS: Normoglycemia rates were best in the iv insulin-cohort (n=22, 50.3%) compared to the CSII group (n=15, 15.6%). Hypoglycemia was very rare in both groups (0.4% vs. 0.0%). CSII therapy appears to require higher insulin doses compared to continuous iv therapy to achieve a similar effect. Subcutaneous Insulin therapy in extremely preterm infants is feasible, at least for prevention of hypoglycemia. However, dose control needs to be improved.
DISCUSSION AND CONCLUSION: The results justify further model validation and clinical trial research to explore a model-based protocol and the use of CSII in this population.

INTRODUCTION: Obesity is a serious health problem that progressively affects individuals’ lives with comorbidities, such as heart disease, stroke, and diabetes mellitus. Since its prevalence has increased, particularly in children less than five years old, its genetic and environmental causes should be determined for prevention and control of the disease. The aim of this study was to detect underlying genetic risk factors in a family with an exclusively breastfed obese infant.
METHODS: A three-generation family was recruited to be evaluated for obesity. Detailed examinations along with body mass index (BMI) calculations were performed on available family members. Whole exome sequencing (WES) was performed on a 7-month-old obese infant. Bioinformatic analyses were performed on the Genomize SEQ platform with variant filtering at minor allele frequencies <1% for all normal populations. Sanger sequencing was applied in variant confirmation and family segregation.
RESULTS: Neuro-motor developmental features were normal and genetic syndromes were excluded from the index. Early-onset severe obesity (+4.25 standard deviation score weight-for-height) was evident in index case; his father and grandmother were also obese (BMIs 38.1 kg/m2 and 31.3 kg/m2, respectively). WES analysis revealed deleterious variants in SH2B1, PDE11A, ADCY3, and CAPN10 genes previously associated with obesity. All variants were evaluated as novel candidates for obesity, except PDE11A, and family segregation confirmed paternal inheritance.
DISCUSSION AND CONCLUSION: This study confirmed the paternal inheritance of all potentially deleterious obesity-related variants. The cumulative effect of individual variants might explain the obesity phenotype in this family. The infant is recommended to be followed up periodically due to increased risk for later childhood obesity.

INTRODUCTION: Delayed puberty is thought to be common in boys with Duchenne muscular dystrophy (DMD) treated with long term oral glucocorticoid. The aim of this study was to report the frequency of delayed puberty in DMD from examination by a paediatric endocrinologist alongside detailed endocrine investigations.
METHODS: All boys with DMD aged at least 14 years in January 2022 known to the paediatric neuromuscular service (2016-2022) were included. Delayed puberty was defined based on testicular volume and genital staging in comparison to a published puberty nomogram.
RESULTS: Twenty-four out of 37 boys (65%) had evidence of delayed puberty and 23/24 (96%) were on glucocorticoid therapy, all of whom were on daily glucocorticoid. However, 7/13 (54%) with normal timing of puberty were on glucocorticoid; 2/7 (29%) were on the intermittent regimen. Of those who were on daily glucocorticoid therapy at the time of assessment of puberty, 23/28 (82%) had evidence of delayed puberty. In boys with delayed puberty, endocrine investigations showed low luteinizing hormone with undetectable testosterone levels, a pre-pubertal response with lutenizing hormone releasing hormone test and sub-optimal testosterone levels with prolonged human chorionic gonadotropin stimulation.
DISCUSSION AND CONCLUSION: The frequency of delayed puberty in boys with DMD was 65%. Eighty-two percent of adolescent boys with DMD on daily glucocorticoid had evidence of delayed puberty. Biochemical investigations point to functional central hypogonadism in these adolescents. Our data supports the routine monitoring of puberty in boys with DMD.

INTRODUCTION: Secondary osteoporosis is a condition when the underlying disease or its treatment causes the bone mass to decrease and the bone structure to deteriorate, increasing the risk of fracture. The importance of diagnosis and treatment during childhood and adolescence is due to the long-term negative effects. In this study, our objectives were to determine the diagnostic findings, treatment efficacy, and follow-up characteristics of children with secondary osteoporosis.
METHODS: Patients diagnosed with secondary osteoporosis between January 2000 and January 2021 were included. The research was a cross-sectional and descriptive study. Study participants had to be under 18 years of age when the primary underlying disease was diagnosed and had received treatment for secondary osteoporosis. Patient data were collected from patient files. Statistical analysis was performed using Statistical Package for the Social Sciences, version 20.0 (IBM Corp, Armonk, NY, USA).
RESULTS: Sixty-one patients (28 female; 45.9%) were evaluated. The most common underlying primary diseases were inflammatory diseases (57.7%), neuromuscular diseases (26.2%), immunodeficiency (13.1%), acute lymphoblastic leukemia (8.2%), metabolic diseases (8.2%), solid organ transplantation (8.2%), bone marrow transplantation (6.6%) and epilepsy (6.6%). The mean±standard deviation chronological age when secondary osteoporosis was diagnosed was 11.89±4.88 years. Patients were evaluated for osteoporosis at a mean of 6.39±5.13 years after the onset of the underlying primary chronic diseases. Most (78.7%) had a history of one or more chronic drug use, including systemic steroids (59%), chemotherapeutics (23%), immunomodulatory drugs (19.7%), antiepileptic drugs (8.2%), inhaled steroids (4.9%), intravenous immunoglobulin (1.6%), and antituberculosis drugs 1.6%.Bone pain was detected in 49.2%. All patients had vertebral fractures before treatment. Bisphosphonate treatment was given to 45 (73.8%). There was a significant increase in mean bone mineral density (BMD) and bone mineral content six months after treatment (both p<0.001). There was a significant increase in BMD Z-score values for chronological and height age (both p<0.001). Overall mean BMD values increased by 31.15% with treatment. Following bisphosphonate treatment, there was a significant reduction in both fracture number and bone pain (p<0.01). Similar benefits from bisphosphonate treatment were evident in those who did or did not receive steroid treatment.
DISCUSSION AND CONCLUSION: Secondary osteoporosis is a condition that is influenced by many factors, such as the primary disease causing osteoporosis and chronic medication use, especially steroids. If left untreated, osteoporosis may lead to clinically important morbidity (bone pain, fractures, immobilization) and reduced linear growth of bone. When used to treat childhood secondary osteoporosis, bisphosphonates significantly improve BMD and reduced fracture risk.

Temple syndrome is a rare imprinting disorder, caused by alterations in the critical imprinted region 14q32 of chromosome 14. It is characterized by pre- and postnatal growth retardation, truncal hypotonia and facial dysmorphism in the neonatal period. We report an 18-year-old girl with a late diagnosis of Temple syndrome presenting with all typical signs and symptoms including small for gestational age at birth, feeding difficulties, muscle hypotonia and delayed developmental milestones, central precocious puberty, truncal obesity and reduced growth. The patient is the second reported in the literature with signs of clinical and biochemical hyperandrogenism and the first treated with Dehydrocortisone®, with a good response. The clinical diagnosis of this patient was made after long-term follow up at a single center for rare endocrine diseases, and a molecular genetics diagnosis of complete hypomethylation of 14q32 chromosome imprinting center (DLK/GTL2) was recently established. Growth hormone treatment was not given and although precocious puberty was treated in line with standard protocols, her final height remained below the target range. Increased awareness of Temple syndrome and timely molecular diagnosis enables improvement of clinical care of these patients as well as prevention of inherent metabolic consequences.

Insulin-like growth factor-1 (IGF-1) is the main driver of growth during prenatal life and acts through IGF-1 receptor (IGF1R). Patients with IGF1R defects exhibit variable phenotypic features. A 10.9-year-old boy presented with severe short stature, microcephaly, minor dysmorphic features and mental retardation. Genetic analysis for IGF1R revealed heterozygous deletion of the complete IGF1R. At the age of 12.3 years, daily subcutaneous recombinant human growth hormone (rhGH) was started and continued for a total of 5.7 years in two courses with improvement of height velocity as well as final height. Puberty was delayed and eventually he did not achieve full puberty, suggesting partial hypogonadotropic hypogonadism. Hypothyroidism initially developed during rhGH therapy. However, low T4 levels persisted after cessation of rhGH therapy and thus central hypothyroidism is a likely diagnosis. rhGH has partial effect for induction of growth in cases with IGF1R defects. However, long-term treatment with an early initiation may have more beneficial effects. In addition, patients with IGF1R defects should be followed for delayed puberty-hypogonadism, and hypothyroidism.

Reset osmostat (RO) is classified as type C among the four subtypes of the syndrome of inappropriate secretion of antidiuretic hormone based on antidiuretic hormone (ADH) secretion. It is characterized by a lower plasma osmolality threshold for ADH excretion when plasma sodium concentration is reduced. We report the case of a boy with RO and a giant arachnoid cyst (AC). The patient had been suspected of having AC since the fetal period, and a giant AC in the prepontine cistern was confirmed by brain magnetic resonance imaging seven days after birth. During the neonatal period, there were no abnormalities in the general condition or blood tests, and he was discharged from neonatal intensive care at 27 days after birth. He was born with a -2 standard deviation score birth length and mild mental retardation. When he was six years old, he was diagnosed with infectious impetigo and had hyponatremia of 121 mmol/L. Investigations revealed normal adrenal and thyroid functions, plasma hypo-osmolality, high urinary sodium, and high urinary osmolality. The 5% hypertonic saline and water load tests confirmed that ADH was secreted under low sodium and osmolality conditions, and the ability to concentrate urine and excrete a standard water load; therefore, RO was diagnosed. In addition, an anterior pituitary hormone secretion stimulation test was performed, which confirmed growth hormone secretion deficiency and gonadotropin hyperreactivity. Hyponatremia was untreated, but fluid restriction and salt loading were started at 12 years old because of the risk of growth obstacles. The diagnosis of RO is important from the viewpoint of clinical hyponatremia treatment options.

Swyer syndrome is a rare congenital condition that serves as a risk factor for developing germ cell tumors. The condition belongs to the group of 46, XY disorders of sexual development, is characterized by complete gonadal dysgenesis (CGD) and is mostly manifested as delayed puberty and primary amenorrhea during adolescence. Individuals with Swyer syndrome are known to be phenotypically female with normal internal and external female genitalia at birth. 46, XY GD involves a high risk of gonadoblastoma development with malignant potential such that the onset is greatest at or after the event of puberty. This report of a 12-year-old phenotypic female with 46, XY GD, who developed an advanced metastatic seminoma, highlights the rarity of the development of a seminoma in the context of 46, XY CGD.

3M syndrome is an autosomal recessive disorder characterized by short stature and skeletal developmental abnormalities. A Chinese girl with 3M syndrome and a novel OBSL1 (obscurin-like 1 gene) variant is presented. The patient is a 2-year-old girl who presented with short stature and had intrauterine growth retardation and low birth weight. Gene analysis revealed compound heterozygote mutations in the OBSL1 gene: c.458dupG (p.L154Pfs*100) and c.427dupG (p.A143Gfs*111). The c.427dupG mutation is novel. The c.458dupG mutation has been documented in five cases, occurring only in Chinese individuals, suggesting ethnic specificity. In cases of children with short stature presenting with intrauterine growth retardation, low birth weight, and skeletal developmental abnormalities, 3M syndrome should be considered. The c.458dupG mutation may be a hotspot mutation in the Chinese population.

Neonatal diabetes mellitus (NDM) is a disorder characterized by persistent, severe hyperglycemia presenting during the first six months of life. These disorders are rare and the incidence is approximately 1 in 90,000 live births. The aim was to describe the clinical presentation, molecular genetics and outcome of patients with NDM from a single paediatric endocrine center from a low-middle income country, Sri Lanka. A retrospective study was conducted on patients diagnosed with NDM. Medical records were reviewed for demographic data and data on clinical, biochemical and genetic analysis. The majority (96%) who underwent mutation analysis had pathogenic genetic mutations on Sanger sequencing. Permanent NDM (PNDM) was diagnosed in 19 patients with three having a syndromic diagnosis. The most common mutation was in KCNJ11. The majority of patients with PNDM (63%) presented with severe diabetic ketoacidosis. All patients with Transient NDM remitted by six months of age. Nearly half (47%) with PNDM were switched to sulfonylurea therapy with good glycemic control (glycosylated haemoglobin A1c ranged 6-7.5%). Data from the Sri Lankan cohort is comparable with other populations. The majority of cases are due to KCNJ11 mutations resulting in PNDM.