Metabolic bone disease (MBD) is an important cause of morbidity in premature, very low birth weight (VLBW) and sick infants and, if left undiagnosed, may lead to structural deformities and spontaneous fractures. MBD is defined as impaired bone mineralization in a neonate with lower than expected bone mineral levels in either a fetus or a neonate of comparable gestational age and/or weight, coupled with biochemical abnormalities with or without accompanying radiological manifestations. MBD has been reported to occur in 16% to 40% of extremely low birth weight neonates and presents by 6-16 weeks after birth. Insufficient calcium and phosphorous stores during the phase of accelerated growth predispose to MBD in neonates along with the use of some medications such as caffeine or steroids, prolonged parenteral nutrition and chronic immobilization. Enhanced physical activity in preterm infants facilitates bone mineralization and weight gain. Biochemical abnormalities tend to worsen significantly, as the severity of disease progresses. These abnormalities may include hypocalcemia, hypophosphatemia, hyperphosphatasia and secondary hyperparathyroidism. In addition, urinary phosphate wasting and hypovitaminosis D can be additional complications. Conversely, biochemical abnormalities may not be accompanied by rachitic changes. Newer diagnostic modalities include non-invasive bone densitometry by quantitative ultrasound over the mid-tibial shaft. The management of MBD includes adequate calcium, phosphorous and vitamin D supplementation, along with optimum nutrition and physical activity. Similarly, preventive strategies for MBD should target nutritional enhancement in combination with enhanced physical activity. MBD usually results in preventable morbidity in preterm and VLBW neonates. Treatment consists of optimum nutritional supplementation and enhanced physical activity.

Cushing’s syndrome (CS) is rare in childhood and adolescence. The most common paediatric cause of CS is exogenous administration of glucocorticoids; either topical, inhaled or oral corticosteroids. Endogenous causes can be classified into adrenocorticotropic hormone (ACTH) independent and ACTH dependent causes. Herein, we report our experience of managing a 12 year old girl who presented with features of CS and was found to have an ectopic, ACTH-secreting bronchial carcinoid tumour, which was resected surgically. Our patient was managed successfully by multidisciplinary approach and has recovered from hypertension and Cushing’s habitus. The English language literature was searched from 2019 back, using PubMed, Google and Google Scholar. Keywords used for the search were; “Ectopic ACTH syndrome (EAS) in children”, “bronchial carcinoid in children” and “Cushing’s Syndrome in children”. Children with bronchial carcinoid tumours causing EAS were identified. Case variables such as age, sex, type of carcinoid, investigations, surgery, recurrences and outcome were reviewed. Fourteen cases of paediatric bronchial carcinoid producing ACTH were found with a mean age of 15.8 years and female preponderance. Most of the patients had a right lung lesion and histological appearance was typical of carcinoid tumour. Bronchial carcinoid is extremely rare in children and only 4% are associated with CS. The postoperative treatment of CS is challenging with a high prevalence of hypertension, increased body mass index and visceral fat mass, impaired cognitive function and decreased quality of life. A careful follow up is indispensable for monitoring recurrence of carcinoid and complete remission of CS.

Objective: Gender assignment in infants and children with disorders of sex development (DSD) is a stressful situation for both patient/families and medical professionals.
Methods: The purpose of this study was to investigate the results of gender assignment recommendations in children with DSD in our clinic from 1999 through 2019.
Results: The mean age of the 226 patients with DSD at the time of first admission were 3.05±4.70 years. 50.9% of patients were 46,XY DSD, 42.9% were 46,XX DSD and 6.2% were sex chromosome DSD. Congenital adrenal hyperplasia (majority of patients had 21-hydroxylase deficiency) was the most common etiological cause of 46,XX DSD. In 46,XX patients, 87 of 99 (89.7%) were recommended to be supported as a female, 6 as a male, and 4 were followed up. In 46,XY patients, 40 of 115 (34.8%) were recommended to be supported as a female, and 70 as male (60.9%), and 5 were followed up. In sex chromosome DSD patients, 3 of 14 were recommended to be supported as a female, 9 as a male. The greatest difficulty in making gender assignment recommendations were in the 46,XY DSD group.
Conclusion: In DSD gender assignment recommendations, the etiologic diagnosis, psychiatric gender orientation, expectation of the family, phallus length and Prader stage were effective in the gender assignment in DSD cases, especially the first two criteria. It is important to share these experiences among the medical professionals who are routinely charged with this difficult task in multidisciplinary councils.

Objective: SHOX gene mutations constitute one of the genetic causes of short stature. The clinical phenotype includes variable degrees of growth impairment, such as Langer mesomelic dysplasia (LMD), Léri-Weill dyschondrosteosis (LWD) or idiopathic short stature (ISS). The aim of this study was to describe the clinical features and molecular results of SHOX deficiency in a group of Turkish patients who had skeletal findings with and without short stature.
Methods: Forty-six patients with ISS, disproportionate short stature or skeletal findings without short stature from 35 different families were included. SHOX gene analysis was performed using Sanger sequencing and multiplex ligation-dependent probe amplification analysis.
Results: Three different point mutations (two nonsense, one frameshift) and one whole SHOX gene deletion were detected in 15 patients from four different families. While 4/15 patients had LMD, the remaining patients had clinical features compatible with LWD. Madelung’s deformity, cubitus valgus, muscular hypertrophy and short forearm were the most common phenotypic features, as well as short stature. Additionally, hearing loss was detected in two patients with LMD.
Conclusion: This study has presented the clinical spectrum and molecular findings of 15 patients with SHOX gene mutations or deletions. SHOX deficiency should be especially considered in patients who have disproportionate short stature or forearm anomalies with or without short stature. Although most of the patients had partial or whole gene deletions, SHOX gene sequencing should be performed in suspected cases. Furthermore, conductive hearing loss may rarely accompany these clinical manifestations.

Objective: Neck circumference (NC) is considered to be an alternative screening method for obesity. The aims were: (1) to examine the correlation between body mass index (BMI) and NC; and (2) to determine diagnostic performance including the best cut-off values of NC for identification of overweight and obese Pakistani children.
Methods: The study sample was 7,921 children, aged 5-14 years, by cross-sectional survey carried-out in four major cities of Pakistan. Receiver operating characteristic analysis was used to investigate the diagnostics performance of NC and to determine the optimal cut-off points for identifying children with overweight and obesity.
Results: The mean of each anthropometric variable (i.e., height, weight, BMI and NC) increased with age in both sexes. In the whole sample, NC had a strong positive correlation (r=0.61, p<0.01) with BMI. NC optimal cut-off points for identifying overweight and obesity in Pakistani boys ranged between 25.00 to 30.35 cm and the corresponding values for the girls were 24.00 to 31.62 cm. In the prepubertal period, NC cut-off points indicative overweight, in both boys and girls were 26.36 cm and 25.27 cm, respectively; the corresponding values for obesity were 26.78 cm and 25.02 cm. During puberty, the cut-off values for overweight and obesity respectively were 28.32 cm and 28.57 cm in boys and 28.70 cm and 28.82 cm in girls.
Conclusion: NC may be used as a simple and widely applicable measure for identification of overweight and obesity with reasonable accuracy in Pakistani children.

Objective: Premature thelarche (PT) is defined as isolated breast development in girls before eight years of age. Gonadotropin-releasing hormone (GnRH) stimulation test is sometimes used to distinguish between PT and central precocious puberty (CPP), although the interpretation of the test at early ages is challenging. The objective of this study was to determine the follicle stimulating hormone (FSH) and luteinizing hormone (LH) responses to GnRH stimulation in girls with PT below 3 years of age.
Methods: A standardized GnRH stimulation test, bone age and pelvic ultrasound were evaluated and those without pubertal progression after a minimum of one-year follow up were included in the study.
Results: On GnRH stimulation test, the median (range) baseline LH was 0.29 (0.10-0.74) IU/L, baseline FSH was 4.96 (3.18-7.05) mIU/mL, and the peak median LH was 5.75 (3.31-8.58) IU/L with the peak mean±standard deviation FSH was 40.38±20.37 mIU/mL. Among the patients, 33.3% (n=10) had baseline LH >0.3 IU/L, 67% (n=20) had peak LH >5 IU/l and 16.6% (n=5) >10 IU/L. The mean peak LH/FSH ratio was 0.17±0.09 and was ?0.43 in all participants.
Conclusion: Although consensus statements usually define baseline LH >0.3-0.5 IU/L, peak LH >5 IU/L, and LH/FSH ratios >0.66-1.0 as diagnostic cut-offs for CPP, in children below 3 years of age, the baseline and peak LH values may be similar to pubertal values, possibly due to mini-puberty. A dominant FSH response on GnRH stimulation test is more valuable than the peak LH response in the diagnosis of PT.

Objective: Potent glucocorticoids (GC) cause iatrogenic Cushing’s syndrome (ICS) due to suppression of hypothalamo-pituitary-adrenal (HPA) axis and may progress to adrenal insufficiency (AI). The aim was to review the clinical and laboratory findings of patients with ICS and to investigate other serious side effects.
Methods: The possibility of AI was investigated by low-dose adrenocorticotrophic hormone test. Hydrocortisone was started in patients with adrenal failure.
Results: Fourteen patients (five boys) with ages ranging from 0.19 to 11.89 years were included. The duration of GC exposure ranged from 1 to 72 months. Ten patients were prescribed topical GC and the rest had oral exposure. Moon face and abdominal obesity were detected in all patients. At presentation, 12 of 14 had AI and two infants had hypercalcemia and nephrocalcinosis. Of 11 patients, ultrasonography revealed hepatosteatosis in five. A cream for diaper dermatitis was used in one infant and the active ingredient was listed as panthenol. However, blood and urine steroid analyses revealed that all endogenous steroids were suppressed. Median (range) time to normalization of HPA axis function was 60 (30-780) days.
Conclusion: The majority (85%) of patients had life-threatening AI and two patients had hypercalcemia. These results highlight the serious side-effects of inappropriate use of potent GCs, especially in infants. The recovery of the HPA axis in children might take as long as three years. Parents should be informed regarding the possibility of some products containing unlisted synthetic GC and to be aware of their side effects.

Objective: We aimed to investigate a possible role of the endocrine disruptors phthalates, di-2-ethylhexyl phthalate (DEHP) and mono (2-ethylhexyl) phthalate (MEHP), in polycystic ovary syndrome (PCOS) aetiopathogenesis. We also wished to evaluate the relationship between phthalates and metabolic disturbances in adolescents with PCOS.
Methods: A total of 124 adolescents were included. Serum MEHP and DEHP levels were determined by high-performance liquid chromatography. Insulin resistance was evaluated using homeostasis model assessment-insulin resistance, quantitative Insulin Sensitivity Check Index, fasting glucose/insulin ratio, Matsuda index, and total insulin levels during oral glucose tolerance test. Participants were further subdivided into lean and obese subgroups according to body mass index (BMI).
Results: Sixty-three PCOS and 61 controls, (mean age 15.2±1.5; range: 13-19 years) were enrolled. Serum DEHP and MEHP concentrations were not significantly different between PCOS and control groups. The mean (95% confidence interval) values of DEHP and MEHP were 2.62 (2.50-2.75) µg/mL vs 2.71 (2.52-2.90) µg/mL and 0.23 (0.19-0.29) µg/mL vs 0.36 (0.18-0.54) µg/mL in PCOS and the control groups respectively, p>0.05. Correlation analysis, adjusted for BMI, showed that both phthalates significantly correlated with insulin resistance indices and serum triglycerides in adolescents with PCOS.
Conclusion: Serum DEHP and MEHP concentrations were not different between adolescents with or without PCOS. However, these phthalates are associated with metabolic disturbances such as dyslipidemia and insulin resistance, independently of obesity, in girls with PCOS.

Objective: Dyslipidemia and endothelial dysfunction are common disorders and major causative factors for atherosclerosis in patients with type 1 diabetes mellitus (T1DM). However, their pathophysiology in young patients with T1DM is still under evaluated. We aimed, for the first time, to assess the expression of exosomal micro-RNA 34a (miR-34a) in serum of children and adolescents with T1DM and correlate this expression with markers of dyslipidemia and endothelial dysfunction.
Methods: The study included 120 T1DM patients and 100 control subjects. Assessment of miR-34a was performed using quantitative real-time polymerase chain reaction. Lipid profile was assessed on an automated analyzer and serum endoglin and intracellular adhesion molecule (ICAM) concentrations were measured using immunometric methods.
Results: Relative expression of miR-34a and serum endoglin and ICAM concentrations were higher in patients than controls (p=0.001) and in patients with dyslipidemia (42 patients) compared to patients without dyslipidemia (78 patients) (p=0.01). Linear regression analysis revealed a strong independent association between exosomal miR-34a expression and total cholesterol, low-density lipoprotein, serum endoglin and serum ICAM after adjustment for other cofactors. The utility of miR-34a as an indicator for associated dyslipidemia was tested using receiver operator characteristic curve analysis which revealed area under the curve: 0.73 with confidence interval: 0.63-0.83 and p=0.001.
Conclusion: This was the first study to show the altered expression of exosomal miR-34a among children and adolescents with T1DM. Moreover, association of miR-34a with markers of dyslipidemia and endothelial dysfunction was identified, suggesting that it could play a role in regulation of lipid metabolism and endothelial function in T1DM.

Objective: The Indonesia Basic Health Research 2018 indicates that Indonesian children are still among the shortest in the world. When referred to World Health Organization Child Growth Standards (WHOCGS), the prevalence of stunting reaches up to 43% in several Indonesian districts. Indonesian National Growth Reference Charts (INGRC) were established in order to better distinguish between healthy short children and children with growth disorders. We analyzed height and weight measurements of healthy Indonesian children using INGRC and WHOCGS.
Methods: 6972 boys and 5800 girls (n=12,772), aged 0-59 months old, from Bandung District were measured. Z-scores of length/height and body mass index were calculated based on INGRC and WHOCGS.
Results: Under 5-year-old Indonesian children raised in Bandung are short and slim. Mean height z-scores of boys is -2.03 [standard deviation (SD) 1.31], mean height z-scores of girls is -2.03 (SD 1.31) when referred to WHOCGS indicating that over 50% of these children are stunted. Bandung children are heterogeneous, with substantial subpopulations of tall children. Depending on the growth reference used, between 9% and 15% of them are wasted. Wasted children are on average half a SD taller than their peers.
Conclusion: WHOCGS seriously overestimates the true prevalence of undernutrition in Indonesian children. The present investigation fails to support evidence of undernutrition at a prevalence similar to the over 50% prevalence of stunting (WHOCGS) versus 13.3% (INGRC). We suggest refraining from using WHOCGS, and instead applying INGRC that closely mirror height and weight increments in Bandung children. INGRC appear superior for practical and clinical purposes, such as detecting growth and developmental disorders.

Mutations in the insulin receptor (INSR) gene are associated with insulin resistance and hyperglycaemia. Various autosomal dominant heterozygous INSR mutations leading to hyperinsulinemic hypoglycaemia (HH) have been described in adults and children (more than 3 years of age) but not in the neonatal period. Family 1: A small for gestational age (SGA) child born to a mother with gestational diabetes presented with persistent hypoglycaemia, was diagnosed with HH and responded well to diazoxide treatment. Diazoxide was gradually weaned and discontinued by 8 months of age. Later, the younger sibling had a similar course of illness. On genetic analysis a heterozygous INSR missense variant p.(Met1180Lys) was found in the siblings, mother and grandfather but not in the father. Family 2: A twin preterm and SGA baby presented with persistent hypoglycaemia, which was confirmed as HH. He responded to diazoxide, which was subsequently discontinued by 10 weeks of life. Genetic analysis revealed a novel heterozygous INSR missense variant p.(Arg1119Gln) in the affected twin and the mother. Family 3: An SGA child presented with diazoxide responsive HH. Diazoxide was gradually weaned and discontinued by 9 weeks of age. Genetic analysis revealed a novel heterozygous INSR p.(Arg1191Gln) variant in the proband and her father. We report, for the first time, an association of INSR mutation with neonatal HH responsive to diazoxide therapy that resolved subsequently. Our case series emphasizes the need for genetic analysis and long-term follow up of these patients.

Abetalipoproteinaemia (ABL) is an autosomal recessive disorder characterized by very low plasma concentrations of total cholesterol and triglyceride (TG). It results from mutations in the gene encoding microsomal TG transfer protein (MTTP). A nine-month-old girl was admitted to hospital because of fever, cough, diarrhea and failure to thrive. She had low cholesterol and TG levels according to her age. The peripheral blood smear revealed acanthocytosis. Thyroid function test showed central hypothyroidism. Cranial magnetic resonance imaging revealed the retardation of myelination and pituitary gland height was 1.7 mm. A homozygous novel mutation [c.506A>T (p.D169V)] was detected in the MTTP gene. Vitamins A, D, E, and K and levothyroxine were started. The coexistence of ABL and central hypothyroidism has not previously been reported. A homozygous novel mutation [c.506A>T (p.D169V)] was detected in the MTTP gene.

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological entity characterized by subcortical vasogenic edema presenting with acute neurological symptoms. Common precipitating causes include renal failure, pre-eclampsia/eclampsia, post-organ transplant, and cytotoxic drugs. Hypercalcemia is a rare cause of PRES; most cases occur in the setting of severe hypercalcemia secondary to malignancy or iatrogenic vitamin D/calcium overdose. Primary hyperparathyroidism (PHPT), as a cause of PRES, is an oddity. We report two cases of adolescent PHPT presenting with generalized tonic-clonic seizures and altered sensorium. On evaluation, both had hypertension, severe hypercalcemia (serum calcium 14.1 mg/dL and 14.5 mg/dL, respectively) and elevated parathyroid hormone levels. Magnetic resonance imaging (MRI) revealed T2/fluid-attenuated inversion recovery hyperintensities located predominantly in the parieto-occipital regions, suggestive of PRES. Identification and excision of parathyroid adenoma led to the restoration of normocalcemia. Neurological symptoms and MRI changes improved subsequently. An extensive literature search revealed only four cases of PHPTassociated PRES; none of them being in the pediatric/adolescent age group. The predominant clinical manifestations were seizures and altered sensorium. All had severe hypercalcemia; three had hypertension at presentation, while one was normotensive. Parathyroid adenomectomy led to normalization of serum calcium and resolution of neurological symptoms and radiological changes. Thus, severe hypercalcemia, although rare in PHPT, can lead to hypercalcemic crisis precipitating acute hypertension that can result in cerebral endothelial dysfunction with the breakdown of the blood-brain barrier, culminating in PRES. We therefore recommend that serum calcium levels should be checked in all patients with PRES and that PHPT be regarded as a differential diagnosis in those with underlying hypercalcemia.

Nonketotic-hypoinsulinemic hypoglycemia (NkHH) is a very rare problem charcterized by increase in glucose consumption without hyperinsulinism. This disorder has mainly been reported in cases with AKT2 mutation and rarely in cases with PTEN mutation. In cases with PTEN or AKT2 mutation, there is no effective therapy other than frequent feeding to counter hypoglycemia. The mammalian target of rapamicin (mTOR) inhibitor, sirolimus, has been used in hyperinsulinemic hypoglycemia that was unresponsive to other medical treatment. In the insulin signaling pathway, both AKT2 and PTEN function upstream of mTOR. However, the role of Sirolimus on hypoglycemia in AKT2 and PTEN mutations is unknown. Case 1: Six month-old female with AKT2 mutation [c.49G>A (p.E17K)] and evidence of NkHH. Frequent feeding was unsuccesful in correcting hypoglycemia and her proptosis continued to worsen. Sirolimus treatment was started at three years of age. Subsequently, blood glucose (BG) levels increased to normal levels. Case 2: In a male with PTEN mutation (p.G132V (c.395G>T), persistent NkHH started at 16 years of age (fasting BG: 27 mg/dL, fasting insulin 1.5 mmol/L, while ketone negative). Sirolimus treatment was started and hypoglycemia was succesfully controlled. NkHH is a very rare and serious disorder which is challenging, both for diagnosis and treatment. Additionally, AKT2 and PTEN mutations may result in NkHH. Sirolimus treatment, through mTOR inhibition, appeared to be effectively controlling the peristent hypoglycemia and may be a life-saving therapy in this NkHH due to AKT2 and PTEN mutations.

Pycnodysostosis is a rare autosomal recessive osteosclerotic bone disorder associated with short stature and multiple bony abnormalities. Growth hormone (GH) deficiency may contribute to short stature in about 50% of patients. Available literature has rarely reported other pituitary hormone deficiencies in pyknodysostosis. Though the management remains conservative, recombinant human GH (rhGH) has been tried in selected patients. Here we present a case of pycnodysostosis which was evaluated for associated co-morbidities and found to have multiple pituitary hormone deficiencies. A 7-year-old girl was referred to our centre for evaluation of short stature. On examination, she had frontal and occipital bossing, limited mouth opening, hyperdontia with multiple carries, short and stubby digits and short stature. Investigation revealed dense sclerotic bones with frontal and occipital bossing, non-fusion of sutures with obtuse mandibular angle, non-pneumatised sinuses, small ‘J’ shaped sella turcica, acro-osteolysis of digits and absent medullary cavities. Cathepsin-K gene mutation analysis confirmed the diagnosis of pycnodysostosis. She was screened for associated co-morbidities and was found to have concomitant GH deficiency. Treatment with rhGH brought about an increase of 1 standard deviation score in height over 2 years and also unmasked central hypothyroidism at three months necessitating thyroxine replacement.