Natural history of ENPP1 deficiency: Nationwide Turkish Cohort Study of autosomal-recessive hypophosphataemic rickets type 2.

OBJECTIVE: Autosomal-recessive hypophosphataemic rickets type 2 (ARHR2) is a rare disease that is reported in survivors of generalized arterial calcification of infancy (GACI). DESIGN, PATIENTS AND MEASUREMENT: The objective of this study was to characterize a multicenter paediatric cohort with ARHR2 due to ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) deficiency and with a diagnosis of GACI or GACI-related findings. The clinical, biochemical and genetic characteristics of the patients were retrospectively retrieved. RESULTS: We identified 18 patients from 13 families diagnosed with ARHR2. Fifteen of the patients had an ENPP1 variation confirmed with genetic analyses, and three were siblings of one of these patients, who had clinically diagnosed hypophosphataemic rickets (HRs) with the same presentation. From nine centres, 18 patients, of whom 12 (66.7%) were females, were included in the study. The mean age at diagnosis was 4.2 ± 2.2 (1.6-9) years. The most frequently reported clinical findings on admission were limb deformities (66.6%) and short stature (44.4%). At diagnosis, the mean height SD was -2.2 ± 1.3. Five of the patients were diagnosed with GACI in the neonatal period and treated with bisphosphonates. Other patients were initially diagnosed with ARHR2, but after the detection of a biallelic variant in the ENPP1 gene, it was understood that they previously had clinical findings associated with GACI. Three patients had hearing loss, and two had cervical fusion. After the treatment of HRs, one patient developed calcification, and one developed intimal proliferation. CONCLUSION: ARHR2 represents one manifestation of ENPP1 deficiency that usually manifests later in life than GACI. The history of calcifications or comorbidities that might be associated with GACI will facilitate the diagnosis in patients with ARHR2, and patients receiving calcitriol and phosphate medication should be carefully monitored for signs of calcification or intimal proliferation.

Optical coherence tomography angiography findings in pediatric patients with graves ophthalmopathy.

PURPOSE: The aim of this study was to evaluate peripapillary, macular microvascular structure, and retinal nerve fiber layer (RNFL) thickness profile in children with Graves Ophthalmopathy (GO). MATERIAL AND METHODS: Thirty-six eyes of 18 children with GO were prospectively compared with 40 eyes of 20-age and sex-matched controls. The severity and activity of the disease were evaluated according to the criteria of the European Group on Graves' Ophthalmopathy (EUGOGO) and Clinical Activity Score (CAS). After complete ophthalmologic and endocrinologic examination, all patients underwent optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) measurements. Retinal nerve fiber layer (RNFL) thickness, macular superficial capillary plexus (SCP), deep capillary plexus (DCP), foveal avascular zone (FAZ) area, acircularity index (AI) of the FAZ and peripapillary microvascular structure were analyzed. RESULTS: The mean age was 12.1 ± 2.4 years in the GO group and 11.2 ± 2.6 years in healthy control group (p = 0.11). Duration of disease was 8.9 ± 4.2 months in the GO group. All patients in GO group had mild and inactive ophthalmopathy. In temporal inferior quadrant, RNFL thickness was significantly thinner in the GO group compared to the control group (p = 0.03). No significant difference was seen between groups both peripapillary and macular microvascular structure (all p > 0.05). CONCLUSION: GO has no effect on optic nerve thickness, peripapillary and macular vascular parameters except inferior temporal RNFL in children.

A National Multicenter Study of Leptin and Leptin Receptor Deficiency and Systematic Review.

CONTEXT: Homozygous leptin (LEP) and leptin receptor (LEPR) variants lead to childhood-onset obesity. OBJECTIVE: To present new cases with LEP and LEPR deficiency, report the long-term follow-up of previously described patients, and to define, based on all reported cases in literature, genotype-phenotype relationships. METHODS: Our cohort included 18 patients (LEP = 11, LEPR = 7), 8 of whom had been previously reported. A systematic literature review was conducted in July 2022. Forty-two of 47 studies on LEP/LEPR were selected. RESULTS: Of 10 new cases, 2 novel pathogenic variants were identified in LEP (c.16delC) and LEPR (c.40 + 5G > C). Eleven patients with LEP deficiency received metreleptin, 4 of whom had been treated for over 20 years. One patient developed loss of efficacy associated with neutralizing antibody development. Of 152 patients, including 134 cases from the literature review in addition to our cases, frameshift variants were the most common (48%) in LEP and missense variants (35%) in LEPR. Patients with LEP deficiency were diagnosed at a younger age [3 (9) vs 7 (13) years, P = .02] and had a higher median body mass index (BMI) SD score [3.1 (2) vs 2.8 (1) kg/m2, P = 0.02], which was more closely associated with frameshift variants (P = .02). Patients with LEP deficiency were more likely to have hyperinsulinemia (P = .02). CONCLUSION: Frameshift variants were more common in patients with LEP deficiency whereas missense variants were more common in LEPR deficiency. Patients with LEP deficiency were identified at younger ages, had higher BMI SD scores, and had higher rates of hyperinsulinemia than patients with LEPR deficiency. Eleven patients benefitted from long-term metreleptin, with 1 losing efficacy due to neutralizing antibodies.

Effects of subclinical emotional and behavioral problems on metabolic control in adolescents with type 1 diabetes: Role of maternal and adolescent personality traits.

BACKGROUND: Personality traits of adolescents with type 1 diabetes mellitus (T1DM) and those of their mothers may lead to poor glycemic control through psychiatric comorbidity. However, it is not yet known how the personality traits of adolescents with T1DM and those of their mothers affect metabolic control in the absence of or before the development of psychiatric disorders. We aimed to determine the effects of subclinical emotional and behavioral problems, as well as maternal and own personality traits, on metabolic control in adolescents with T1DM. METHODS: A total of 48 adolescents with diabetes (19 females and 29 males), with a median age of 14 years, who did not meet diagnostic criteria for a psychiatric condition, and their mothers completed the Junior Temperament and Character Inventory (J-TCI) as well as the adolescent and parent forms of the Strengths and Difficulties Questionnaire (SDQ) and the TCI for adults. The mean HbA1c levels measured in the past year were obtained from medical records. RESULTS: Personality traits and the emotional and behavioral difficulties in adolescents with poor metabolic control were similar to those with good metabolic control (p>.05). However, the self-directedness and cooperativeness subscale scores of the TCI completed by the mothers of those in the poor metabolic control group were significantly lower than the others: 25.5 vs. 30.4; t(39)= 3.737, p= .001, and 27.3 vs. 31.5; t(46)= 2.759, p= .008; respectively. CONCLUSION: Our study showed that adolescents' personality and subclinical symptoms were not related to HbA1c levels in the absence of psychiatric comorbidity, while some maternal personality traits were associated with metabolic control. Management of T1DM should be tailored to adolescents and their needs with the proper involvement of mothers.

The effect of GnRH stimulation on AMH regulation in central precocious puberty and isolated premature thelarche.

OBJECTIVES: There is a complex interaction between the anti-müllerian hormone (AMH) and hypothalamic-pituitary-gonadal axis. However, the effect of gonadotropin-releasing hormone (GnRH) stimulation on AMH levels is not clearly known. In the study, we aimed to evaluate the effect of GnRH stimulation on AMH levels in central precocious puberty (CPP) and isolated premature thelarche (PT) groups. METHODS: Sixty-three girls with breast development before the age of 8 were enrolled in the study. GnRH test was performed on all subjects. Blood samples for follicle-stimulating hormone (FSH), luteinizing hormone (LH), and AMH levels were taken at basal, 40th, and 90th minute of GnRH test. Subjects were grouped as CPP and PT group. RESULTS: After GnRH stimulation, AMH levels increased significantly at the 40th minute and the stimulating effect of GnRH on AMH continued till the 90th minute (p: 0.0001). There was a positive correlation between basal and 90th-minute AMH levels (r: 479, p: 0.0001). The highest FSH, LH, and AMH times were significantly different after the GnRH stimulation (p: 0.001, p: 0.001, and p: 0.007). Although the CPP group had a lower basal AMH level than the PT group's basal AMH level; AMH response to GnRH stimulation was not different (p>0.05). CONCLUSIONS: In our study, which examined the effect of GnRH stimulation on AMH levels in early pubertal development disorders for the first time, GnRH stimulated AMH secretion rapidly, correlated with basal AMH. Basal AMH levels were lower in patients with CPP than in those with PT; however, the effect of GnRH stimulation on AMH levels was similar in both groups.

A rare cause of salt-wasting in early infancy: Transient pseudohypoaldosteronism.

Three infants aged between 38 days and 43 days all presented with poor weight gain, hyponatremia, hyperkalemia, and were diagnosed as having urinary tract infections, which were accompanied by urinary tract malformations in our cases. Hydration and infection treatments were given. A few days after admission, hormonal studies revealed normal cortisol and 17-hydroxy progesterone levels and markedly high aldosterone levels, thus the patients were diagnosed as having transient pseudohypoaldosteronism. After the proper treatment was given, the transient pseudohypoaldosteronism resolved. In conclusion, when an infant with urinary tract infection or malformation has electrolyte abnormalities, pediatricians should consider the diagnosis of transient pseudohypoaldosteronism.

Clitoromegaly caused by ovarian stimulation in a preterm newborn: ovarian hyperstimulation syndrome of preterm babies.

BACKGROUND: Preterm ovarian hyperstimulation syndrome (POHS) is an uncommon disorder characterized by prematurity, hypogastric and upper leg swelling, high serum estradiol and gonadotropin levels, and ovarian cysts. Immaturity of the gonadal axis is accepted as the cause. But still, other etiological factors are suspected. CASE: A preterm baby who was born at 24 gestational weeks was referred to our clinic for ambiguous genitalia on day 118 of life. Labia majora and clitoris was edematous. Clitoris length was 1.5 cm. On laboratory evaluation: 17OH-Progesterone: 1.84 ng/ml, dehydroepiandrosterone sulphate (DHEA-S): 139 µg/dl, total testosterone (T.T): 88 ng/dl, luteinizing hormone (LH): 22.5 mIU/l, Follicle stimulating hormone (FSH): 15.7 mIU/l, estradiol (E2): 447 pg/ml. Karyotype analysis was 46, XX. There was a 25x14x12 mm ovarian cyst detected on ultrasound. On follow-up, E2 levels and cyst size increased, and there was 4 mm pericardial effusion on echocardiography at the time. CONCLUSION: In this paper, we present a case with POHS and to discuss possible pathophysiological mechanisms and treatment. This is the first case of POHS developing pericardial effusion.

Serum Fetuin-A and Insulin Levels in Classic Congenital Adrenal Hyperplasia.

Androgens play a pivotal role in non-reproductive organs such as the kidney, heart, liver, and pancreas. As androgen receptors are expressed in pancreatic and liver cells, excess testosterone can result in hypersecretion of insulin and fetuin-A, a protein produced in the liver. The expression of fetuin-A, a natural inhibitor of tyrosine kinase activity in muscle and liver, leads to insulin resistance. In addition, insulin and fetuin-A levels are thought to be affected by drugs such as glucocorticoids (GCs) and fludrocortisone. However, whether fetuin-A and insulin levels are affected by androgens and GCs in patients with classic congenital adrenal hyperplasia (CAH) is unknown. This cross-sectional study included 56 CAH patients and 70 controls. Analyses were stratified by sex and prepubertal/pubertal status to control for potential changes in serum metabolic/inflammatory markers associated with the production of sex steroids. Fasting blood glucose, insulin, triglyceride, total cholesterol, high density lipoprotein-cholesterol, aspartate aminotransferase, alanine aminotransferase, fetuin-A, and high-sensitivity C-reactive protein (hs-CRP) levels were measured in blood samples. In addition, 17α-hydroxyprogesterone, androstenedione, total testosterone, free testosterone, and dehydroepiandrosterone sulfate levels were measured before medication was administered. Insulin and fetuin-A levels were significantly higher in CAH patients than in controls. The unfavourably high levels of these substances exhibited a positive correlation with total and free testosterone. Regression analysis revealed that fetuin-A and free testosterone were the only independent predictors of the insulin level, while insulin and free testosterone levels significantly predicted the fetuin-A level (R2=42.7% and 59.8%). Differences were also observed in triglyceride and hs-CRP levels between the pubertal and prepubertal groups. We conclude that serum fetuin-A and insulin levels may be associated with androgens in CAH patients.

Evaluation of Gonadotropin Responses and Response Times According to Two Different Cut-Off Values in Luteinizing Hormone Releasing Hormone Stimulation Test in Girls.

BACKGROUND: In this study, we aimed to evaluate FSH, LH responses obtained during LHRH-ST according to two different cut-off values, to determine the diagnostic response times, and to find the optimal blood collection times that could reduce the economic and time burden of LHRH-ST. MATERIALS AND METHODS: Patients who underwent LHRH-ST in our clinic with the preliminary diagnosis of precocious puberty (PP) between 01/08/2016 and 31/12/2017 were retrospectively enrolled to the study. In this study 207 girls with PP were included and some of them (102 according to C1 and 139 according to C2) had central PP (CPP). Test response and response times were evaluated according to both cut-off values of stimulated peak LH pubertal responses as 5 mIU/ml (the 1st cut-off = C1) and 3.3 mIU/ml (the 2nd cut-off = C2). RESULTS: Totally, 207 girls with a mean age of 7.5 ± 1.22 (3.4-9.5) years were included in the study. With LHRH-ST; 49.2% (n = 102), 67% (n = 139) of the cases were in pubertal period according to C1, C2, respectively. According to C1; pubertal LH was present in 94.1% (n = 96) of 102 patients who reached pubertal LH value in 45th minutes. The highest pubertal response was obtained in the 45th minute. According to C2, of 139 patients who reached pubertal LH; pubertal LH was determined in 98.5% (n = 137) in the 45th minute. Pubertal LH levels were determined according to both cut-off values in all 27 patients with baseline LH ≥0.31 mIU/ml. CONCLUSION: It was determined that measuring LH at 45th minutes during LHRH-ST was sufficient in 94.1% of the cases according to C1 and 97.1% of the cases according to C2. It was concluded that the 30th, 45th, and 60th minute samples were enough to assess pubertal LH response in 100%of the cases. If the basal LH is found to be ≥0.31 mIU/ml in girls with puberty findings, we recommend that the diagnosis of precocious puberty would be made without performing LHRH-ST.

Effect of gonadotropin-releasing hormone analog treatment on final height in girls aged 6-10 years with central precocious and early puberty.

AIM: To determine the effects of gonadotropin-releasing hormone analog treatment on final height and body mass index in girls with central precocious puberty. MATERIAL AND METHODS: All cases with diagnosis age <8 years constituted group 1 (n=19) and those with ≥8 years constituted group 2 (n=35). RESULTS: There was no significant difference in height standard deviation score, body mass index standard deviation score, bone age/chronologic age, predicted final height at the time of diagnosis, and follow-up between group 1 and group 2. There was no significant difference in final height (standard deviation score) between the groups. The number of obese and overweight cases at diagnosis and final height was similar. The target height (standard deviation score), predicted final height (standard deviation score), and final height (standard deviation score) were similar in both Group 1 and Group 2. CONCLUSION: We found that between the ages of 6-9.8 years, girls with central precocious puberty who received gonadotropin-releasing hormone analog treatment reached a final height within their target height range. It is concluded that gonadotropin-releasing hormone analog treatment increases body mass index during treatment and when patients reach the final height, they return to their pretreatment body mass index. Younger age and greater height at the time of diagnosis are the positive factors on final height.

The effect of 2000 iu/day vitamin D supplementation on insulin resistance and cardiovascular risk parameters in vitamin D deficient obese adolescents.

Bilici ME, Savas Erdeve S, Çetinkaya S, Aycan Z. The effect of 2000 iu/day vitamin D supplementation on insulin resistance and cardiovascular risk parameters in vitamin D deficient obese adolescents. Turk J Pediatr 2019; 61: 723-732. The aim of this study was to determine the vitamin D deficiency prevalence in obese adolescents and to investigate the effect of vitamin D supplementation on insulin resistance and cardiovascular risk parameters in obese adolescents with vitamin D deficiency. Ninety-six obese adolescents aged 10-18 years were divided in 2 groups according to their vitamin D levels: Deficient group ( < 12ng/ ml) and sufficient group (≥12ng/ml). All patients in the vitamin D deficiency group were recommended 2000IU/day vitamin D supplementation. Fifty four (56.3%) patients had vitamin D deficiency. The only difference between the two groups was PTH level which was higher in the vitamin D deficiency group. Vitamin D reached sufficient levels in 22 (95.6%) out of the 23 patients with the 3 month supplementation of 2000 IU/day vitamin D. There was a significant decrease in weight Standard Deviation Score (SDS), Body Mass Index (BMI) SDS, hip circumference, total cholesterol, LDL, HbA1c, AST, PTH and interleukin-6 while no significant change was seen in measurements of glucose, insulin, HOMA-IR, C-peptide and the rate of metabolic syndrome. There were decreases in levels of total cholesterol and LDL with vitamin D treatment, while there was no significant change in insulin resistance. Vitamin D reduced interleukin-6 levels by its antiinflammatory effect.

Congenital long-QT syndrome in type 1 diabetes: a unique association.

Kurnaz E, Savas Erdeve S, Özgür S, Keskin M, Özbudak P, Çetinkaya S, Aycan Z. Congenital long-QT syndrome in type 1 diabetes: a unique association. Turk J Pediatr 2019; 61: 791-793. In contrast to acquired long QT syndrome (LQTS), congenital LQTS is a relatively rare channelopathy with an incidence of 1/2,500. We describe a patient found to have a prolonged QTc in the setting of newly diagnosed Type 1 DM. To the best of our knowledge, this unique association has not been previously reported. Currently, it is shown that glucose ingestion aggravated cardiac repolarization disturbances in LQT2 patients and prolonged the cardiac repolarization phase in healthy controls. Our case presented to the hospital with syncope after increased glucose level. Therefore, it seems that increased glucose level may have prolonged QTc interval and aggravated cardiac repolarization disturbances in the presented case. By this report, we want to emphasize the importance of hyperglycaemia in congenital LQTS.

Response to growth hormone treatment in very young patients with growth hormone deficiencies and mini-puberty.

BACKGROUND: The aim of the study was to assess the response to growth hormone (GH) treatment in very young patients with GH deficiency (GHD) through a national, multi-center study. Possible factors affecting growth response were assessed (especially mini-puberty). METHODS: Medical reports of GHD patients in whom treatment was initiated between 0 and 3 years of age were retrospectively evaluated. RESULTS: The cohort numbered 67. The diagnosis age was 12.4±8.6 months, peak GH stimulation test response (at diagnosis) as 1.0±1.4 ng/mL. The first and second years length gain was 15.0±4.3 and 10.4±3.4 cm. Weight gain had the largest effect on first year growth response; whereas weight gain and GH dose were both important factors affecting second year growth response. In the multiple pituitary hormone deficiency (MPHD) group (n=50), first year GH response was significantly greater than in the isolated GH deficiency (IGHD) group (n=17) (p=0.030). In addition first year growth response of infants starting GH between 0 and 12 months of age (n=24) was significantly greater than those who started treatment between 12 and 36 months of age (n=43) (p<0.001). These differences were not seen in the second year. Δ Length/height standard deviation score (SDS), Δ body weight SDS, length/height SDS, weight SDS in MPHD without hypogonadism for the first year of the GH treatment were found as significantly better than MPHD with hypogonadism. CONCLUSIONS: Early onsets of GH treatment, good weight gain in the first year of the treatment and good weight gain-GH dose in the second year of the treatment are the factors that have the greatest effect on length gain in early onset GHD. The presence of the sex steroid hormones during minipubertal period influence growth pattern positively under GH treatment (closer to the normal percentage according to age and gender).

Vaginal bleeding and a giant ovarian cyst in an infant with 21-hydroxylase deficiency.

BACKGROUND: Increased adrenal androgen hormones in congenital adrenal hyperplasia (CAH) can rarely cause giant ovarian cysts in the neonatal period. Although the exact mechanism of the development of ovarian cysts is unknown, it is thought that increased androgen levels stimulate folicle development by increasing follicle stimulating hormone (FSH) levels. CASE PRESENTATION: A 16-day-old newborn with ambiguous genitalia was presented to our clinic. Laboratory test results were as follows: sodium: 126 mEq/L, potassium: 5.4 mEq/L, renin: 132 pg/mL, adrenocorticotropic hormone (ACTH): 207 pg/mL, cortisole: 7.8 µg/dL, basal 17OH progesterone: 21 ng/mL, androstenedione: 5.1 ng/mL, testosterone: 1188 ng/dL and dehydroepiandrosterone sulfate (DHEAS)>1500 µg/dL. Karyotype analysis resulted in 46,XX. A homozygous mutation of R356W was detected in the CYP21A2 gene. The classical severe form of salt wasting 21 hydroxylase deficiency was diagnosed and treatment was started with hydrocortisone and fludrocortisone. Good metabolic control was ensured by monthly visits but the baby presented with vaginal bleeding as soiling at 4 months. The cystic lesion which extended to the epigastric area from the pelvis in the midline abdomen, had a size of 90×80×60 mm and medially, thin ovarian parenchyma was detected in ultrasonography. CONCLUSIONS: The findings in our patient suggest that a decline in adrenal androgens after glucocorticoid treatment resulted in an increase in gonadotropin levels and the giant cyst is developed by activation of gonadotropin cascade and increased gonadotropin receptors, instead of androgens.

The Etiology and Clinical Features of Non-CAH Gonadotropin-Independent Precocious Puberty: A Multicenter Study.

AIM: The causes of gonadotropin-independent precocious puberty are diverse, and often have overlapping clinical and biochemical features. With the exception of congenital adrenal hyperplasia (CAH), disorders that cause gonadotropin-independent precocious puberty (GIPP) are uncommon. The literature is devoid of any large-scale studies on the etiologic distribution of GIPP. The aim of this study was to determine the frequency of each etiology in a cohort of patients with GIPP (excluding those with CAH), and to evaluate the clinical and laboratory features of these patients. MATERIALS AND METHODS: This multicenter, nationwide web-based study collected data on patients who presented with non-CAH GIPP in Turkey. RESULTS: Data were collected for 129 patients (102 girls and 27 boys) from 29 centers. Based on the data collected, the estimated prevalence of non-CAH GIPP in the studied population was 14 in 1 000 000 children. Functional ovarian cyst was the most common etiology, accounting for 37% of all cases, followed by McCune-Albright syndrome (MAS) (26%). Among the patients with MAS, 11.7% had fibrous dysplasia, 32.3% had café-au-lait spots, and 52.9% had both. Human chorionic gonadotrophin-secreting tumors included choriocarcinoma of the liver, hepatoblastoma, and germ cell tumors of the sellar-suprasellar region and mediastinum. Patients with adrenocortical tumors presented at an earlier age than those with other etiologies. Ovarian tumors included mature cystic teratoma, dysgerminoma, juvenile granulosa tumor, and steroid cell tumor. Despite overlapping features, it was possible to identify some unique clinical and laboratory features associated with each etiology. CONCLUSION: This largest cohort of patients with non-CAH GIPP to date yielded an estimation of the frequency of non-CAH GIPP in the general pediatric population and showed that girls were affected at a rate 4-fold greater than that of boys owing to functional ovarian cysts and MAS, which were the two most common etiologies. The data collected also provided some unique characteristics associated with each etiology.