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.

Adherence to Growth Hormone Treatment in Children During the COVID-19 Pandemic

Objective: Treatment adherence is crucial for the success of growth hormone (GH) therapy. Reported non-adherence rates in GH treatment have varied widely. Several factors may have an impact on adherence. Apart from these factors, the global impact of the Coronavirus disease-2019 (COVID-19) pandemic, including problems with hospital admission and routine follow-up of patients using GH treatment, may have additionally affected the adherence rate. The primary objective of this study was to investigate adherence to treatment in patients receiving GH. In addition, potential problems with GH treatment during the pandemic were investigated. Methods: This was a multicenter survey study that was sent to pediatric endocrinologists during the pandemic period (June-December 2021). Patient data, diagnosis, history of pituitary surgery, current GH doses, duration of GH therapy, the person administering therapy (either parent/patient), duration of missed doses, reasons for missed doses, as well as problems associated with GH therapy, missed dose data and the causes in the recent year (after the onset of the pandemic) were questioned. Treatment adherence was categorized based on missed dose rates over the past month (0 to 5%, full adherence; 5.1 to 10% moderate adherence; >10% non-adherence). Results: The study cohort consisted of 427 cases (56.2% male) from thirteen centers. Median age of diagnosis was 8.13 (0.13-16) years. Treatment indications were isolated GH deficiency (61.4%), multiple pituitary hormone deficiency (14%), Turner syndrome (7.5%), idiopathic GH deficiency (7.5%), small for gestational age (2.8%), and "others" (6.8%). GH therapy was administered by parents in 70% and by patients in 30%. Mean daily dose was 32.3 µg/kg, the annual growth rate was 1.15 standard deviation score (minimum -2.74, maximum 9.3). Overall GH adherence rate was good in 70.3%, moderate in 14.7%, and poor in 15% of the patients. The reasons for non-adherence were mainly due to forgetfulness, being tired, inability to access medication, and/or pen problems. It was noteworthy that there was a negative effect on adherence during the COVID-19 pandemic reported by 22% of patients and the main reasons given were problems obtaining an appointment, taking the medication, and anxiety about going to hospital. There was no difference between genders in the adherence rate. Non-adherence to GH treatment decreased significantly when the patient: administered the treatment; was older; had longer duration of treatment; and during the pandemic. There was a non-significant decrease in annual growth rate as non-adherence rate increased. Conclusion: During the COVID-19 pandemic, the poor adherence rate was 15%, and duration of GH therapy and older age were important factors. There was a negative effect on adherence during the pandemic period.

Comprehensive Insights Into Pediatric Craniopharyngioma: Endocrine and Metabolic Profiles, Treatment Challenges, and Long-term Outcomes from a Multicenter Study

Objective: Craniopharyngiomas (CPG) have complex treatment challenges due to their proximity to vital structures, surgical and radiotherapeutic complexities, and the tendency for recurrence. The aim of this study was to identify the prevalence of endocrine and metabolic comorbidities observed during initial diagnosis and long-term follow-up in a nationwide cohort of pediatric CPG patients. A further aim was to highlight the difficulties associated with CPG management. Methods: Sixteen centers entered CPG patients into the ÇEDD NET data system. The clinical and laboratory characteristics at presentation, administered treatments, accompanying endocrine, metabolic, and other system involvements, and the patient's follow-up features were evaluated. Results: Of the 152 evaluated patients, 64 (42.1%) were female. At presentation, the mean age was 9.1±3.67, ranging from 1.46 to 16.92, years. The most common complaints at presentation were headache (68.4%), vision problems (42%), short stature (15%), and nausea and vomiting (7%). The surgical procedures were gross total resection (GTR) in 97 (63.8%) and subtotal resection in 55 (36.2%). Radiotherapy (RT) was initiated in 11.8% of the patients. Histopathological examination reported 92% were adamantinamatous type and 8% were papillary type. Postoperatively, hormone abnormalities consisted of thyroid-stimulating hormone (92.1%), adrenocorticotropic hormone (81%), antidiuretic hormone (79%), growth hormone (65.1%), and gonadotropin (43.4%) deficiencies. Recombinant growth hormone treatment (rhGH) was initiated in 27 (17.8%). The study showed hesitancy among physicians regarding rhGH. The median survival without relapse was 2.2 years. Median (range) time of relapse was 1.82 (0.13-10.35) years. Relapse was related to longer followups and reduced GTR rates. The median follow-up time was 3.13 years. Among the last follow-up visits, the prevalence of obesity was 38%, but of these, 46.5% were already obese at diagnosis. However, 20% who were not obese at baseline became obese on follow-up. Permanent visual impairment was observed in 26 (17.1%), neurological deficits in 13 (8.5%) and diabetes mellitus in 5 (3.3%) patients. Conclusion: Recurrence was predominantly due to incomplete resection and the low rate of postoperative RT. Challenges emerged for multidisciplinary regular follow ups. It is suggested that early interventions, such as dietary restrictions and increased exercise to prevent obesity, be implemented.

17α Hydroxylase/17,20 lyase deficiency: clinical features and genetic insights from a large Turkey cohort.

PURPOSE: 17α Hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia, typically diagnosed in late adolescence with symptoms of pubertal delay and hypertension. This study aimed to determine the clinical and laboratory characteristics of 17OHD cases and gather data on disease management. METHODS: Data from 97 nationwide cases were analyzed using the CEDD-NET web system. Diagnostic, follow-up findings, and final heights of patients were evaluated. RESULTS: Mean age at admission was 13.54 ± 4.71 years, with delayed puberty as the most common complaint. Hypertension was detected in 65% at presentation; hypokalemia was present in 34%. Genetic analysis revealed Exon 1-6 homozygous deletion as the most frequent mutation, identified in 42 cases. Hydrocortisone replacement was universal; pubertal replacement was administered to 66 cases. Antihypertensive treatment was required in 57 (90%) patients. Thirty-seven cases reached final height, with an average SD of 0.015 in 46,XX and -1.43 in 46,XY. Thelarche and pubarche did not develop properly in some cases despite estradiol treatment. CONCLUSION: This study represents the largest cohort of pediatric cases of 17-hydroxylase deficiency (17OHD) documented in the literature. Hypertension and hypokalemia can serve as guiding indicators for early diagnosis.The final height is typically considered to be normal. The relationship between genotype and phenotype remains elusive. The initial genetic test for exon 1-6 deletions may be MLPA in our region.

Type 1 Diabetes Incidence Trends in a Cohort of Turkish Children and Youth.

OBJECTIVE: The aim was to analyze the incidence trend and annual average incidence change of type 1 diabetes (T1DM) in the population <18 years of age in Malatya province. MATERIALS AND METHODS: Medical files of patients followed up with T1DM in pediatric endocri- nology clinics were reviewed. The data for the child census was taken from the Turkish Statistical Institute (TUIK), and T1DM incidence was analyzed according to the calendar year, gender, and age groups. Recently diagnosed T1DM patients per 100 000 children per year were calculated. In addition, the trend in annual incidence change over the period 2007-2019 was analyzed. RESULTS: The mean incidence of T1DM during the 13 years was 13.1/105 child years (13.8/105 child years for girls and 12.4/105 child years for boys). During the 13-year follow-up period, a sig- nificant increasing trend in the incidence of T1DM was detected. The average annual percent change (AAPC) was 8.3%. According to age groups, the average AAPC was 8.1% between 0 and 4 years old, 9.4% between 5 and 9 years old, 12.1% between 10 and 14 years old, and 30.1% between 15 and 17 years old. CONCLUSION: The incidence of T1DM in children under 18 years of age in Malatya, one of the larg- est cities in the Eastern Anatolia region of Turkey, was determined as 13.1/105 child years in the last 13 years and the average annual increase rate was 8.3%.

Liraglutide Treatment in a Morbidly Obese Adolescent with a MC4R Gene Variant: Side Effects Reduce Success

Variants of the melanocortin-4 receptor (MC4R) gene are the most common cause of monogenic obesity. It has been shown that, while obesity cannot be controlled with diet and exercise, glucagon-like-peptide-1 receptor agonists (GLP-1 RA) provide weight loss in the short term. In this paper, our experience with liraglutide treatment in an adolescent patient carrying a MC4R gene variant is presented. A female patient was admitted first at the age of 12.5 years with a complaint of progressive weight gain. She had marked excess of appetite since infancy. On physical examination of the pubertal female patient with a body mass index (BMI) of 36.1 kg/m2 (3.48 standard deviation score), there was no pathological finding except diffuse acanthosis nigricans. Laboratory examinations revealed only insulin resistance. Weight loss was not achieved with lifestyle changes, metformin and orlistat treatments. On genetic examination, a sporadic heterozygous c.206T>G(p.I69R) variant that had been reported previously, was found in MC4R gene. Treatment with the GLP-1 RA, liraglutide, was initiated and a 19.2% reduction was achieved in the body weight and BMI at the end of 32 weeks. However, the patient, whose treatment compliance was disrupted due to significant gastrointestinal complaints, returned to her former weight within a few months (13 weeks) after treatment was stopped. In this case with a known pathogenic variant in MC4R gene, decrease of appetite and weight loss were achieved with liraglutide treatment, but side-effects of this treatment led to discontinuation of therapy. In such cases, there is need for effective and tolerable treatment options.

Factors Associated with Low Bone Mineral Density at the Time of Diagnosis in Children with Celiac Disease

Objective: It has been reported that bone mineral density (BMD) is decreased in children with Celiac disease (CD) compared to their healthy peers. The aim of this study was to reveal possible risk factors for low BMD in Turkish children newly diagnosed with CD. Methods: Eighty-six patients (2-18 years old) with CD were included in this retrospective study. The relationship between their lumbar BMD z-scores calculated according to their chronological age (CA) and height age (HA) and their clinical, laboratory [biochemical parameters, tissue transglutaminase antibody-IgA (TTGA) levels, human leukocyte antigen (HLA) types] and histopathological parameters were evaluated. Results: The mean age of the patients at diagnosis was 8.06±4.08 years. The BMD z-score CA was ≤-2 standard deviation (SD) in 26.7% of the patients. The BMD z-score HA was ≤-2 SD in 12.8% of the patients. The BMD z-score HA only correlated with their age at diagnosis of CD (rs value 0.269). However, there was no statistically difference between the BMD z-score HA >-2 SD and ≤-2 SD subgroups regarding their clinical, laboratory and histopathological parameters. Conclusion: Low BMD is common in children with newly diagnosed CD. Age at diagnosis, gender, body size, Celiac symptoms, biochemical parameters, TTGA level, HLA type, and histopathological stage had no predictive values in terms of low BMD in this patient group.

Presentation, Diagnosis, and Follow-Up Characteristics of 17α-Hydroxylase Deficiency Cases with Exon 1-6 Deletion (Founder Mutation) in the CYP17A1Gene: 20-Year Single-Center Experience.

CONTEXT: 17α-Hydroxylase/17,20-lyase deficiency (17OHD) is characterized by decreased sex steroids and cortisol synthesis, as well as an increased mineralocorticoid effect. AIM: This study aimed to evaluate the clinical, biochemical, and molecular characteristics of patients with 17OHD and to discuss the diagnosis, treatment, and follow-up process. METHODS: Age, symptoms, anthropometric measurements, blood pressure, and hormonal, biochemical, and chromosomal analysis results of 13 patients diagnosed with 17OHD between 2003 and 2022 were recorded at admission and during follow-up. Whole gene next-generation sequencing was performed for the CYP17A1 gene. Multiplex ligation-dependent probe amplification was used to detect deletions in patients without point mutations in CYP17A1. RESULTS: The median age at diagnosis was 14.0 (3.5-16.8) years. Nine of 13 patients (69.2%) had 46,XY karyotypes. All patients were phenotypically female and were raised as girls. The most common reasons for admission were the absence of puberty and amenorrhea (n = 8, 61.5%), followed by hypertension (n = 3, 23.0%), and family screening (n = 2, 15.3%). At the time of diagnosis, hypertension was detected in 10 (76.9%) patients, and 11 (84.6%) patients had hypokalemia. CONCLUSIONS: 17OHD should be considered in patients with pubertal delay/primary amenorrhea, hypertension, and hypokalemia. Adrenal function should be included in the clinical study of hypergonadotropic hypogonadism, after excluding Turner syndrome, in all 46,XX females. Deletion in the CYP17A1 gene, including exons 1-6, is the founder mutation for Turkey's east and southeast regions.

Clinical Characteristics and Genetic Analyses of Patients with Idiopathic Hypogonadotropic Hypogonadism

Objective: Idiopathic hypogonadotropic hypogonadism (IHH) is classified into two groups-Kalman syndrome and normosmic IHH (nIHH). Half of all cases can be explained by mutations in >50 genes. Targeted gene panel testing with nexrt generation sequencing (NGS) is required for patients without typical phenotypic findings. The aim was to determine the genetic etiologies of patients with IHH using NGS, including 54 IHH-associated genes, and to present protein homology modeling and protein stability analyzes of the detected variations. Methods: Clinical and demographic data of 16 patients (eight female), aged between 11.6-17.8 years, from different families were assessed. All patients were followed up for a diagnosis of nIHH, had normal cranial imaging, were without anterior pituitary hormone deficiency other than gonadotropins, had no sex chromosome anomaly, had no additional disease, and underwent genetic analysis with NGS between the years 2008-2021. Rare variants were classified according to the variant interpretation framework of the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology. Changes in protein structure caused by variations were modeled using RoseTTAFold and changes in protein stability resulting from variation were analyzed. Results: Half of the 16 had no detectable variation. Three (18.75%) had a homozygous (pathogenic) variant in the GNRHR gene, one (6.25%) had a compound heterozygous [likely pathogenic-variants of uncertain significance (VUS)] variant in PROK2 and four (25%) each had a heterozygous (VUS) variant in HESX1, FGF8, FLRT3 and DMXL2. Protein models showed that variants interpreted as VUS according to ACMG could account for the clinical IHH. Conclusion: The frequency of variation detection was similar to the literature. Modelling showed that the variant in five different genes, interpreted as VUS according to ACMG, could explain the clinical IHH.

Chronic Disease Management of Children Followed with Type 1 Diabetes Mellitus

Objective: With the diagnosis of chronic illness in children, a stressful period is likely to begin for both the affected child and their families. The aim of this study was to investigate the factors affecting chronic disease management by the parents of children diagnosed with type 1 diabetes mellitus (T1DM). Methods: The sample consisted of 110 children, aged between 4-17 years and their mothers. The patients had been diagnosed with T1DM for at least one year, and had attended pediatric endocrinology outpatients or were hospitalized in a single center. First, sociodemographic information about the child with T1DM were obtained. Then, the "Family Management Measure" (FaMM) was applied. The FaMM is constructed to measure family functioning and management in families who have a child with a chronic illness. Results: Paternal years of education (p=0.036), family income (p=0.008), insulin pump use (p=0.011), and time elapsed after diagnosis (p=0.048) positively affected both the management of T1DM and the child's daily life. However, presence of chronic diseases in addition to T1DM (p=0.004) negatively affected diabetes management. Higher maternal education year (p=0.013) and family income level (p=0.001) increased parental mutuality scores. However, as the time after diagnosis increased, parental mutuality scores decreased. Conclusion: It is important to evaluate the child with chronic disease with a biopsychosocial approach. This approach aims to evaluate the problems of the child and his/her family who experience the disease with a holistic approach.