Clinical features, diagnosis and treatment outcomes of Cushing's disease in children: A multicenter study.

OBJECTIVE: Since Cushing's disease (CD) is less common in the paediatric age group than in adults, data on this subject are relatively limited in children. Herein, we aim to share the clinical, diagnostic and therapeutic features of paediatric CD cases. DESIGN: National, multicenter and retrospective study. PATIENTS: All centres were asked to complete a form including questions regarding initial complaints, physical examination findings, diagnostic tests, treatment modalities and follow-up data of the children with CD between December 2015 and March 2017. MEASUREMENTS: Diagnostic tests of CD and tumour size. RESULTS: Thirty-four patients (M:F = 16:18) from 15 tertiary centres were enroled. The most frequent complaint and physical examination finding were rapid weight gain, and round face with plethora, respectively. Late-night serum cortisol level was the most sensitive test for the diagnosis of hypercortisolism and morning adrenocorticotropic hormone (ACTH) level to demonstrate the pituitary origin (100% and 96.8%, respectively). Adenoma was detected on magnetic resonance imaging (MRI) in 70.5% of the patients. Transsphenoidal adenomectomy (TSA) was the most preferred treatment (78.1%). At follow-up, 6 (24%) of the patients who underwent TSA were reoperated due to recurrence or surgical failure. CONCLUSIONS: Herein, national data of the clinical experience on paediatric CD have been presented. Our findings highlight that presenting complaints may be subtle in children, the sensitivities of the diagnostic tests are very variable and require a careful interpretation, and MRI fails to detect adenoma in approximately one-third of cases. Finally, clinicians should be aware of the recurrence of the disease during the follow-up after surgery.

Evaluation of aggression level in adolescent girls with classical congenital adrenal hyperplasia.

OBJECTIVE: In patients with classical congenital adrenal hyperplasia (CAH), virilization affects the brain and external genitalia due to antenatal androgen exposure. There are few studies on how the effects of androgens on brain virilization are reflected in behavior. However, there is no study focused on the adolescence period. The aim of this study was to evaluate the level of aggression in adolescent girls with classical CAH (due to 21 hydroxylase and 11ß hydroxylase deficiency) and to investigate the disease-related factors that may affect aggression. DESIGN: Twenty female and 20 male patients aged 13-20 years, diagnosed with classical CAH, with 21 hydroxylase deficiency and 11ß hydroxylase deficiency, and 20 healthy girls and 20 boys from the same age group were included. The Buss-Perry Aggression Scale (BPAS), which consists of four subgroups measuring physical aggression, verbal aggression, hostility, and angry behaviors, was used. RESULTS: The ages of the male and female patients with CAH were 16.30 ± 2.65 and 16.60 ± 2.41 years, respectively. Total aggression scale scores were 73.3 ± 14.6 in adolescent girls with CAH, 74.1 ± 11.2 in healthy girls, 71.5 ± 14.8 in boys with CAH, and 75.3 ± 14.5 in healthy boys (p > .05). There was no difference between the subscale scores of patients and healthy adolescents. Aggression scores in adolescents with CAH increased significantly with age. CONCLUSIONS: In this study, we found no difference between the aggression scores of adolescents with classical CAH compared to their healthy peers. The total aggression score and subscale were similar in unaffected female adolescents.

Assessment of the Retinal Nerve Fibre Layer, Retina, and Choroid in Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a genetic disorder in which there are problems in tissues containing type I collagen, predominantly the cornea and sclera in the eye. Although there are many studies on problems with the anterior segment of the eye in patients with OI, studies on posterior structures are limited. Involvement of the sclera may affect the retinal nerve fibre layer (RNFL), which is indirectly related to intraocular pressure. In addition, the retina and choroid containing type I collagen may be affected. The aim of the study was to compare the posterior segment structures of the eye, including the RNFL, retina, and choroid, in patients with OI to those of healthy control subjects. METHODS: This cross-sectional study recruited 19 patients with OI, as well as 22 age- and gender-similar healthy control subjects. Measurements of the RNFL, retina, and choroid were obtained with optical coherence tomography (Spectralis SD-OCT, Heidelberg Engineering, Heidelberg, Germany). RESULTS: Patients with OI (mean age 14.32 ± 5.08 years) and the control group (mean age 13.73 ± 3.56 years) had similar age, refractive error, and intraocular pressure values (p > 0.05). There was no difference between groups in terms of RNFL thickness, including the superonasal, nasal, inferonasal, inferotemporal, temporal, and superotemporal sectors, retinal thickness, and choroidal thickness from five different locations (p > 0.05, for all). CONCLUSION: According to these results, OI does not clinically affect the RNFL, retina, and choroid in childhood.

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.

Evaluation of permanent and transient congenital hypothyroidism in cases referred from National Neonatal Screening Program.

AIM: The incidence of congenital hypothyroidism (CH) has increased world-wide. Lowering cut-off in screening programs has led to an increase in the rate of transient CH. We aimed to evaluate the rates of permanent and transient CH in cases referred from the screening program and to investigate the clinical and laboratory factors which predict transient CH. METHODS: In 109 cases referred from the neonatal screening program to our hospital, from September 2015 to April 2018, 52 primarily diagnosed CH cases were prospectively evaluated. Regularly followed up, 44 CH cases were included in the study at the end of 3 years. RESULTS: 38.2 ± 1.31 weeks (w) and mean birthweight 3021.3 ± 389.6 gram (g) in the transient CH group; both were significantly lower compared to permanent CH cases with 39.06 ± 1.33 w and 3375.3 ± 425.3 g (P = 0.025, P = 0.007) respectively. Transient CH rate was found to be 50% (all hypoplastic) in the dysgenesis group and 73.3% in groups with normal and hyperplasic thyroid gland. While fT4 , thyroid-stimulating hormone, and thyroglobulin levels at diagnosis do not predict transient/permanent CH, levothyroxine (LT-4) dosage was significantly lower in the transient CH group in all years. The optimal cut-off value with highest sensitivity and specificity for LT-4 dosage as a predictive marker to differentiate transient CH from permanent CH was 2.27 µg/kg/day (P = 0.004; sensitivity: 71%, specificity: 83%) at 1st year, 1.85 µg /kg/day (P = 0.013; sensitivity: 66%, specificity: 72%) at 2nd year and 1.69 µg /kg/day at 3rd year (P < 0.0001; sensitivity: 90%, specificity: 83%). CONCLUSION: Transient CH is more frequent than expected. Our results suggest that LT-4 requirement may be a good marker for predicting transient CH, while thyroid hormone levels at the time of diagnosis do not significantly predict permanent and transient CH. Therefore, infants with CH requiring LT-4 doses <2.27 µg/kg/day at 1st year, <1.85 µg /kg/day at 2nd year may be re-evaluated earlier to discriminate transient CH rather than at 3 years of age.

Urinary levels of phthalate esters and heavy metals in adolescents with thyroid colloid cysts.

We aimed to evaluate 14 urinary phthalate metabolites and 4 toxic metals in adolescents having thyroid colloid cyst (TCC) and compare with age and sex-matched others without TCC. Phthalate metabolites were analysed with UPLC-MS/MS and heavy metals with ICP-MS. TCC ratios in tertile subgroups of pollutants were compared with multiple logistic regression analysis after adjusting for age, sex, z-scores for body mass index and urinary creatinine values. Adolescents having the highest tertile of mono (2-ethylhexyl) phthalic acid and mercury had increased odds and those with the highest tertiles of monocarboxy-isononyl phthalate, mono (3-carboxypropyl) phthalate, monoisobutyl phthalate had lower odds for TCC than counterparts. The odds of TCC were lower for those in the second and the third tertiles. No differences in TCC ratios were detected with other pollutants. Given phthalate esters' and toxic metals' specific interactions on TCC, further studies were necessary to assess the influence of chemicals on TCC.

Functional assessment of variants associated with Wolfram syndrome.

Wolfram syndrome (WS) is a heterogeneous multisystem neurodegenerative disorder with two allelic variations in addition to a separate subtype known as WS type 2. The wide phenotypic spectrum of WS includes diabetes mellitus and optic atrophy which is often accompanied by diabetes insipidus, deafness, urological and neurological complications in combination or in isolation. To date, the understanding of the genotype-phenotype relationship in this complex syndrome remains poorly understood. In this study, we identified and explored the functionality of rare and novel variants in the two causative WS genes WFS1 and CISD2 by assessing the effects of the mutations on the encoded proteins Wolframin and ERIS, in a cohort of 12 patients with autosomal recessive WS, dominant WS and WS type 2. The identified pathogenic variants included missense changes, frameshift deletions and insertions in WFS1 and an exonic deletion in CISD2 which all altered the respective encoded protein in a manner that did not correlate to the phenome previously described. These observations suggest the lack of genotype-phenotype correlation in this complex syndrome and the need to explore other molecular genetic mechanisms. Additionally, our findings highlight the importance of functionally assessing variants for their pathogenicity to tackle the problem of increasing variants of unknown significance in the public genetic databases.

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.

Renal complications of lipodystrophy: A closer look at the natural history of kidney disease.

OBJECTIVES: Lipodystrophy syndromes are a group of heterogeneous disorders characterized by adipose tissue loss. Proteinuria is a remarkable finding in previous reports. STUDY DESIGN: In this multicentre study, prospective follow-up data were collected from 103 subjects with non-HIV-associated lipodystrophy registered in the Turkish Lipodystrophy Study Group database to study renal complications in treatment naïve patients with lipodystrophy. METHODS: Main outcome measures included ascertainment of chronic kidney disease (CKD) by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR). Kidney volume was measured. Percutaneous renal biopsies were performed in 9 patients. RESULTS: Seventeen of 37 patients with generalized and 29 of 66 patients with partial lipodystrophy had CKD characterized by proteinuria, of those 12 progressed to renal failure subsequently. The onset of renal complications was significantly earlier in patients with generalized lipodystrophy. Patients with CKD were older and more insulin resistant and had worse metabolic control. Increased kidney volume was associated with poor metabolic control and suppressed leptin levels. Renal biopsies revealed thickening of glomerular basal membranes, mesangial matrix abnormalities, podocyte injury, focal segmental sclerosis, ischaemic changes and tubular abnormalities at various levels. Lipid vacuoles were visualized in electron microscopy images. CONCLUSIONS: CKD is conspicuously frequent in patients with lipodystrophy which has an early onset. Renal involvement appears multifactorial. While poorly controlled diabetes caused by severe insulin resistance may drive the disease in some cases, inherent underlying genetic defects may also lead to cell autonomous mechanisms contributory to the pathogenesis of kidney disease.

Clinical and genetic characterisation of a series of patients with triple A syndrome.

Triple A syndrome (TAS) or Allgrove syndrome (OMIM #231550) is a rare autosomal recessive disorder characterised by adrenocorticotropic hormone-resistant adrenal insufficiency, alacrima, achalasia, and neurological and dermatological abnormalities. Mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN have been reported in these patients. Between 2006 and 2017, we evaluated six patients with a clinical diagnosis of TAS, based on the presence of at least two symptoms, usually adrenal insufficiency and alacrima. In all cases, genetic analysis revealed homozygous mutations in the AAAS gene. One novel mutation was detected: a homozygous 10-bp deletion (c.1264_1273del, p.Q422NfsX126) in exon 14 of the AAAS gene that caused a frameshift that introduced an aberrant stop codon after 126 amino acids. This genetic variant is likely to be pathogenic because it caused a significant change in protein structure. A precise genotype-phenotype correlation was impossible to establish. CONCLUSIONS: Based on our experience, we recommend that molecular analysis should be performed in the presence of alacrima and at least one more symptom of TAS. Our cases share many clinical features of TAS and underline the variability in this syndrome, as well as the need for thorough investigation following a multidisciplinary approach. What is known: • Triple A syndrome is characterised by achalasia, alacrima, adrenal insufficiency, neurological impairment, and dermatological abnormalities. • A precise genotype-phenotype correlation has proved impossible to establish. What is new: • These cases add to a large number of similar case reports with limited novel information. • The newly identified AAAS gene mutation was reported.

Near final height in patients with idiopathic growth hormone deficiency: A single-centre experience.

AIM: We analysed near final height (NFH) data in children with growth hormone deficiency (GHD) treated with recombinant human GH (rhGH). METHODS: We divided the idiopathic GHD patients into two groups, isolated GHD (IGHD) and multiple pituitary hormone deficiency, to evaluate NFH. Then, data were grouped according to gender, pre-pubertal/pubertal status and spontaneous or induced puberty. The trial was performed as a retrospective study. Median values are given, and measurements are expressed as standard deviation scores (SDSs). RESULTS: rhGH therapy was started at a median age of 12.1 (range 9.1-14.9) years in the IGHD group (n = 162, 83 males) and 9.1 (range 4.9-13.4) years in the multiple pituitary hormone deficiency group (n = 33, 22 males) at a median dose of 0.20 mg/kg/week. Height SDSs at the onset of therapy were -3.2 (range -4.4 to -2.6) and -3.9 (-6.8 to -2.8) in the two groups, respectively (P < 0.001). NFH SDSs were -1.8 (-2.9 to -1) and -1.6 (-3.1 to -0.4) (P = 0.139), and delta height SDSs (finish - start) were 1.4 (0.3-2.5) and 2.6 (1.5-4.6) (P < 0.001), respectively. Total delta height was 1.4 SDS (0.4-3.1) in patients who started rhGH treatment in the pre-pubertal period and 1.3 SDS (0.3-2.4) (P = 0.106) in those who started rhGH in the pubertal period. CONCLUSIONS: About 85% of the cases reached their genetic height potential. Delta height SDSs were higher than expected in cases that started treatment during the pubertal period. Therefore, it is possible to achieve NFH within the mid-parental height range in patients who start therapy during puberty.

A Newborn with Transient Diabetes Mellitus Accompanied by Ketoacidosis Attributable to a ZFP57 Mutation.

Hyperglycemia commencing within the first 6 months of life requires exogenous insulin therapy and, if the condition persists for >2 weeks, is termed neonatal diabetes mellitus (NDM). This rare illness is of two types: transient and permanent NDM. Most cases come to medical attention because of nonspecific symptoms, including intrauterine growth retardation, dehydration, difficulties in feeding and inadequate weight gain. In the present article, we describe an infant who smelt of ketones during examination and who was diagnosed with transient NDM caused by a ZFP57 mutation, accompanied by ketoacidosis. This is the first report of such a condition.

Efficacy and safety of pamidronate in children with vitamin D intoxication.

BACKGROUND: Bisphosphonates are used in the treatment of vitamin D intoxication (VDI) after failure of conventional therapy including prednisolone. Safety concerns restrict the use of bisphosphonates from being used as first-line therapy for VDI in children. The aim of this study was to evaluate the efficacy and safety of pamidronate in comparison with prednisolone in children with VDI. METHODS: We reviewed the hospital records of children consecutively diagnosed with VDI at two medical centers in a 15 year period. RESULTS: The subjects consisted of 21 children (age, 0.3-4.2 years) who were treated with prednisolone and/or bisphosphonates. Pamidronate (n = 18) or alendronate (n = 3) was used in six patients after unsuccessful prednisolone treatment, and in 15 patients from baseline. Initial serum calcium and 25-hydroxyvitamin D were 16.1 ± 1.9 mg/dL and 493 ± 219 ng/mL, respectively. The median time to reach normocalcemia in the pamidronate, alendronate and prednisolone groups was 3 days (range, 2-12 days), 4 days (range, 3-6 days) and 17 days (range, 12-26 days), respectively (P = 0.013). The pamidronate group had a fivefold shorter hospital stay than the prednisolone group. Three patients initially treated with prednisolone developed nephrocalcinosis but this did not occur in any patient treated with bisphosphonates from baseline. Apart from transient fever and moderate hypophosphatemia, no side-effect of bisphosphonate treatment was observed. CONCLUSIONS: Pamidronate is efficient and safe for the treatment of VDI in children. Pamidronate use significantly shortens the duration of treatment, and thereby may prevent the development of nephrocalcinosis. Instead of prednisolone, pamidronate should be used together with hydration and furosemide as the first-line therapy for VDI.

Adherence to growth hormone therapy: results of a multicenter study.

OBJECTIVE: To evaluate the adherence to growth hormone (GH) therapy and identify the influencing factors and outcomes in children. METHODS: A total of 217 GH-naïve patients in 6 pediatric endocrinology clinics were enrolled in the study. Structured questionnaires were filled out and patients were evaluated at the initiation and 3rd, 6th, and 12th months of therapy. Patients were categorized into 4 adherence segments based on percentage of doses omitted at each evaluation period, classified as excellent if 0%, good if 5%, fair if 5 to 10%, and poor if > 10%. RESULTS: There was a decrement in adherence to GH therapy during the study period (P = .006). Patients who showed excellent and good adherence to therapy had better growth velocity and growth velocity standard deviation scores (SDSs) (P = .014 and P = .015, respectively). A negative correlation between growth velocity SDS and number of missed injections was also observed (r = -.412; P = .007). A positive correlation between delta insulin-like growth factor-1 (IGF-1) SDS and growth velocity was demonstrated (r = .239; P = .042). IGF-1 levels were significantly higher in patients who showed excellent and good adherence to therapy (P = .01). Adherence was better in boys than in girls (P = .035), but adherence rates were not associated with age, cause of GH treatment, socioeconomic status, person who administered the injections, type of injection device, or GH product. CONCLUSION: Poor adherence to GH therapy was common in our group of patients and was one of the factors underlying suboptimal growth during therapy. Before considering other problems that can affect growth, clinicians should confirm good adherence to therapy.

Kidney growth and renal functions under the growth hormone replacement therapy in children.

OBJECTIVE: The aim of this study was to investigate the kidney growth and renal functions in children receiving recombinant human growth hormone (rhGH) treatment. MATERIALS AND METHODS: A total of 37 children who received rhGH for 1.5 years before the study was started and 48 healthy controls were included at first evaluation. Hormone levels were determined and kidney sizes were measured by ultrasound. Kidney functions were assessed by serum creatinine and estimated glomerular filtration rate (eGFR). After 3 years of first evaluation, 23 patients were re-assessed. RESULTS: Kidney sizes were found to be lower in rhGH received children compared with controls at first evaluation (p<0.05). Significant positive correlations were found between anthropometric measurements and kidney length and kidney volume (p<0.05). Height was the most significant predictor of kidney volume in rhGH received children (p<0.001). After 3-years of follow-up significantly increases were found in kidney length and volume compared with the first measurements (p<0.05). Increase percentage of body height was similar to increasing percent of kidney length and liver long axis (14.2%, 11.7.1% and 7.7%, respectively, p>0.05). Although no abnormal renal function test results were found at first and second evaluations; rhGH received children had significantly lower eGFR, at first evaluation, compared with controls; however, renal functions significantly increased after 3 years of follow-up (p<0.05). CONCLUSIONS: In conclusion, effect rhGH treatment on kidney growth is parallel to growth in body height and other visceral organs. A 3-years rhGH treatment resulted in significant increases in renal functions.

Corneal biomechanical characteristics in children with diabetes mellitus.

To compare the corneal biomechanical properties in children with type 1 diabetes mellitus (DM) and healthy children. In this cross-sectional study, the study and control groups were composed of 68 children with DM and 74 healthy children, respectively. The corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated intraocular pressure (IOPg) and corneal-compensated intraocular pressure (IOPcc) were measured with the ocular response analyzer (ORA). Associations between ocular and diabetic parameters were also evaluated. There were no statistically significant differences between the two groups in age or gender distribution. The mean CH was 10.8 ± 1.5 and 10.7 ± 1.7 mmHg while the mean CRF was 10.9 ± 1.9 and 10.5 ± 1.6 mmHg in the diabetic group and control group, respectively. The mean IOPg was 15.9 ± 3.7 and 15.2 ± 3.4 mmHg, and the mean IOPcc was 15.8 ± 3.0 and 15.3 ± 3.4 mmHg in the diabetic and control group, respectively. There were no statistically significant differences between the two groups for CH, CRF, IOPg, and IOPcc measurements (independent t test, p = 0.624, p = 0.207, p = 0.263, p = 0.395, respectively). This study shows that type 1 DM does not have any effect on the corneal biomechanical parameters in childhood.

Long-acting Growth Hormone Therapy, Rational and Future Aspects.

Recombinant growth hormone (GH) is administered as daily subcutaneous injections. Daily treatment can be challenging for children/adolescents as well as for parents and/or caregivers (legal representatives, guardians of children in institutional care). Challenges associated with daily treatment may result in missing several doses and non-adherence with treatment leads to inadequate growth response. As an inadequate growth response does not meet criteria for continuing treatment, payers (commercial or public) may decide to end reimbursement. Novel long-acting GH formulations (LAGH) with extended half-life can be administered less frequently and target to improve patient convenience and consequently to improve adherence and responses to treatment. LAGH formulations can restore growth velocity and body composition as effectively as daily treatment, without unexpected adverse effects as reported in randomized clinical trials.

Effect of Adrenocorticotropic Hormone Stimulation on Ischemiamodified Albumin Levels in vivo

Objective: Ischemia-modified albumin (IMA) formation is associated with increased reactive oxygen species (ROS) production, while increased cortisol leads to decreased ROS levels. We aimed to evaluate the effect of adrenocorticotropic hormone (ACTH) stimulation on IMA levels and whether the effect was dose-dependent or not. Methods: A total of 99 subjects with normal ACTH test results were included in the study. Of these, 80 had standard-dose ACTH test while 19 had low-dose ACTH test. Blood samples were collected to determine cortisol and IMA levels; at minutes 0, 30, and 60 following the standard-dose ACTH test and at minutes 0 and 30 following the low-dose ACTH test. Results: IMA levels decreased significantly within 30 minutes and the decrease continued up to the sixtieth minute (p=0.002) after standard-dose ACTH stimulation. After ACTH stimulation, a weak negative correlation was found between peak cortisol and IMA levels at the thirtieth minute (r=0.233, p=0.02). There was no significant difference in IMA levels after low-dose ACTH stimulation, despite an increase in cortisol (p=0.161). Conclusion: IMA levels decreased rapidly after standard-dose ACTH stimulation, while a decrease in IMA levels was not observed after low-dose ACTH stimulation. The lack of decrease in IMA levels after low-dose ACTH stimulation suggests a possible dose-dependent relationship between ACTH and IMA. The moderate increase in cortisol with no reduction in IMA levels after low-dose ACTH stimulation and the weak correlation between peak cortisol and 30-minute IMA levels after standard-dose ACTH stimulation suggest that ACTH may have a direct effect on IMA.

Decreased calcium permeability caused by biallelic TRPV5 mutation leads to autosomal recessive renal calcium-wasting hypercalciuria.

Hypercalciuria is the most common metabolic risk factor in people with kidney stone disease. Its etiology is mostly multifactorial, although monogenetic causes of hypercalciuria have also been described. Despite the increased availability of genetic diagnostic tests, the vast majority of individuals with familial hypercalciuria remain unsolved. In this study, we investigated a consanguineous pedigree with idiopathic hypercalciuria. The proband additionally exhibited severe skeletal deformities and hyperparathyroidism. Whole-exome sequencing of the proband revealed a homozygous ultra-rare variant in TRPV5 (NM_019841.7:c.1792G>A; p.(Val598Met)), which encodes for a renal Ca2+-selective ion channel. The variant segregates with the three individuals with hypercalciuria. The skeletal phenotype unique to the proband was due to an additional pathogenic somatic mutation in GNAS (NM_000516.7:c.601C>T; p.(Arg201Cys)), which leads to polyostotic fibrous dysplasia. The variant in TRPV5 is located in the TRP helix, a characteristic amphipathic helix that is indispensable for the gating movements of TRP channels. Biochemical characterization of the TRPV5 p.(Val598Met) channel revealed a complete loss of Ca2+ transport capability. This defect is caused by reduced expression of the mutant channel, due to misfolding and preferential targeting to the proteasome for degradation. Based on these findings, we conclude that biallelic loss of TRPV5 function causes a novel form of monogenic autosomal recessive hypercalciuria, which we name renal Ca2+-wasting hypercalciuria (RCWH). The recessive inheritance pattern explains the rarity of RCWH and underscores the potential prevalence of RCWH in highly consanguineous populations, emphasizing the importance of exploration of this disorder within such communities.

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

Objective: Treatment adherence is crucial for the success of growth hormone (GH) therapy. Reported nonadherence rates in GH treatment have varied widely. Several factors may have an impact on adherence. Apart from these factors, the global impact of the 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. Materials and Methods: This was a multicenter survey study that was sent to pediatric endocrinologists in pandemic period (June 2021-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, and missed dose data and the causes in the recent year (after the onset of the pandemic) were queried. 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% nonadherence). 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 mcg/kg, the annual growth rate was 1.15 SDS (min -2.74, max 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 nonadherence 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. Nonadherence 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 nonadherence 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.