Review of patients with achondroplasia: a single-center's experience with follow-up and associated morbidities.

Achondroplasia (ACH; MIM #100,800), caused by a heterozygous gain of function pathogenic variant in the fibroblast growth factor receptor 3 gene (FGFR3; MIM*134,934), is the most prevalent and most readily identifiable cause of disproportionate short stature that is compatible with life. In addition, individuals with achondroplasia face significant medical, functional, and psychosocial challenges throughout their lives. This study assessed associated morbidities in patients with achondroplasia at a single center in Turkey. In this study, the clinical findings and associated morbidities of a group of patients with achondroplasia (n = 68) with clinical multidisciplinary follow-up at a single center between the years 2005-2023 are evaluated retrospectively. A total of 68 patients, 30 male (44.1%) and 38 female (55.9%), were evaluated. In the majority (84.2%) of patients, shortness of extremities was detected in the prenatal period at an average of 28.7 gestational weeks (± 3.6 SDS) with the aid of ultrasonography. More than half (n = 34/63, 54%) of the patients had a father of advanced paternal age (≥ 35 years). Among the complications, respiratory system manifestations, including obstructive sleep apnea (70%), ear-nose-throat manifestations including adenoid hypertrophy (56.6%) and otitis media (54.7%), neurological manifestations due to foramen magnum stenosis (53.2%), and skeletal manifestations including scoliosis (28.8%), are represented among the most common. The mortality rate was 7.3% (n = 5/68).Conclusion: This study not only represents the first retrospective analysis of the associated morbidities of patients with achondroplasia from a single center in Turkey but also will provide a reference point for future studies.

Calcineurin inhibitor-related hyperkalemia is caused by hyporeninemic hypoaldosteronism and fludrocortisone is an effective treatment: Report of a case series and review of the literature.

INTRODUCTION: Calcineurin inhibitors (CNIs) are widely used in transplantation. Although CNI-related hyperkalemia is common (10%-60.6%), the underlying pathogenetic mechanism is not well-elucidated and may lead to dose adjustment or treatment withdrawal. OBJECTIVE: The aim of this study is to describe CNI-related hyperkalemia due to hyporeninemic hypoaldosteronism in pediatric transplant recipients who were successfully treated with fludrocortisone. METHOD: In a total of 55 hematopoietic stem cell (HSCT) and 35 kidney transplant recipients followed according to institutional immunosuppression protocols, recipients diagnosed with CNI-related hyperkalemia were reviewed. Recipients who were receiving intravenous fluid, potassium, or were diagnosed with hemolysis, acute graft rejection, or had an eGFR < 30 mL/min/1.73m2, were excluded. A detailed analysis of clinical history as well as biochemical studies was carried out to reveal possible pathophysiology. RESULTS: Three pediatric transplant recipients (one HSCT, two kidney transplantation) with findings of hyperkalemia, hyponatremia, and a mild elevation in blood urea nitrogen while on CNIs were recruited. Urinary potassium excretion was diminished while sodium excretion was increased. Plasma aldosterone levels were low, and renin was not increased in response. Primary adrenal insufficiency was ruled out, and hyporeninemic hypoaldosteronism was diagnosed. CNI-related hyperkalemia was detected earlier in case 1, who had HSCT (22 days), than in the second and third cases, who had kidney transplantation (24 and 30 months post-transplantation, respectively). The discrepancy was hypothesized to be explained by higher overall CNI dose due to higher serum target CNI used in HSCT than kidney transplantation. Electrolyte imbalance was reversed upon administration of physiologic dose fludrocortisone (0.05 mg, daily), while fludrocortisone was ceased after CNI withdrawal in case 1, which is additional evidence for the etiological association of CNIs and hyporeninemic hypoaldosteronism. CONCLUSION: Our three cases strengthen the premise that CNI-related hyperkalemia may be due to hyporeninemic hypoaldosteronism, and the timing and severity may be related to CNI dose. Fludrocortisone is a safe and effective treatment in CNI-related hyperkalemia, providing maintenance of CNIs, which are one of the essential therapeutic agents for pediatric transplantation.

Psychosocial Impact of the COVID-19 Pandemic on Children with Congenital Adrenal Hyperplasia and Their Families.

OBJECTIVE: This study aimed to investigate the psychosocial impact of the pandemic in pediatric patients with congenital adrenal hyperplasia and their families and whether congenital adrenal hyperplasia imposes an additional burden compared to other endocrine disorders. MATERIALS AND METHODS: Patients with congenital adrenal hyperplasia (n = 38) and congenital hypothyroidism (n = 41) and their families were enrolled in the prospective longitudinal survey study. Questionnaires that were completed remotely in June 2020 and in July 2021 included Depression Anxiety Stress Scale short form, The State-Trait Anxiety Inventory for Children, and purpose-built daily routine, parent, and child COVID information scores, factors affecting drug usage, and parents' thoughts about the pandemic. At the end of 1 year, Depression Anxiety Stress Scale short form and State-Trait Anxiety Inventory for Children were repeated in the congenital adrenal hyperplasia group and they were questioned about the incidence and severity of coronavirus infection. RESULTS: Median Depression Anxiety Stress Scale short form and State-Trait Anxiety Inventory for Children scores were similar between the congenital adrenal hyperplasia and congenital hypothyroidism groups. In the congenital adrenal hyperplasia group, median purpose-built daily routine was higher in those who had a State-Trait Anxiety Inventory for Children-State score above the threshold (P = .048), also Depression Anxiety Stress Scale short form-Depression, Depression Anxiety Stress Scale short form-Anxiety, Depression Anxiety Stress Scale short form-Stress, Parent COVID Information Score were higher among parents who followed news/data because of chronic diseases/medications of the child (P = .010, P = .034, P = .044, P = .045, respectively), and State-Trait Anxiety Inventory for Children-State was higher among parents who believed "having chronic diseases" and "using medications" increase the risk of COVID-19 infection (P = .011, P = .016, respectively). In the second survey, State-Trait Anxiety Inventory for Children-State, Depression Anxiety Stress Scale short form-Anxiety, and Depression Anxiety Stress Scale short form-Stress decreased significantly (P < .01, P = .009, P = .008, respectively). Three patients with congenital adrenal hyperplasia who reported positive nasopharyngeal swab tests revealed mild symptoms. CONCLUSION: The pandemic has negative consequences on the mental well-being of individuals with chronic diseases, albeit from different causes.

Management of prolactinomas in children and adolescents; which factors define the response to treatment?

PURPOSE: Prevalence, presentation and clinical outcome of prolactinomas vary in children and adults. In this study, we evaluated the clinical features and outcome of children and adolescents with prolactinoma to identify the differences from that of adults, and thus to establish the management strategies for this age group. METHODS: Patients with prolactinoma diagnosed before 18 years of age from a single center in the last 20-years were included. Clinical and laboratory data, radiological findings and treatment outcome were evaluated retrospectively. RESULTS: Twenty-eight patients (23 female; 82.1%) with prolactinoma were included. Median age at diagnosis was 15.2 years (12.6-17.7 years) in girls, 12.9 years (12.0-16.7 years) in boys. First line treatment was cabergoline in 82% of patients and normal prolactin level was achieved with maximum dose of 2 mg/week in 78%. Surgery was required in 28% of patients. Adenomas < 13.5 mm responded conventional doses of CAB. Adenomas > 30 mm were drug resistant or required surgery. Adenomas between 13.5 mm and 30 mm with invasion/extension were more likely to have drug resistance. CAB had to be continued following surgery in all patients. One macroprolactinoma had an increase in size which was accompanied with increasing prolactin level. CONCLUSIONS: All microprolactinomas responded well to DA treatment. However, all adenomas larger than 30 mm was resistant to CAB or required surgery. Probability of drug resistance and requirement of second line therapy were higher in adenomas between 13.5 mm and 30 mm with invasion/extension. Doses over 2 mg/week of CAB in drug-resistant patients may not provide additional benefit. The frequency of follow-up MRI could be determined based on prolactin levels and emergence of new neurological symptoms.

Menstrual Suppression in Gender Minority Youth

The purpose of this case series was to evaluate menstrual suppression in sex assigned at birth female adolescents identifying as male or gender non-conforming. A retrospective chart review of four gender minority youth (GMY), age 14-17, was performed for gender identity history, type and success of menstrual suppression, method satisfaction, side effects and improvement in menstrual distress. Menstrual suppression was successful in three patients, one patient discontinued use due to side effects that caused an increase in gender dysphoria. Menstrual distress and bleeding pattern improved in the majority of GMY in this series but side effects, as well as contraindications, may limit their use. In conclusion, menstrual dysphoria can be life-threatening for GMY and it is important that clinicians consider menstrual suppression in GMY with menstrual dysphoria. This series emphasizes the importance of individualized treatment plans.

Long-term effect of conventional phosphate and calcitriol treatment on metabolic recovery and catch-up growth in children with PHEX mutation.

OBJECTIVES: Hereditary hypophosphatemic rickets (HR) is conventionally treated with phosphate and calcitriol. Exploring genotype and phenotypic spectrum of X-linked hypophosphatemic rickets (XLHR), focusing on short-term, long-term, and pubertal impact of conventional treatment was aimed. METHODS: Sixteen patients from 12 unrelated families with HR were analyzed for phosphate regulating endopeptidase homolog X-linked (PHEX) mutation. Initially Sanger sequencing analysis was performed. If PHEX mutation was not detected, multiplex ligation-dependent probe amplification (MLPA) was performed. If molecular defect was detected, first-degree relatives were analyzed. Thirteen patients (81%) and five first-degree relatives with XLHR were evaluated for genotype-phenotype or gender-phenotype correlation. Clinical characteristics and response to conventional treatment were determined retrospectively. RESULTS: Nine different PHEX mutations were identified; four splice-site, three point mutations, and two single exon deletions. Four were novel mutations. Despite conventional treatment, median adult height was lower than median height on admission (-3.8 and -2.3 SDS, respectively), metabolic and radiographic recovery were not achieved, adherence was low (30%). Although mean adult height was better in compliant patients than noncompliants (-2.6 vs. -3.7 SDS, respectively), they were still short. Correlation between phenotype and genotype or gender could not be shown. Median phosphate decreased significantly throughout puberty (p=0.014). Median pubertal height was lower than prepubertal height (-4.4 vs. -3.6 SDS; respectively), pubertal growth spurt was not observed. Among five patients with a follow-up longer than five years, three had nephrocalcinosis (60%), two had hyperparathyroidism (40%), 4/6 (33%) required correction osteotomy. CONCLUSIONS: Conventional treatment appears to have limited effect on metabolic, clinical and radiographic recovery in XLHR. Metabolic control and growth worsened during puberty. Although, long-term adverse effects are yet to be seen, introduction of burosumab as first-line treatment may be an alternative after infancy.

Approach to pheochromocytoma and paraganglioma in children and adolescents: A retrospective clinical study from a tertiary care center.

AIM: Pheochromocytoma (PCC) and paraganglioma (PGL) are rare tumors in childhood. They are catecholamine secreting tumors and present with signs or symptoms related to their excess. Most common signs and symptoms are hypertension, headache and diaphoresis. The management of children usually depend on experience of adulthood. This study is conducted to present the clinical characteristics, surgical management and outcome of childhood PCC and PGL in a tertiary care center. MATERIAL AND METHODS: We reviewed clinical records of all patients operated for PCC and PGL between 2000 and 2020 retrospectively. RESULTS: There were 18 children operated for PCC and PGL in the study period. The female to male ratio was 1:1. The median age at diagnosis was 13 (IQR, 9-15) years. The most common presenting symptoms were headache and diaphoresis. Hypertension was the most common sign. Three patients had von Hippel-Lindau (VHL). Tumors of two patients with VHL were detected during routine follow-up. Three patients had multifocal disease. Medical preparation for surgery was carried out in all patients. Antihypertensive treatments were administered preoperatively. Since the patients are at risk for postoperative hypotension due to chronic vasoconstriction and blood volume contraction, high salt diet was recommended. Intravenous normal saline at a rate of 3000 ml/m2 body surface area per day was started for intravascular volume expansion preoperatively. The mean duration for preoperative medication to achieve normal blood pressure was 22 days (range, 16-30). Twenty-five tumors were excised in eighteen patients. One patient who had bone metastases on diagnosis and is on I131MIBG therapy. The median follow-up time was 5.6 years (range, 1 months - 21 years). Five patients reached adulthood during the study period. Four of these had recurrent metastases (n = 2) and new tumors (pancreatic neuroendocrine tumor, n = 1 and pancreatic neuroendocrine tumor and renal cell carcinoma, n = 1) after the age of 18. CONCLUSION: Multidisciplinary approach is necessary to achieve safe surgical treatment and surveillance of PCC and PGL. Detection of associated familial cancer susceptibility syndromes and long-term follow-up is essential to detect late recurrences and new tumors.

Which parameters predict the beneficial effect of GnRHa treatment on height in girls with central precocious puberty?

OBJECTIVE: Data about GnRHa on adult height in girls with central precocious puberty (CPP) have shown variable results, ranging from improvement of growth prognosis to lack of any benefit. This study was designed to delineate the criteria to decide which girls with idiopathic CPP (iCPP) will have a height benefit from GnRHa treatment. DESIGN: Retrospective PATIENTS: 102 girls with iCPP who had reached final height (FH) were included. MEASUREMENTS: Auxological, hormonal and radiological findings at treatment onset, and FHs were extracted from records. RESULTS: Most important factor affecting height gain was chronological age (CA) at treatment onset. All the girls treated ≤6.4 years of age achieved a height gain of ≥1SDS, while none of the girls treated ≥8.3 years of age made the target. 75.6% of patients who started GnRHa between the ages of 6.4 and 8.3 years had a height gain of ≥1SDS. Most important factors affecting height gain in those treated 6.4-8.3 years were advanced bone age (BA), basal estradiol (E2 ) and pubertal stage (r2 : 0.906; P < .001). All individuals with BA advancement of ≥2.6 years or E2 of ≥32.6 pg/ml or pubertal stage of ≥3 had significant height gain, and none of the cases with BA advancement of <2 years or E2 of <21.5 pg/ml or pubertal stage of <2 had a height gain of ≥1SDS. CONCLUSIONS: Treatment with GnRHa is unquestionably beneficial to improve FH in girls with iCPP when initiated ≤6.4 years of age. GnRHa treatment after 8.3 years of age may not improve FH. Girls between the ages of 6.4 and 8.3 years at presentation can have a better height gain if BA (≥2.6 years over CA) and pubertal findings (pubertal stage ≥3 or E2 ≥32.6 pg/ml) are well-advanced.

A Patient With AIRE Mutation Who Presented With Severe Diarrhea and Lung Abscess.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (polyglandular endocrinopathy type 1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE). The major clinical features of APECED are hypoparathyroidism, adrenal insufficiency (Addison disease), and chronic mucocutaneous candidiasis. This disease is also associated with multiple other and uncommon autoimmune (autoimmune hepatitis, autoimmune enteropathy, atrophic gastritis with or without pernicious anemia, gonadal failure, diabetes mellitus, hypothyroidism, functional hyposplenism), ectodermal (alopecia and vitiligo), and inflammatory (intestinal lung disease, nephritis) features. Here, we report a case of a 13-year-old Turkish boy who presented wih enteropathy and lung abscess. Molecular genetic analysis demonstrated a homozygous frameshift mutation (p.Asp70fs, c.208_209insCAGG) in exon 2, in AIRE gene. APECED may present with severe, life-threatening infections due to functional hyposplenism. Multidisciplinary approach, careful follow-up, and molecular genetic studies are needed.

Long-term effects of GnRH agonist treatment on body mass index in girls with idiopathic central precocious puberty.

Introduction Studies evaluating effects of gonadotropin-releasing hormone agonist (GnRHa) on weight and body-mass-index (BMI) in girls with idiopathic central precocious puberty (iCPP) include short-term effects. The aim of this study is to investigate changes in BMI during and 2 years after completion of GnRHa to determine the factors that may impact BMI in girls with iCPP. Methods Medical files of 138 girls who completed GnRHa were evaluated. All patients had weight and height measurements at the beginning and end of treatment, and 111 patients had anthropometric measurements 2 years after the completion of treatment. Results In the beginning, 82 (59.4%) had normal weight (NW), 42 (30.4%) were overweight (OW), and 14 (10.2%) were obese (OB). Analysis of BMI-standard deviation score (SDS) in the whole group showed an overall increase during GnRHa treatment (0.92 ± 0.74 vs. 1.20 ± 0.51, p < 0.001). Changes in BMI-SDS (ΔBMI-SDS) during GnRHa differed between NW and OW/OB (0.45 ± 0.31 vs. 0.03 ± 0.20, p < 0.001). BMI-SDSs of both groups returned to baseline scores (or initial levels) 2 years after the completion of treatment. Two factors affecting ΔBMI-SDS in multiple linear regression analyses were baseline BMI and Δheight-SDS, both correlated negatively with ΔBMI-SDS. Conclusions The present study is one of the studies evaluating BMI change over a long period of time in girls with CPP. Although BMI-SDS increased during GnRHa in NW girls, it was reversible in follow-up after treatment. However, BMI-SDS did not change during and in follow-up in OW/OB girls. Conserving BMI-SDS in OW/OB girls may be related to the fact that weight management programs were recommended for these patients. Dietary recommendations should be provided for children with NW who undergo GnRHa, as is the case for OW patients.

Need for comprehensive hormonal workup in the management of adrenocortical tumors in children.

OBJECTIVE: Clinical findings do not reflect the excess hormonal status in adrenocortical tumors (ACTs) in children. Identification of abnormal hormone secretion may help provide the tumor marker and delineate those patients with a risk of adrenal suppression following tumor removal. To analyze the impact of complete hormonal assessment regardless of the clinical presentation in hormone-secreting ACTs in childhood. METHODS: Association of hormonal workup at diagnosis with the clinical findings and frequency of adrenal suppression postoperatively were analyzed in 18 children with ACT. RESULTS: Seventeen of the 18 patients had functional ACT. Clinical findings suggested isolated virilization and isolated Cushing's syndrome in 38.8% and 17.6% of patients, respectively. Hormonal workup revealed a frequency of 83.3% for hyperandrogenism. The majority of the tumors (50%) had mixed type hormonal secretion. Hypercortisolism existed in 28.5% of children with isolated virilization and hyperandrogenism was found in 2/3 of children with isolated Cushing's syndrome. Various androgens other than dehydroepiandrosterone sulfate were also determined to be high in hyperandrogenism. Increased testosterone was a highly prevalent tumor marker. Nine patients (3 with no signs of hypercortisolism) had adrenal suppression following tumor removal which lasted 1-24 months. CONCLUSION: Complete hormonal workup showed the predominance of mixed hormone-secreting type of tumor in the patients who lacked the appropriate clinical findings and also showed that patients lacking signs of Cushing's syndrome could have postoperative adrenal suppression. Clinical findings may not reflect the abnormal hormone secretion in all cases and tumor markers as well as risk of postoperative adrenal suppression can best be determined by complete hormonal evaluation at the time of diagnosis.

GnRH stimulation test in precocious puberty: single sample is adequate for diagnosis and dose adjustment.

OBJECTIVE: Gonadotropin stimulation test is the gold standard to document precocious puberty. However, the test is costly, time-consuming and uncomfortable. The aim of this study was to simplify the intravenous gonadotropin-releasing hormone (GnRH) stimulation test in the diagnosis of precocious puberty and in the assessment of pubertal suppression. METHODS: Data pertaining to 584 GnRH stimulation tests (314 tests for diagnosis and 270 for assessment of pubertal suppression) were analyzed. RESULTS: Forty-minute post-injection samples had the greatest frequency of "peaking luteinizing hormone (LH)" (p<0.001) in the diagnostic tests when the cut-off value was taken as 5 IU/L for LH, 40th minute sample was found to have 98% sensitivity and 100% specificity in the diagnosis of precocious puberty, while the sensitivity and specificity of the 20th minute sample was 100% in the assessment of pubertal suppression. CONCLUSION: LH level at the 40th minute post-injection in the diagnosis of central precocious puberty and at the 20th minute post-injection in the assessment of pubertal suppression is highly sensitive and specific. A single sample at these time points can be used in the diagnosis of early puberty and in the assessment of pubertal suppression.