Volume 38, Issue 1

The formation of functional bone requires a delicate interplay between osteogenesis and osteolysis. Disturbances in this subtle balance result in an increased risk for fractures. Besides its mechanical function, bone tissue represents a key player in the regulation of calcium homeostasis. Impaired bone formation results in bone fragility, which is especially pronounced in osteogenesis imperfecta (OI). This rare genetic disorder is characterized by frequent fractures as well as extraskeletal manifestations. The current classification of OI includes 23 distinct types. In recent years, several new mutations in different genes have been identified, although the exact pathomechanisms leading to the clinical presentation of OI often remain unclear. While bisphosphonates are still the standard of care, novel therapeutic approaches are emerging. Especially, targeted antibody therapies, originally developed for osteoporosis, are increasingly being investigated in children with OI and represent a promising approach to alleviate the consequences of impaired osteogenesis and improve quality of life in OI patients. This review aims to provide insight into the pathophysiology of OI and the consequences of distinct disease-causing mutations affecting the regulation of bone homeostasis. In this context, we describe the four most recently identified OI-causing genes and provide an update on current approaches for diagnosis and treatment.

21-Hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia (CAH), leads to impaired cortisol synthesis and androgen excess. Current treatments of patients with classic 21OHD with supraphysiological doses of glucocorticoids pose risks such as impaired growth and metabolic complications. We discuss the CRH receptor antagonist as a therapeutic option for children with classic 21OHD. A phase three trial of crinecerfont, a CRH receptor antagonist, offers a promising new treatment option. Crinecerfont helped to reduce glucocorticoid doses and to lower androgen levels. However, the study population may not be fully representative of the general 21OHD population. Successful implementation depends on patient adherence and monitoring to avoid possible complications such as adrenal crises. Overall, crinecerfont represents a valuable development, but further research and careful clinical management are needed to optimize its use in CAH treatment.

Objectives Type 1 diabetes mellitus (T1D) is a heterogeneous condition. We aimed to study the associations between age and sex with clinical characteristics at the onset of pediatric T1D. Methods A secondary analysis was conducted on data collected retrospectively from 706 children newly diagnosed with T1D at a large tertiary hospital in southeastern USA. Age (stratified across three cohorts from 0.84 to 18.08 years), sex, and their interaction were compared for associations with clinical characteristics of T1D at presentation by multivariable regression analyses and pairwise comparisons. Results Within the participants (mean age 9.71 (SD 4.10), 48.3 % female, 21.0 % Hispanic, 15.3 % non-Hispanic black and 58.7 % non-Hispanic white), children under 6 years had higher glucose (p<0.001), lower hemoglobin A 1c (HbA 1c ) (p<0.001), and lower C-peptide (p<0.001) than the older age groups. Diabetic ketoacidosis (DKA) was more prevalent in the youngest (p=0.005) and the intermediate-aged cohorts (p=0.005), compared to the oldest group. Among the children with DKA, bicarbonate was lower in the youngest (p<0.001) and middle cohorts (p=0.013), compared to the oldest group. Younger age was associated with higher prevalence of insulin autoantibodies (IAA; p<0.001) and IA-2 autoantibodies (IA-2A; p=0.006). Males had higher glucose (p=0.001), but lower HbA 1c (p=0.003), lower C-peptide (p<0.001), and lower GAD autoantibody (GADA) prevalence (p=0.001) than females. There was no significant interaction between age and sex. Conclusions In children with new onset T1D, younger age and male sex were associated with findings suggestive of more rapid and aggressive T1D preclinical course, including poorer beta-cell function, and distinct islet autoantibody profiles.

Objectives Geographic Information System (GIS) mapping, is a novel way to provide insights into spatial distribution of type 1 diabetes (T1D) and associations between T1D outcomes and potential predictors. We aimed to explore GIS in children with T1D, and identify predictors of poor glycemic control. Methods Design: Cross-sectional; Participants: 402 children and youth (187 boys) with T1D. Place of residence (coordinates) of participants were geocoded in GIS. They were divided into two groups living in urban or peri-urban areas using ArcGIS Pro. The characteristics of urban/peri-urban living were linked to sociodemographic and biochemical data and spatial autocorrelation analysis was performed. Association between glycemic control and distance to our unit was studied. Results Mean age was 13.2 ± 4.7 years; 196 children were living in urban areas, 206 in peri-urban areas. There was significant difference in HbA 1c between groups (Urban 9.9 (9.7, 10.2) %, Peri-urban 10.5 (10.1, 10.8) %) (p=0.004); mean difference 0.5 (0.1, 1.0) with poorer glycemic control and higher prevalence of vitamin D sufficiency in peri-urban and higher prevalence of hypothyroidism in urban areas. There was significant correlation between glycemic control (HbA 1c ) and distance to our unit r=0.108 (0.023, 0.218) (p=0.031). Individuals with an HbA 1c  ≥9.5 were residing farther away (58.9 (49.4, 68.5) km) as compared to those with HbA 1c <9.5 (44.5 (35.1, 53.9) km) (p<0.05). Conclusions Children with T1D when grouped using GIS had differences in glycemic control and comorbidities; peri-urban participants and those residing further away from our unit had poorer glycemic control. Future efforts may be aimed at identifying centers and channelizing resources towards children showing poor glycemic control, thus optimizing disease management.

Objectives The effects of thyroid hormones on body composition are well-known. We aimed to examine the body composition of children with and without Hashimoto’s thyroiditis (HT) by bioelectrical impedance analysis (BIA) while they were still euthyroid. Methods Between the ages of 5 and 18, 53 girls and 12 boys in each group, 65 children with HT, and 65 healthy children were included in this study. The Tanita MC-780 MA model was used to evaluate body composition parameters. These are fat mass (FM), fat-free mass (FFM), muscle mass (MM), bone mass (BM), total body water (TBW), phase angle, the ratio of muscle mass to fat mass (MFR), basal metabolic rate (BMR), and sarcopenic index (SI). Weight, height, body mass index standard deviation scores (SDSs), and pubertal status were examined. Additionally, TSH, Free-T4, Free-T3, Anti-TPO, Anti-Tg, serum lipid levels, and thyroid volumes were compared. Results We observed that TBW (27.5 ± 7.5 kg vs. 24.8 ± 6.6 kg; p=0.029) and BMR (1,403 ± 253 kcal vs. 1,324 ± 200 kcal; p=0.049) were higher in the HT group. These differences are due to differences in age and muscle mass in the male group. The FM, FFM, MM, BM, MFR, SI, and phase angle scores did not differ between females with and without HT in euthyroid children by the BIA method. Conclusions There is no significant change in body composition in euthyroid females with HT at admission.

Objectives It was aimed to investigate the outcomes of babies referred to a tertiary health center in Turkey for evaluation primary congenital hypothyroidism (CH) through newborn screening. Methods The hospital files of 328 newborns who were referred for CH from newborn screening between June 2013 and June 2020 were retrospectively reviewed. The newborns were evaluated with their clinical characteristics at admission, as well as their follow-up data and final diagnoses. Results Sixteen (4.9 %) newborns were diagnosed with transient neonatal hyperthyrotropinemia after follow-up. Treatment was initiated in 166 (50.6 %) of the cases with a diagnosis of CH. The median age at initiation of treatment was 17 days (5–69). Treatment was initiated in 88.3 % of the cases in the first month of the life. After at least 3 years of follow-up, 30/120 (20.0 %) of the cases were diagnosed with permanent CH and 11/30 (36.7 %) of them were diagnosed with thyroid dysgenesis. All of the cases who used >37.5 µg per day levothyroxine at the age of 1 or 2 years were diagnosed with permanent CH during their follow-up. For the prediction of transient CH, the sensitivity and specificity of levothyroxine doses of ≤25 µg per day at 1 year of age were calculated as 96.2 and 46.2 %, and for 2 years of age, the sensitivity and specificity were calculated as 97.8 and 65.2 %. Conclusions In this cohort, 10 % of all referrals result in permanent CH. Thyroid imaging with ultrasonography and levothyroxine dose during follow-up can be guiding in predicting permanent CH.

Objectives Congenital hypothyroidism (CHT) is a treatable cause of intellectual disability. Late diagnosis and delayed initiation of treatment leads to irreversible neurodevelopmental and intellectual disability. Thus, newborn screening is crucial. However, 71 % of babies are born in an area with no established newborn screening program and Kenya is not an exception. We aimed to determine the incidence of CHT, developmental outcomes of patients in the absence of newborn screening. Methods A retrospective data of subjects who met the inclusion criteria, newborn and infants from 3 days to 2 years whose thyroid function test (TFT) was undertaken during well baby visit or clinical suspicion of CHT were collected. Laboratory reference range for age was used to interpret the result and TSH>10 Uiu/mL after 6 weeks of life is considered abnormal according to ESPE guideline. Developmental outcome of children was collected from patient file documented by primary physician and parental concern. Results Of 1,426 children met inclusion criteria, 90 had elevated TSH. Out of which 70 repeat TFT showed normal TSH and free T4. The incidence of abnormal TSH across the different age groups was 2.4 , 7.2 and 10.5 % for ages 0–29 days, 1–11 months, and 1–2 years, respectively with p-value of =0.0002. While 20 cases with CHT identified with incidence of 14 per 1,000 children (1.4 %; 95 % CI: 0.9–2.1 %). Out this 12 (60 %) had poor developmental outcomes. Down’s syndrome was the common associated condition 9/20 (45 %). All cases were primary CHT. Conclusions This study shows high incidence of CHT in a small cohort of patients over 5-year period with poor development outcome.

Objectives Immune checkpoint inhibitors (ICIs) are emerging treatment options for children with brain tumors, who are already at risk for developing endocrinopathies due to tumor location and treatment. Endocrine ICI-related adverse effects (irAEs) are common in adults but poorly characterized in the pediatric population. The aims of this study were to determine in pediatric brain tumor patients in a single institution (1) if endocrine surveillance took place before and after ICIs were initiated, and (2) the occurrence of endocrine irAEs. Methods This is a retrospective chart review of 22 pediatric brain tumor patients treated with ICIs at Children’s Hospital Los Angeles between 2010 and 2022. We analyzed endocrine laboratory results, patient demographics, and treatment course. Results Most patients (82 %) received surveillance in at least one endocrine system before ICI treatment – all had thyroid function tested (100 %) whereas non-thyroid endocrine functions were seldomly assessed (6–22 %). Only those patients with surveillance prior to treatment had ongoing surveillance after ICI initiation – 100 % for thyroid function and 17–39 % for other endocrine systems. Hypothyroidism was the only endocrine problem diagnosed after ICI initiation, in two patients (9 %). Of note, most patients (68 %) expired during or shortly after ICI treatment. Conclusions This is one of the first institutional surveys of pediatric ICIs in a high-volume pediatric brain tumor center. Thyroid surveillance commonly occurred in pediatric patients, revealing diagnoses of hypothyroidism, which is consistent with adult data. However, little information is available for non-thyroid endocrine conditions, reflecting the need for comprehensive and systematic endocrine surveillance.

Objectives Maple syrup urine disease (MSUD) is considered one of the intoxication-type inborn errors of metabolism (IT-IEM). Patients with MSUD are afflicted with a chronic illness, and the disease and its management have both physical and psychological consequences for the patients and their families. The aim of this study was to assess the quality of life (QoL) and its main determining factors for patients with MSUD and their families under follow-up in Sohag University Hospital. Methods Parents of 36 patients with MSUD participated in a questionnaire translated into Arabic to assess their QoL. Subsequently, a file review was conducted to identify any key factors that could potentially influence the parents’ QoL. Results The results of the study indicated that 27 (75 %) of the MSUD patients exhibited poor QoL, while only 9 (25 %) patients reported good QoL across all studied aspects. Significant differences were observed between the two groups in terms of the disease onset, whether acute or asymptomatic (diagnosed before acute metabolic decompensation) (p=0.001) and the type of screening employed (p=0.007). Conclusions There is a paucity of data on the QoL of pediatric patients with IT-IEM, including MSUD. The methodological approaches and assessment instruments utilized in existing studies are inconsistent. Identifying the factors that affect QoL would be beneficial for improving patient care, evaluating outcomes and treatments, and planning effective social and psychological interventions to enhance the patients’ QoL.

Objectives Growth failure can result from various underlying causes, necessitating a thorough evaluation. Reninoma, a rare renin-secreting tumor, is an uncommon cause of hypertension, especially in paediatric patients, and has not been associated with growth failure until now. Case presentation An 11-year-old girl presented with complaints of poor height gain, headaches, increased thirst, and vomiting. The evaluation revealed severe hypertension and hypokalemic alkalosis. Investigations indicated renin-dependent hypertension, and imaging identified a right renal mass. Renal venous sampling confirmed renin production from the tumor. A right open partial nephrectomy was performed, resulting in the normalization of blood pressure and improved growth. Over the following years, she achieved a significant catch-up growth, regaining her original height percentile and the target adult height. Conclusions This case adds to the limited literature on paediatric reninoma. It highlights a rare presentation of reninoma causing hypertension and growth failure in a child. The growth failure was likely due to hypokalemic alkalosis-induced low insulin-like growth factor 1 (IGF-1) levels, a mechanism not previously documented in paediatric reninoma cases. Surgical excision of the tumor led to normalization of blood pressure and metabolic alkalosis with significant growth recovery.

Objectives Congenital syphilis can cause severe morbidities such as hydrops fetalis, preterm birth, low birth weight, hepatosplenomegaly, pneumonia, hypoglycemia, etc., and mortality. Despite hypoglycemia being reported in congenital syphilis and hyperinsulinism, only one case was described. In this article, we aimed to present a newborn with congenital syphilis born to a syphilitic mother who was diagnosed with persistent hyperinsulinemic hypoglycemia with a focal lesion during follow-up. Case presentation A female patient was born with a weight of 2,450 g in the 32 +3rd week of pregnancy from a 30-year-old syphilitic mother who had pleural effusion and ascites, cholestasis, thrombocytopenia, and anemia at birth. Hypoglycemia was detected on the 10th day of the patient’s follow-up (47 mg/dL). The patient was unresponsive to diazoxide, and octreotide, nifedipine, and glucagon treatments were started gradually. No variants were detected in the HH gene panel, but a focal pancreatic head lesion was detected in the pancreatic head in fluorine-18 L-3,4 dihydroxyphenylalanine positron emission tomography-computed tomography. Focal lesionectomy was recommended for the patient. Conclusions In this article, we present a neonate with severe early congenital syphilis and focal pancreatic lesions with persistent hyperinsulinemic hypoglycemia unresponsive to diazoxide. Although hypoglycemia can be seen in congenital syphilis and has been reported before, hypoglycemia associated with hyperinsulinism is very rare; only a few patients have been presented, and a focal pancreatic lesion has not been previously reported. The pathology is unknown, but pancreatitis may cause this entity.

Objectives Cushing’s disease (CD) in the context of chronic kidney disease (CKD) is very rare. CKD causes physiological hypercortisolism making the diagnosis of CD extremely difficult. To report 3 females with CKD and CD and to outline the principles that may guide the diagnosis of CD in this context. Case presentation P1. A 12.3-year-old patient with CKD secondary to steroid-resistant nephrotic syndrome on hemodialysis (HD) and a medical history of aseptic meningitis. She was referred due to the incidental finding of pituitary macroadenoma. P2. A patient with CKD secondary to bilateral renal hypodysplasia in conservative treatment. At age 16.4 years, she had significant weight gain, purple-red stretch marks, galactorrhea, and menstrual irregularities. P3. A 15.3-year-old patient with CKD secondary to steroid resistant nephrotic syndrome in conservative treatment was referred for weight gain, secondary amenorrhea, and hypertension. In all patients, diagnosis of CD was confirmed by clinical and biochemical findings. P1 and P3 underwent transsphenoidal surgery, and in P2, transcranial surgery resection was performed. Histopathological examination revealed a corticotroph adenoma in P1 and P2, and in P3, immunohistochemistry demonstrated ACTH predominance. All patients achieved remission. P1 and P2 developed pituitary deficiencies. Conclusions To the best of our knowledge, these are the first three reported cases of the diagnostic association of CD and CKD in children. In all cases, CS was clinically suspected and CD was confirmed through complementary exams. Given the current lack of clear diagnostic criteria for CD in CKD patients, a thorough clinical evaluation remains essential for guiding the diagnosis.

Objectives Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of the urea cycle, caused by mutations in the OTC gene located on the X chromosome. OTCD presents in early and late-onset forms, with variable severity. Despite the high genetic heterogeneity, genotype-phenotype correlations help in prognosis and treatment planning. This study presents a novel missense mutation in an Iranian girl with OTCD, occurring de novo , contributing to the understanding of the disease’s genetic landscape. Case presentation A 2-year-old girl from a consanguineous marriage presented with nausea, recurrent vomiting, and seizure. Elevated plasma ammonia, liver enzyme tests, and hepatomegaly suggested metabolic disorders. Following whole exome test, a novel heterozygous missense mutation in exon 7 of the OTC gene (c.674C>T) was identified in the patient. Despite maternal and paternal testing, no mutation was detected. Conclusions Identifying new mutations in populations helps mitigate the high mortality rates associated with OTCD hyperammonemic episodes and provides the best course of treatment, especially considering the diverse phenotypic variations.