Benign transient hyperphosphatasemia in the pediatric population: a single center cohort study.

OBJECTIVES: Alkaline phosphatase (ALP) can be increased in a benign condition known as benign-transient hyperphosphatasemia (BTH). We aimed to evaluate the demographic, and clinical characteristics of infants and children with BTH. METHODS: In our retrospective study, infants and children diagnosed with BTH between September 2019 and September 2023 were included. RESULTS: Of 249 children with elevated ALP levels, 95 (38.1 %) had BTH. The mean age at diagnosis of children with BTH was 2.4 ± 1.3 years (min 0.6 - max 6.2 years). ALP mean value was 2,587 ± 1252 U/L (min 972 - max 5757 U/L). ALP value was an average 7.4 ± 3.6 times higher than the corresponding upper limit of normal. The second measurement was made after an average of 13.2 ± 6 days, and a statistically significant difference was detected compared to the first value, with a decrease of 61 ± 23 % in the ALP value (p<0.001). ALP value returned to normal in an average of 44 ± 29.2 days. Elevated ALP was detected during infection in 49 (51.6 %) children. When the sample was divided into those under 2 years of age and aged 2 and over, no statistical difference was observed in ALP levels in the time it took for ALP levels to return to the normal range (p=0.480). CONCLUSIONS: BTH should be kept in mind if high serum ALP is detected in children without clinical or laboratory suspicion of bone or liver disease. In the follow up detecting a significant decrease trend compared to the first value may be guiding for BTH.

Comparison of the optical coherence tomography-angiography (OCT-A) vascular measurements between molecularly confirmed MODY and age-matched healthy controls.

AIMS: Previous structural, vascular density, and perfusion studies have mostly comprised type 1 and type 2 diabetes, even in the absence of retinopathy. The current study aimed to compare macular vessel density (VD) measurements between maturity-onset diabetes of the young (MODY) patients and controls. METHODS: The macular VD of superficial, deep retina, and choriocapillaris (CC), and central macular thickness (CMT), foveal avascular zone (FAZ), FAZ perimetry, VD of the total retina at 300 µm around the FAZ (FD), and acirculatory index (AI) measurements were taken and analyzed via OCT-A (RTVue XR 100-2 Avanti, AngioVue) and were compared between molecularly confirmed MODY (glucokinase (GCK) variants) patients and healthy controls. RESULTS: Twenty-five MODY patients and 30 healthy controls were included in the study. The mean plasma hemoglobin A1c level in the MODY group was 6.39 ± 0.38. The mean age was 13.8 ± 2.1 in the MODY group and was 12.6 ± 2.5 years among controls. There was no significant difference in terms of the age, superficial and deep retinal VD, FAZ, FAZ perimetry, CMT, FD, or AI between the groups. Compared to the healthy controls, a slight but significant increase in the CC-VD was detected in the MODY group, but only in the parafoveal and perifoveal regions (p = 0.034, p = 0.009). CONCLUSION: The significant CC-VD increase in the MODY group might be associated with hyperglycemia and/or relatively poor and vulnerable peripheral vascular CC perfusion compared to the central. Previous thickness and VD results of childhood or adolescent diabetes were distributed in a wider range, suggesting that various factors, including some not yet clearly defined, may affect the choroidal vasculature independently of glycemia or as a contributing factor.

Body mass index evolution and ovarian function in adolescent girls who received GnRH agonist treatment for central precocious puberty or early and fast puberty.

OBJECTIVES: Gonadotropin-releasing hormone agonist (GnRHa) has been used for central precocious puberty (CPP) or early and fast puberty. It was aimed to assess changes in body mass index (BMI), polycystic ovary syndrome (PCOS) frequency, and anti-Müllerian hormone (AMH) in girls who had been treated with GnRHa. METHODS: Fifty-eight adolescent girls treated with GnRHa for CPP or early and fast puberty (3.75 mg/28 days), between 2011 and 2015, were re-evaluated in 2020-2022 at least 2 years after menstruation. Hormonal analyses were compared with 51 healthy adolescents. RESULTS: In the GnRHa-treated group, a statistically significant increase was observed when the BMI standard deviation score (SDS) at the beginning of the treatment was compared with the BMI SDS at the end of the treatment (p=0.038). A statistically significant decrease was observed when the BMI SDS at the end of the treatment was compared with the BMI SDS in late adolescence (p=0.012). When the BMI SDS at the beginning of the treatment was compared with the BMI SDS in late adolescence, it was observed that there was no statistically significant difference (p=0.196). Of the 58 girls in the GnRHa-treated group, 8 (14 %) had PCOS. Serum AMH levels did not differ between the GnRHa-treated and the control group. CONCLUSIONS: GnRHa treatment causes no adverse effect on BMI, at least in late adolescence. Girls treated with GnRHa were not found to be prone to developing PCOS. AMH levels were similar in the GnRHa-treated group as in the control group.

Comparison of internet usage and internet addiction scores in healthy children and children with type 1 diabetes mellitus.

OBJECTIVES: The Internet, an integral part of modern life, can lead to internet addiction, which negatively affects academic performance, family relationships, and emotional development. This study aimed to evaluate the Internet addiction scores (IAS) during COVID-19 in children with type 1 diabetes mellitus (T1DM) compared with healthy controls. METHODS: Children with T1DM and healthy controls aged 8-18, were evaluated with the Parent-Child Internet Addiction Test (PCIAT20). Internet addiction scores of the participants were assessed. The relationship between diabetes duration, mean HbA1c level and IAS were also examined in children with T1DM. RESULTS: The study included 139 patients with T1DM and 273 controls. The IAS were significantly lower in patients compared with controls (25.28 ± 15.52 vs. 29.69 ± 19.08, p=0.019). There was a weak negative correlation between the duration of diabetes and IAS in children with diabetes (r=-0.21, p=0.021). There was no significant association between IAS and mean HbA1c (r=0.14, p=0.128) or age (r=0.08, p=0.115). Furthermore, there was no statistically significant difference in IAS between children with well-controlled diabetes (n=17) and those with poorly-controlled diabetes (n=122) (IAS: 27.1 ± 17.2; 24.8 ± 15.5, p=0.672, respectively). CONCLUSIONS: Internet addiction scores were lower in patients with T1DM compared with their healthy peers. Unlike previous studies reporting an increase in problematic internet use, the results of the present study did not confirm internet use as a real challenge in front of the diabetes management for the majority of children with T1DM. This result may be attributed to the important role played by families in the management of T1DM.

The Relationship Between Internet Usage Style and Internet Addiction and Food Addiction in Obese Children Compared to Healthy Children.

OBJECTIVE: The frequency of using the internet and social media increases in childhood, which leads to a decrease in physical activity. We aimed to investigate the effects of such technological applications on the internet and food addiction in obese and nonobese children. MATERIALS AND METHODS: A total of 180 obese and 180 nonobese children were included in this study. Turkish version of the Parent-Child Internet Addiction Scale and Dimensional Yale Food Addiction Scale Version 2.0 for Children were applied. RESULTS: The frequency of internet addiction in the sample was 1.7%. The mean internet addiction scores of males were found to be significantly higher than females (34.9 ± 20.6, 26 ± 17.2; P < .001). Children, who used the internet for information and homework had significantly lower internet addiction scores and food addiction scores, respectively (P = .002, P = .009). Watching movies, TV series, or sports events (P < .001, P = .009); following food recipes, campaigns, or advertisements (P = .04, P < .001); and eating snacks in front of the screen (P < .001, P < .001) were found to cause higher internet addiction scores and food addiction scores. It was observed that body mass index showed a positive and significant correlation with internet addiction scores and food addiction scores. CONCLUSIONS: Internet addiction and social media applications were found to be significantly related. Considering the relationship between body mass index and addiction, the effect of internet usage style and internet addiction and food addiction on obesity is striking.

The First Case of 4H Syndrome with Type 1 Diabetes Mellitus.

4H syndrome is a rare progressive hypomyelinating leukodystrophy. Hypomyelination, hypodontia, and hypogonadotropic hypogonadism are the 3 classic features of 4H syndrome. Biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K gene cause 4H leukodystrophy. Herein, we present clinical features in two siblings with 4H syndrome. The first patient (16 years) presented hypogonadotropic hypogonadism, euthyroid Hashimoto's thyroiditis and type 1 diabetes mellitus. The second patient (13.5 years) showed normal physical, biochemical and hormonal examination at presentation. It was learned that he was followed up for epilepsy between the ages of 6 months and 6 years, his epilepsy medication was discontinued at the age of 6, and he did not have seizure again. T2-weighted magnetic resonance images showed increased signal intensity secondary to hypomyelination at patients. They were subsequently found to have homozygous mutation in the POLR3A gene. 4H syndrome may present with neurological and non-neurological findings in addition to classic features of 4H syndrome. Progressive neurological deterioration may occur and endocrine dysfunction may be progressive. Although multipl endocrine abnormalities associated with this disorder have been reported to date, a case accompanied by type 1 DM has not been seen in the literature. We do not know exactly whether this is coinsidans or the expansion of the phenotype. So that reporting such cases helps to determine the appropriate genotype-phenotype correlation in patients.

Bisphosphonate treatment at spondylo-ocular syndrome due to a novel compound heterozygote variant in XYLT2 and review of the literature.

Spondylo-ocular syndrome is a rare autosomal recessive disorder characterized by generalized osteoporosis, hearing loss, visual impairment due to cataract, and platyspondyly. Previous studies have revealed that the syndrome is caused by pathogenic variants in the XYLT2 gene. A patient with spondylo-ocular syndrome and two heterozygous pathogenic variant in the XYLT2 gene in compound state are described here. The patient presented with osteoporosis, platyspondyly, ocular findings, hearing loss, kyphosis, scoliosis, facial findings, intellectual disability, and undescended testicles. Previous reports of bisphosphonate treatment response were variable, whereas a long-term follow-up with bisphosphonate treatment in this case resulted in normalization of vertebral structures. Reporting such cases helps to determine the appropriate genotype-phenotype correlation in patients with XYLT2-related pathogenesis.

Novel sphingosine-1-phosphate lyase mutation causes multisystemic diseases: case report.

BACKGROUND: Sphingosine phosphate lyase insufficiency syndrome (SPLIS) caused by inactivating mutations in the human SGPL1 gene results in congenital nephrotic syndrome, adrenal insufficiency, ichthyosis, immunodeficiency, and a wide range of pathological neurological features. We present a novel mutation in the SGPL1 gene causing hypocalcemia, primary adrenal insufficiency (PAI), nephrotic syndrome, subclinical hypothyroidism, lymphopenia, ptosis, and pathologic neuroimaging findings. CASE: A Turkish male infant presented with bruising at 2 months of age and was diagnosed with hypocalcemia, PAI, and subclinical hypothyroidism. At the age of 15 months, he was admitted to the hospital with ptosis. Other systemic manifestations included persistent lymphopenia and nephrotic syndrome. Magnetic resonance imaging (MRI) of the brain and orbit demonstrated asymmetric contrast enhancement in the left cavernosal sinus, orbital apex, and thinning at the bilateral optic nerve. Whole exome sequencing (WES) revealed a homozygous c.1432C > G (p.Gln478Glu) variant in the SGPL1 gene (NM_003901.4), which has not previously been reported in the literature. CONCLUSIONS: Novel mutations in SGPL1 are still being identified. This case reminded us that SPLIS should not be considered for patients with nephrotic syndrome alone. Still, PAI may also include patients with neurological disorders, hypocalcemia, and pathological neuroimaging findings such as thinning at the bilateral optic nerve.

Clinical, biochemical, and echocardiographic evaluation of neonates with vitamin D deficiency due to maternal vitamin D deficiency.

OBJECTIVE: There are a few number of case reports and small-scale case series reporting dilated cardiomyopathy due to vitamin D-deficient rickets. The present study evaluates the clinical, biochemical, and echocardiographic features of neonates with vitamin D deficiency. PATIENTS AND METHODS: In this prospective single-arm observational study, echocardiographic evaluation was performed on all patients before vitamin D3 and calcium replacement. Following remission of biochemical features of vitamin D deficiency, control echocardiography was performed. Biochemical and echocardiographic characteristics of the present cohort were compared with those of 27 previously published cases with dilated cardiomyopathy due to vitamin D deficiency. RESULTS: The study included 148 cases (95 males). In the echocardiographic evaluation, none of the patients had dilated cardiomyopathy. All of the mothers were also vitamin D deficient and treated accordingly. Comparison of patients with normocalcaemia and hypocalcaemia at presentation revealed no statistically significant difference between the ejection fraction and shortening fraction, while left ventricle end-diastolic diameter and left ventricle end-systolic diameter were higher in patients with hypocalcaemia. Previously published historical cases were older and had more severe biochemical features of vitamin D deficiency. CONCLUSION: To the best of our knowledge, in this first and largest cohort of neonates with vitamin D deficiency, we did not detect dilated cardiomyopathy. Early recognition and detection before developing actual rickets and preventing prolonged hypocalcaemia are critically important to alleviate cardiac complications.

Acromesomelic dysplasia-Maroteaux type, nine patients with two novel NPR2 variants.

OBJECTIVES: Acromesomelic dysplasia, type Maroteaux, is an autosomal recessive skeletal dysplasia caused by biallelic loss of function variations of NPR2, which encodes a cartilage regulator C-type natriuretic peptide receptor B. NPR2 variations impair skeletal growth. It is a rare type of dwarfism characterized by shortening of the middle and distal segments of the limbs with spondylar dysplasia. METHODS: We performed detailed clinical and radiological evaluation and sequence analysis for NPR2. RESULTS: Herein, we report nine patients from eight families with two novel NPR2 pathogenic variants. CONCLUSIONS: This study describes typical clinical phenotypes of Maroteaux type acromesomelic dysplasia, and enriches the variant spectrum of NPR2 by reporting one nonsense and one missense novel variant. We emphasize the importance of detailed clinical evaluation before genetic testing in diagnosing rare skeletal disorders.

Identification of Three Novel and One Known Mutation in the WFS1 Gene in Four Unrelated Turkish Families: The Role of Homozygosity Mapping in the Early Diagnosis

Objective: Bi-allelic mutations in the wolframin gene (WFS1) cause Wolfram syndrome 1 (WS1 or DIDMOAD) characterized by nonautoimmune diabetes mellitus, optic atrophy, diabetes insipidus, sensorineural deafness, urinary tract abnormalities, and neuropsychiatric disorders. Patients presenting with an incomplete phenotype of WS1 were evaluated using homozygosity mapping and subsequent whole-exome sequencing. Methods: Four unrelated consanguineous Turkish families, including seven affected children, and their unaffected parents and siblings were evaluated. Homozygosity mapping was performed, followed by whole-exome sequencing of WFS1. Mutations were classified according to results of "in silico" analyses, protein prediction, and functional consequences. Results: Homozygosity mapping confirmed shared homozygous regions on chromosome 4 (chr4p16.1) between the affected individuals, that was absent in their unaffected siblings. Exome sequencing identified three novel (c.1215T>A, c.554G>A, c.1525_1540dup) and one known (c.1522_1523delTA) mutations in WFS1. All mutations were predicted to cause stop codon leading to early termination of protein synthesis and complete loss-of-function. All patients were found to be homozygous for the change, with parents and other unaffected siblings being carriers. Conclusion: Our study expands the mutation spectrum of WSF1 mutations with three novel mutations. Homozygosity mapping may provide enrichment for molecular genetic analysis and early diagnosis of WS1 patients with incomplete phenotype, particularly in consanguineous pedigrees.

Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations.

CONTEXT: Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized. OBJECTIVE: To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations. SETTING: Twelve tertiary pediatric endocrine referral centers. PATIENTS: Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years. MAIN OUTCOME MEASURES: Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis. RESULTS: Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = -3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: -2.35, median BMI SDS: -0.52 SDS) with 20/29 (69%) cases having growth retardation. CONCLUSION: We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.

Diagnosis and treatment of hyperinsulinaemic hypoglycaemia and its implications for paediatric endocrinology.

Glucose homeostasis requires appropriate and synchronous coordination of metabolic events and hormonal activities to keep plasma glucose concentrations in a narrow range of 3.5-5.5 mmol/L. Insulin, the only glucose lowering hormone secreted from pancreatic ß-cells, plays the key role in glucose homeostasis. Insulin release from pancreatic ß-cells is mainly regulated by intracellular ATP-generating metabolic pathways. Hyperinsulinaemic hypoglycaemia (HH), the most common cause of severe and persistent hypoglycaemia in neonates and children, is the inappropriate secretion of insulin which occurs despite low plasma glucose levels leading to severe and persistent hypoketotic hypoglycaemia. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) constitute the underlying molecular mechanisms of congenital HH. Since insulin supressess ketogenesis, the alternative energy source to the brain, a prompt diagnosis and immediate management of HH is essential to avoid irreversible hypoglycaemic brain damage in children. Advances in molecular genetics, imaging methods (18F-DOPA PET-CT), medical therapy and surgical approach (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This up to date review article provides a background to the diagnosis, molecular genetics, recent advances and therapeutic options in the field of HH in children.

Severe Hypercalcemia in a Child With Acute Lymphoblastic Leukemia Relapse: Successful Management With Combination of Calcitonin and Bisphosphonate.

Hypercalcemia is a rare complication of hematological malignancy in children. An 8-year-old girl with CALLA (+) Pre-B-cell ALL developed hypercalcemia during bone marrow relapse. She had nausea, vomiting, leg pain, polyuria, polydipsia, and muscle weakness. At the time of relapse, the ionized calcium level was 1.99 mmol/L. Rehydration with 0.9% saline and furosemide and methylprednisolone (MP) treatment were used for the treatment of hypercalcemia. The serum ionized calcium level increased to 2.2 mmol/L despite hydration, furosemide, and MP treatment. Then, a single-dose pamidronate (1 mg/kg/dose) was administered. Despite pamidronate treatment, the calcium level continued to rise. Next, calcitonin at a dose of 8 IU/kg/dose, 4 doses per day, was added to the treatment. After commencement of calcitonin treatment, her ionized calcium level decreased to normal reference ranges. In conclusion, because of the postponed effect of bisphosphonate treatment, pamidronate and calcitonin combination is an effective treatment option in the early resolution of malignancy-related hypercalcemia.

Severe hyponatremia and repeated intestinal resections for intestinal dysmotility mimicking congenital aganglionic megacolon due to delay in the diagnosis of congenital hypothyroidism.

Congenital hypothyroidism (CH) may present with nonspecific signs and symptoms, though, majority of infants can be asymptomatic. Therefore, understimation and delay in diagnosis may result in severe complications. A 5-month-old female admitted to our clinic with the history of repeated surgical operations due to the diagnosis of congenital aganglionic megacolon. Investigations performed in our clinic revealed the diagnosis of congenital (primary) hypothyroidism due to thyroid agenesis. Histopathologic evaluation of previously resected colon sample revealed normal ganglionic cell included colon. During follow-up she developed severe hyponatremia with a plasma sodium level of 106 mEq/L. Eunatremia was maintained following achievement of euthyroid state. In conclusion, since presenting symptoms can be variable and nonspecific, hypotyhroidism should be kept in mind in the differential diagnosis of patients with persistent abdominal distention mimicking aganglionic megacolon and severe hyponatremia of unknown origin.

Platelet aggregation, secretion, and coagulation changes in children with asthma.

The chronic inflammation in asthma evolves by cells including eosinophils, mast cells and lymphocytes. Despite their principal function in hemostasis, platelets contribute to pathogenesis of asthma that activation of platelets occurs following antigen provocation and during asthma attack. Our aim was to evaluate the platelet functions and other hemostatic features of children with asthma, both during symptom-free period and asthma attack. We enrolled patients with asthma attack (n = 33), mild intermittent asthma (n = 18), mild persistent asthma (n = 15) and healthy children (n = 20). Demographic characteristics and disease-related features were noted. Platelet aggregation and secretion tests (expressed as ATP release) were performed by lumiaggregometer method by stimulation with collagen, epinephrine, ADP, thrombin, ristocetin and arachidonic acid. Plasma levels of D-dimer, factor VIII (FVIII) and von Willebrand factor (vWF) were assessed. There were no differences in platelet aggregation induced by agonists between study groups. ATP release from platelets of patients with asthma exacerbation induced by ADP was lower compared with mild intermittent asthma (P < 0.001). Epinephrine-stimulated ATP secretion was also lower in patients with asthma attack than mild intermittent (P = 0.039) and mild persistent asthma (P = 0.011) and controls (P = 0.018). vWF measurements were higher in children with asthma attack than other study groups (P = 0.001). However, FVIII was increased in patients with severe asthma attack. Asthma is a disease in which many immune cells play a role, one of which is the platelet. Distinctions in platelet secretion profiles and plasma levels of vWF and FVIII provide evidence that coagulation mechanisms might be critical for asthma pathogenesis.