Band 36, Heft 4

Rickets is the disease of a growing skeleton and results from impaired apoptosis of hypertrophic chondrocytes and mineralization of the growth plate. Nutritionally induced rickets, secondary to vitamin D and/or calcium deficiency, remains a major global problem. In this review, we discuss pathogenesis, clinical signs, investigation and management of nutritional rickets.

Subclinical hyperthyroidism (SH) is defined as serum thyroid-stimulating hormone (TSH) below the lower limit of the reference range in the presence of normal free T4 and free T3 levels. Depending on the degree of TSH suppression, SH could be defined as mild (TSH, 0.1–0.45 mU/L) or severe (TSH<0.1 mU/L). Patients with SH are often asymptomatic when symptoms are present, they are similar to the symptoms in patients with overt hyperthyroidism, although they are usually milder. The management of the SH is uncertain and should be individualized. We present this review after an extensive literature search and long-standing clinical experience. This review provides the prevalence, causes, clinical presentation, investigation, and therapeutic approach of SH in children.

Objectives We aimed to evaluate the stiffness of the thyroid parenchyma with Shear wave elastography (SWE) in children with Hashimoto’s thyroiditis (HT) and healthy controls. Methods A total of 130 children with HT and 46 healthy controls were included in this study. The clinical and laboratory characteristics of the groups, thyroiditis stages in thyroid ultrasonography, and SWE scores which was obtained as kilopascal (kPa), were analysed. Results We observed that SWE scores were significantly higher in children with HT compared to healthy controls, and SWE scores increased significantly in HT group, as the thyroiditis stage increased (p<0.001). Median, 1st (Q1) and 3rd (Q3) quartiles of SWE scores were as follows; healthy control: 7.4 kPa (6–10.6), stage 1 HT: 9.6 kPa (7.4–11.2), stage 2 HT: 15.2 kPa (10.8–19.9), stage 3 HT: 17.9 kPa (13.7–25.8), (p<0.001). Children with HT were divided into subgroups according to serum TSH and free T4 levels as euthyroid (103; 79.2% of children), euthyroid but subclinical TSH elevation (7; 5.4% of children), hypothyroidism (11; 8.5% of children) and hyperthyroidism (9; 6.9% of children). The SWE scores were significantly higher in children with hypothyroidism with HT compared to healthy controls 17.9 kPa (13.6–27.5) vs. 7.4 kPa (6–10.6), and in euthyroid children with HT compared to healthy controls 11.5 kPa (9.2–15.6) vs. 7.4 kPa (6–10.6), (p=0.006 and p<0.001, respectively). Conclusions The SWE scores increase as the thyroiditis stage increases in children with HT. There was no significant difference in SWE scores between stage 2 and stage 3 thyroiditis.

Objectives More than one third of children with congenital hypothyroidism (CH) and thyroid gland in situ  (or eutopic gland) have transient hypothyroidism. It remains difficult to determine early on whether hypothyroidism will be transient which may cause overtreatment and its complications in these children. Our primary aim was to determine prognostic factors for transient hypothyroidism in children with congenital hypothyroidism and eutopic gland or thyroid hemiagenesis. Methods We retrospectively reviewed medical records of 111 children, born between 1996 and 2017, diagnosed with congenital hypothyroidism and eutopic gland or hemiagenesis and treated at the Nancy Regional and University Hospital. Results Fifty four infants (48.6%) had permanent congenital hypothyroidism (PCH) and 57 (51.4%) transient congenital hypothyroidism (TCH). Prognostic factors for TCH included prematurity, twin pregnancy, low birth weight and Apgar score <7, while low FT3 at diagnosis, maternal levothyroxine treatment, a family history of thyroid dysfunction and TSH ≥10 mUI/L while receiving treatment were associated with PCH. Knee epiphyses on X-ray at diagnosis were absent only in children with PCH. The median levothyroxine dose during follow-up was significantly lower in the TCH group compared to the PCH group. A levothyroxine dose of ≤3.95, ≤2.56, ≤2.19 and ≤2.12 μg/kg/day at 6 months, 1, 2 and 3 years of follow-up, respectively, had the best sensitivity-to-specificity ratio for predicting TCH. Conclusions Even though it remains difficult to predict the course of hypothyroidism at diagnosis, we were able to identify several prognostic factors for TCH including perinatal problems and lower levothyroxine requirements that can guide the physician on the evolution of hypothyroidism. Clinical Trial Registration Number: NCT04712760.

Objectives Congenital hypothyroidism (CH) is still one of the most common causes of preventable cognitive impairment in children, and its early detection and treatment prevent irreversible neurodevelopmental delay. Depending on the underlying cause, cases with CH may be transient or permanent. This study aimed to compare the developmental evaluation results of transient and permanent CH patients and to reveal any differences. Methods A total of 118 patients with CH, who were followed up jointly in pediatric endocrinology and developmental pediatrics clinics, were included. The patients’ progress was evaluated per the International Guide for Monitoring Child Development (GMCD). Results Of the cases, 52 (44.1%) were female, and 66 (55.9%) were male. While 20 (16.9%) cases were diagnosed with permanent CH, 98 (83.1%) were diagnosed with transient CH. According to the results of the developmental evaluation made with GMCD, the development of 101 (85.6%) children was compatible with their age, while 17 (14.4%) children had delays in at least one developmental area. All 17 patients had a delay in expressive language. Developmental delay was detected in 13 (13.3%) of those with transient CH and 4 (20%) with permanent CH. Conclusions There is difficulty in expressive language in all cases of CH with developmental delay. No significant difference was found between the developmental evaluations of permanent and transient CH cases. The results revealed the importance of developmental follow-up, early diagnosis and interventions in those children. GMCD is thought to be an important guide to help monitoring the development of patients with CH.

Objectives Epicardial adipose tissue (EAT) thickness, a novel marker of cardiovascular disease (CVD), is increased in children with a healthy weight and type 1 diabetes (T1D). The prevalence of obesity has increased in children with T1D and may confer additional CVD risk. The purpose of this study was to examine EAT thickness in youth with and without T1D in the setting of overweight/obesity. Methods Youth with overweight/obesity and T1D (n=38) or without T1D (n=34) between the ages of 6–18 years were included in this study. Echocardiogram using spectral and color flow Doppler was used to measure EAT and cardiac function. Waist circumference, blood pressure, and HbA 1c , were used to calculate estimated glucose disposal rate (eGDR) to estimate insulin resistance in children with T1D. Results EAT thickness was not significantly different in youth with T1D compared to controls (2.10 ± 0.67 mm vs. 1.90 ± 0.59 mm, p=0.19). When groups were combined, EAT significantly correlated with age (r=0.449, p≤0.001), BMI (r=0.538, p≤0.001), waist circumference (r=0.552, p≤0.001), systolic BP (r=0.247, p=0.036), myocardial performance index (r=−0.287, p=0.015), ejection fraction (r=−0.442, p≤0.001), and cardiac output index (r=−0.306, p=0.009). In the group with T1D, diastolic BP (r=0.39, p=0.02) and eGDR (r=−0.48, p=0.002) correlated with EAT. Conclusions EAT was associated with measures of adiposity and insulin resistance but does not differ by diabetes status among youth with overweight/obesity. These findings suggest that adiposity rather than glycemia is the main driver of EAT thickness among youth with T1D.

Objectives The study aimed to determine the prevalence of PAD in children with T1DM and to correlate PAD with clinical characteristics in children with T1DM. Methods A comparative cross-sectional study was conducted involving 90 subjects (forty-five with T1DM and 45 apparently healthy comparative subjects that were matched for age and gender). Systolic blood pressure was measured in all limbs using the pocket Doppler machine (Norton Doppler scan machine). Ankle brachial index (ABI) was calculated as a ratio of ankle to arm systolic blood pressure. Peripheral arterial disease was defined as ABI less than 0.9. Results The prevalence of PAD was significantly higher in children with T1DM than in the matched comparison group (37.8% vs. 6.7%, p<0.001). Average values of waist circumference, hip circumference, weight, height and body mass index were comparable in subjects with TIDM and the comparison group (p>0.05). Subjects with PAD had a poorer glucose control evident by higher average values of glycated haemoglobin than those without PAD (13.47 ± 3.2% vs. 8.16 ± 2.3%, p<0.001). There is a strong negative correlation between ABI scores and glycated haemoglobin among subjects with T1DM (r=−0.626, p<0.001). Conclusions With these findings, it is recommended that screening for PAD in children who have T1DM and poor glycaemic control should be done early to prevent cardiovascular complications before they arise.

Objectives To evaluate the WHO-5 tool in pediatric and young adult subjects with type 1 diabetes, and to analyse associations with demographic/psychological characteristics. Methods We included 944 patients with type 1 diabetes 9–25 years of age, documented in the Diabetes Patient Follow-up Registry between 2018 and 2021. We used ROC curve analysis to determine optimal cut-off values for the WHO-5 scores to predict psychiatric comorbidity (ICD-10-diagnoses) and analysed associations with obesity, HbA 1c , therapy regimen, and lifestyle via logistic regression. All models were adjusted for age, sex, and diabetes duration. Results In the total cohort (54.8% male), the median score was 17 [Q1-Q3: 13–20]. Adjusted for age, sex, and diabetes duration, the WHO-5 scores<13 were associated with psychiatric comorbidity, especially depression and ADHD, poor metabolic control, obesity, smoking, and less physical activity. There were no significant associations with therapy regimen, hypertension, dyslipidemia, or social deprivation. In subjects with any diagnosed psychiatric disorder (prevalence 12.2%), the odds ratio for conspicuous scores was 3.28 [2.16–4.97] compared to patients without mental disorders. Using ROC analysis, the optimal cut-off to anticipate any psychiatric comorbidity in our cohort was 15, and 14 for depression. Conclusions The WHO-5 questionnaire is a useful tool to predict depression in adolescents with type 1 diabetes. ROC analysis suggests a slightly higher cut-off for conspicuous questionnaire results compared to previous reports. Due to the high rate of deviant results, adolescents and young adults with type-1 diabetes should be screened regularly for signs of psychiatric comorbidity.

Objectives The aim of study was to evaluate the 2D shear wave sonoelastography (SWE) findings of the thyroid gland in children with type 1 diabetes mellitus (T1DM) with normal gray-scale findings and without thyroid autoimmunity (AIT) and obtain data that will be useful for the early detection of glandular involvement. Methods The study included 46 T1DM patients (mean age: 11.28 ± 3.3 years) and 46 healthy children (mean age: 12.01 ± 3.8 years) as the control group. The thyroid gland mean elasticity value was obtained as kPa and compared in groups. A correlation was investigated between elasticity values and age at diabetes, serum free T4, thyroid stimulating hormone (TSH), anti-thyroglobulin, anti-tissue peroxidase, and hemoglobin A1c values. Results No difference was found between T1DM patients and the control group in the thyroid 2D SWE evaluation (the median kPa value: 17.1 (10.2) in the study group and 16.8 (7.0) in the control group) (p=0.15). No significant correlation was found between 2D SWE kPa values and age at diagnosis, serum free T4, TSH, anti-thyroglobulin, anti-tissue peroxidase, and hemoglobin A1c levels in T1DM patients. Conclusions Our study showed that the elasticity of the thyroid gland in T1DM patients without AIT was not affected differently from that of the normal population. If 2D SWE is used in routine follow-up in T1DM patients before the development of AIT, we think that it will be useful in the early detection of thyroid gland affections and AIT, and long-term comprehensive studies in this direction will contribute to the literature.

Objectives Central precocious puberty (CPP) develops as a result of early stimulation of the hypothalamic-pituitary-gonadal (HPG) axis. The loss-of-function mutations in the Makorin-ring-finger3 (MKRN3) gene appear to be the most common molecular cause of familial CPP. We aimed to identify MKRN3 gene mutations in our CPP cohort and to investigate the frequency of MKRN3 mutations. Methods 102 patients with CPP included. 53 of them had family history of CPP in the first and/or second-degree relatives. MKRN3 gene was analyzed by next-generation sequencing. Results Possible pathogenic variants were found in 2/53 patients with family history of CPP (3.8%) and 1/49 patient without family history (2%). A novel heterozygous c.1A>G (p.Met1Val) mutation, a novel heterozygous c.683_684delCA (p.Ser228*) and a previously reported c.482dupC (Ala162Glyfs*) frameshift variations were detected. The two novel variants are predicted to be pathogenic in silico analyses. Conclusions In our cohort, possible pathogenic variants in MKRN3 gene were detected in 2.9% of the total cohort, 3.8% of the familial and 2% of the nonfamilial cases, slightly lower than that reported in the literature. Two novel variants detected contribute to the molecular repertoire of MKRN3 defects in CPP. Classical pattern of paternal inheritance has been demonstrated in all three cases. However, the father of the patient 3 did not have history of CPP suggesting that the father inherited this variant from his mother and had phenotype skipping. Therefore, we emphasize that the absence of history of CPP in the father does not exclude the possibility of a MKRN3 mutation.

Objectives Asparagine-dependent glycosylation 11-congenital disorders of glycosylation (ALG11-CDG) is a rare autosomal recessive N-glycosylation defect with multisystem involvement particularly neurological symptoms such as epilepsy and neuromotor developmental delay. Case presentation A 31-month-old male patient admitted to our center with complaints of axial hypotonia, drug-resistant myoclonic seizures, microcephaly and deafness. The electroencephalography (EEG) showed a burst-suppression pattern without hypsarrhythmia. Basal metabolic investigations were unremarkable. Progressive cerebral atrophy, hypomyelination and corpus callosum hypoplasia were striking features in brain MRI images taken during our follow-up. Compound heterozygous mutations of the ALG11 gene were found by whole exome sequencing (WES) analysis. It was determined that the c.476T>C mutation is a novel mutation. CDG type 1 pattern was detected with the examination of carbohydrate-deficient transferrin (CDT) by capillary zone electrophoresis. Conclusions In patients with a possible congenital defect of glycosylation, a screening test such as CDT analysis is suggested. To discover novel mutations in this rare disease group, expanded genetic analysis should be performed.

Objectives Betamethasone causing iatrogenic Cushing’s syndrome (CS) in infants are rarely reported. Case presentation In this case report, there were severe signs of CS, such as considerable weight acceleration and concurrent height deceleration, hirsutism and ecchymosis of the face, and buffalo pad, which are often found in adults. Clobetasol propionate, diflucortolone valerate, and dexamethasone nasal sprays were used in the majority of previously reported cases of corticosteroid abuse, whereas this is the first case of CS in an infant as a result of the use of betamethasone cream, also known as betnesol, which is frequently used by mothers in developing countries as a treatment for rashes. In this instance, a severe medication interaction caused by systemic betamethasone cream buildup led to the creation of CS. For the professionals, these patients are a challenge because of drug use without prescription. Conclusions Topical corticosteroid usage puts infants at risk for CS. Because of excessive betamethasone treatment in this child with diaper dermatitis, he acquired CS. It is said to draw attention to the risks of self-medication in developing nations.

Objectives Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation (ROHHAD) is a rare syndrome associated with high morbidity and mortality. Diagnosis is often challenging. We describe three cases of ROHHAD with heterogeneous presentations but some consistent clinical features, including hyperprolactinaemia at diagnosis. We highlight when the diagnosis of ROHHAD should be considered at an early stage. Case presentation All three patients presented between 4 and 6 years old with rapid-onset obesity. They all have central hypoventilation requiring nocturnal BiPAP, varying degrees of hypothalamic dysfunction with hyperprolactinaemia being a consistent feature, and autonomic dysfunction. One patient has a neuro-endocrine tumour (NET) and two have glucose dysregulation. Conclusions High prolactin was a consistent early feature. Central hypoventilation and NET may present later and therefore regular sleep studies and screening for NETs are required. A high suspicion of ROHHAD is warranted in patients with rapid, early-onset obesity and hyperprolactinaemia without structural pituitary abnormality.

Objectives Lathosterolosis is a rare autosomal recessive congenital disease that occurs due to homozygous or compound heterozygous mutations in the sterol C5-desaturase ( SC5D ) gene. We report a male patient with biallelic missense variant detected in the SC5D gene. Case presentation An eight-month-old male patient was referred to the department of paediatric neurology for status epilepticus. He had no remarkable dysmorphic features except micrognathia, ptotic ear and thin-stranded hair. Laboratory tests revealed an alanine aminotransferase level of 502 IU/L and an aspartate aminotransferase level of 279 IU/L; other biochemical test results were normal. The brain MRI revealed atrophic changes in both hemispheres. A decrease in the volume of brain stem and thin corpus callosum were noticeable. Whole exome sequencing was performed because of consanguineous marriage and sibling death in his medical history, and the encountered features were consistent with suspected neurometabolic disease in the cranial imaging and the presence of borderline psychomotor retardation. A biallelic missense variant, c.656T>C p.(Leu219Ser), was identified in the SC5D gene. Conclusions Lathosterolosis is a rare cholesterol metabolism disorder and can be presented with a wide range of clinical features by newly reported cases. Lathosterolosis should be considered in cases with cataracts, delayed neuromotor developmental milestones and high levels of liver enzymes.

Objectives Classic treatment for syndrome of inappropriate antidiuretic hormone (SIADH) is fluid restriction. However, this is not ideal for infants who need large fluid volumes to ensure adequate caloric intake for growth. The use of urea has not been thoroughly studied in children. Case presentation This infant had SIADH complicated by poor growth, solitary central incisor, and NF1. Following failed attempts to correct hyponatremia with fluid restriction and other therapeutics, urea normalized sodium levels and allowed liberalization of formula volumes, which resulted in improved weight gain. Conclusions Urea is a safe, cost-effective, long-term treatment for SIADH in infants who are unable to fluid restrict due to caloric goals.