Objective: The major part of craniopharyngioma (CP) morbidity is the tumor and/or treatment-related damage, which results in impaired function of the hypothalamic-pituitary axes and metabolic derangements. The aim of the study was to analyze the prevalence of long-term endocrine and metabolic comorbidities in a national cohort of CP patients based on the age at diagnosis and histology criteria. Design: A retrospective-prospective longitudinal cohort analysis. Methods: Forty-six patients with CP treated from 1979 onwards (19 with childhood-onset disease) in a single university institution were included in our study. Median follow-up from presentation was 12.8 years (interquartile range: 8.3–22.2 years) and comparable between age-at-diagnosis and histological subtype groups. Data on tumor histology were extracted from patients’ records and re-evaluated if tissue samples were available (n = 32). Results: Childhood-onset patients presented more frequently with headache, and adult-onset with visual impairment. Prevalence of at least one pituitary axis affected increased from 54% at presentation to 100% at follow-up in childhood-onset and from 41 to 93% in adult-onset CP. Growth hormone deficiency, central diabetes insipidus, and panhypopituitarism were more prevalent in childhood-onset adamantinomatous CP (aCP) and least prevalent in adult-onset papillary CP (pCP). At follow-up, metabolic syndrome (MetS) was diagnosed in 80% of childhood-onset and 68% of adult-onset patients (p = 0.411). In the latter group, it tended to be more frequent in the aCP than pCP subtype (80 vs. 50%, p = 0.110). Conclusions: Long-term endocrine and metabolic complications are very frequent in childhood- and adult-onset CP patients of both histological subtypes. The prevalence of MetS was higher compared to the largest cohort previously reported.

Craniopharyngiomas (CP) are rare low-grade malignancy epithelial tumors of the sellar, supra, and parasellar region. The overall incidence is 1.2–1.5 per million/year with no difference between gender or race. The average age of CP diagnosis has a bimodal distribution, with peaks between 5–14 and 50–74 years of age [1, 2].

Despite their benign histology and high overall survival rate, tumor and/or treatment-related damage results in impaired function of the hypothalamic-pituitary axes and optic structures, causing severe morbidity. Visual and neurological deficits are a frequent consequence of CP treatment; however, the major constituents of CP morbidity are hormonal deficits and metabolic derangements [3‒5]. The type of surgery in the past, which was not hypothalamus-sparing, is accountable for a significant percentage of these problems. Up to 99% of patients have hypopituitarism, more than 50% are obese, and approximately 50% have metabolic syndrome (MetS) [5‒7]. All the mentioned complications are identified as important risk factors for cardio/cerebrovascular disease, which, together with acute adrenal insufficiency and tumor progression, is the most important cause of their premature mortality [8‒10].

There is evidence that presurgical hypothalamic involvement has a priori impact on long-term outcome and that treatment-related hypothalamic lesions lead to further impairments in quality of survival after CP, therefore treatment strategies aiming at preventing additional hypothalamic damage are suggested [10‒12]. Hypothalamic damage is recognized as the primary cause of obesity mediated by hyperinsulinemia, impaired sensitivity to feeding-related signals for leptin, insulin, and ghrelin, altered energy expenditure, increased daytime sleepiness, and reduced physical activity [13, 14].

Adamantinomatous CP (aCP) is the main histological subtype in childhood, and papillary CP (pCP) occurs mostly in the adult population. In pCP, BRAF′ mutation is the principal oncogenic driver and is recently a molecularly targeted therapy (BRAF inhibitor) in recurrent tumors, showed promising results, with dramatic reduction in tumor size [15‒20]. In aCP, mutations in CTNNB1 are found in two thirds of patients, activating the WNT/β-catenin pathway, leading to activation/inhibition of several other pathways. Further studies of these pathways and tumor pathogenesis are needed to identify a causative target for possible future therapeutic use [15, 21]. With the promise of novel therapeutic options, which are CP histology subtype dependent, it is therefore important to increase the knowledge regarding outcomes of CP not only based on the age at diagnosis but also on the histology of the tumor.

The objective of the study was to analyze the prevalence of endocrine and metabolic comorbidities in a national cohort of CP patients both at presentation and at long-term follow-up, based on age at diagnosis and histology criteria.

Data Collection

All childhood-onset CP patients treated in the period from 1979 to September 2019 at the Department of Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Center Ljubljana, were included in the analysis. Because this is the only pediatric endocrine center in Slovenia, we presume that all of the diagnosed children with CP in that period were included in the study (n = 19). Adult-onset CP patients were identified by data-mining of the medical documentation of the patients who were managed for endocrine sequelae following brain tumor surgery at the national referral center at the Department of Endocrinology, Diabetes and Metabolism, Internal medicine, University Medical Center, from January 2006 to December 2017. This is a national referral endocrinology center for brain postsurgical endocrine care; therefore, we presume that the vast majority of adult-onset patients in that period with CP in Slovenia were included in the study. Altogether, 47 patients were identified; we chose to include patients with sufficient follow-up data available (n = 46). Of these 46 patients, 19 were <18 years of age (childhood-onset) and 27 were ≥18 years of age (adult-onset) at the time of disease manifestation. Their median follow-up period from presentation was 12.8 years (interquartile range: 8.3–22.2 years). Data on tumor histology were extracted from patients’ records and when possible, tissue samples from the national Institute of Pathology, Faculty of Medicine, University of Ljubljana, were re-evaluated by a single experienced pathologist (n = 32) [22].

Demographic, endocrine, metabolic, ophthalmological, and neurological data were collected from medical documentation at the time of diagnosis, after the surgical procedure, and at the last follow-up. Treatment-related and long-term health condition data (cardiovascular morbidity, treatment for epilepsy, or psychiatric condition) were also collected from the medical records. Recurrence was defined as reappearance or regrowth of the CP after the primary surgical treatment.

All patients were invited for a follow-up visit, where we additionally evaluated patients’ long-term endocrine and metabolic outcome. Height (cm), weight (kg), and waist and hip circumference (cm) were measured by trained medical professionals using validated stadiometers and electronic digital scales in the morning following an overnight fast. The measurements were rounded to the first decimal place. BMI was calculated for adult patients (≥18 years of age); overweight was defined as BMI between 25 and 30 kg/m2 and obesity as BMI >30 kg/m2. For pediatric patients (<18 years of age), overweight was defined as BMI at or above the 85th percentile and below the 95th percentile and obesity as BMI at or above the 95th percentile for children of the same age and sex [23]. Patients’ blood was withdrawn in the early morning for evaluation of all pituitary axes. Growth hormone (GH) deficiency in our cohort has been routinely assessed by measuring IGF1 and IGFBP3 among patients with adult-onset disease. Data on their use of hormonal substitution therapy were recorded. Panhypopituitarism was defined by 3 or more anterior pituitary hormone deficiencies (GH deficiency, thyroid-stimulating hormone deficiency, adrenocorticotropic hormone deficiency, and late puberty in children or hypogonadism in adults).

At the additional follow-up we also evaluated parameters reflecting components of MetS. Patients who were not already diagnosed with diabetes type 2 underwent an oral glucose tolerance test. MetS was diagnosed when the following criteria were fulfilled: central obesity (waist circumference ≥90th percentile in children <16 years, ≥94 cm for European males, and ≥80 cm for European females or obesity) – as an obligatory part, and 2 of the following 4 criteria: hypertension (blood pressure ≥130/85 mm Hg or medical treatment), elevated triglycerides (≥1.7 mmol/L) or specific treatment for high triglycerides, lowered HDL cholesterol (<1.0 mmol/L in males and children <16 years, <1.3 mmol/L in females) or medical treatment for reduced HDL cholesterol, and hyperglycemia (elevated fasting glucose level or previously diagnosed diabetes type 2) [24]. Prediabetes was defined as impaired fasting glucose and/or impaired glucose tolerance and/or hemoglobin A1c 5.7–6.4% [25, 26].

Magnetic Resonance Imaging

When available, preoperative MRI scans were re-evaluated by a single experienced neuroradiologist to determine possible associations between tumor characteristics and long-term hormonal and metabolic complications. The following parameters were determined: presence of hydrocephalus, optic nerve involvement, and hypothalamic tumor involvement according to the Puget grading [27] – grade 0 (no hypothalamic involvement), grade 1 (tumor displacing the hypothalamus or pushing against the bottom of the third ventricle), or grade 2 (hypothalamic involvement or unidentifiable hypothalamus).

For the evaluation of the role of posttreatment CNS sequelae for the development of complications, the most recent MRI scans were used. The following parameters were assessed: hypothalamic damage (minimal or severe combined with third ventricle floor damage), optic nerve damage, and the suprachiasmatic nucleus area damage.

Statistical Analysis

Statistical analysis was conducted using the Statistical Package for Social Sciences (SPSS 25) as well as with R programming language [28]. The evaluations in each case were based on the number of patients with available data. Continuous variables were described as median and interquartile range, and discrete variables as frequencies and percentages. For comparison of different groups for categorical variables, Fisher’s exact test was performed. A p value <0.05 (two-tailed) was considered statistically significant. Since the nature of the study was rather the description of the patient population than hypothesis driven, the correction for multiple testing was not performed.

Patient Characteristics at Diagnosis

Forty-six patients, 19 with childhood-onset and 27 with adult-onset CP, were included in the analysis. Data on histology were available in 32 patients – 12 patients with childhood-onset CP (all aCP) and 20 with adult-onset CP (12 aCP and 8 pCP). As shown in Figure 1, the distribution of age at diagnosis was bimodal. aCP subtype was present in all childhood-onset CP and 60% of adult-onset CP (Fig. 1). In childhood- and adult-onset aCP there was a male predominance, whereas in the adult-onset pCP genders were equally distributed. According to our data, national incidence since the year 2000 is estimated at 0.79 per million/year. Since 1980 an increase in incidence has not been observed.

Fig. 1.

Frequency of craniopharyngioma diagnosis according to age at diagnosis and histological subtype. Data on histological type was missing in 6 childhood- and 7 adult-onset craniopharyngioma patients.

Fig. 1.

Frequency of craniopharyngioma diagnosis according to age at diagnosis and histological subtype. Data on histological type was missing in 6 childhood- and 7 adult-onset craniopharyngioma patients.

Close modal

Presenting symptoms, endocrine deficiencies, and tumor characteristics at diagnosis are summarized in Table 1 (additional division by histological subtype is presented in Table 2). Headache and nausea were the more common presenting symptoms in the childhood-onset population (87%, p = 0.016 and 40%, p = 0.010, respectively), whereas visual impairment was more common in the adult-onset population (74%, p = 0.049). At the time of diagnosis, at least one anterior pituitary hormonal axis was affected in half of the childhood-onset CP patients, GH deficiency being the most common. In the adult-onset CP, at least one hormonal axis was affected in 41% of subjects. Distribution of the affected axis was relatively equal in contrast to childhood-onset CP. The frequency of central diabetes insipidus at the diagnosis was comparable in the two groups. No differences at presentation were observed between histological subtypes. In preoperative imaging, hydrocephalus and hypothalamic involvement of the tumor (grade 2) were more common in the childhood-onset disease (Table 1). There was no reversal of pre-existing pituitary hormone deficiencies after surgical intervention in any of the patients.

Table 1.

Childhood- and adult-onset craniopharyngioma patients’ characteristics at diagnosis

 Childhood- and adult-onset craniopharyngioma patients’ characteristics at diagnosis
 Childhood- and adult-onset craniopharyngioma patients’ characteristics at diagnosis
Table 2.

Childhood- and adult-onset craniopharyngioma patients’ characteristics at diagnosis according to histological subtype

 Childhood- and adult-onset craniopharyngioma patients’ characteristics at diagnosis according to histological subtype
 Childhood- and adult-onset craniopharyngioma patients’ characteristics at diagnosis according to histological subtype

Craniopharyngioma Treatment

Data on surgical approach and type of resection in this study were limited. Therefore, we were not able to determine the effect of type of resection (surgical approach, gross total vs. partial resection) on the hormonal or metabolic outcome. In the University Medical Center of Ljubljana, Department of Neurosurgery, a study by Bosnjak et al. [29] was published about short-term outcomes of 8 adult-onset aCP patients who underwent transsphenoidal surgery between the years 2007 and 2011, with the goal of complete tumor resection. All these patients were included in our study. Bosnjak et al. studied the rate of panhypopituitarism in these patients, which was similar to the rate in our cohort, without taking treatment approach into account (63 vs. 67%, respectively). The standard surgical approach in our center until recently was gross total resection whenever feasible. In the presented cohort subtotal resection was not consistently followed by radiotherapy. It was more commonly chosen as a treatment modality for tumor recurrence as an alternative to further surgery, or after the second resection. There was no difference in the recurrence rate between childhood- or adult-onset CP or between histological subtypes.

Patient Characteristics at Follow-Up

Long-term endocrine and metabolic outcomes are shown in Tables 3 and 4. At the last follow-up 100% of childhood-onset and 93% of adult-onset CP patients had an endocrine deficiency. Comparing groups by the age at diagnosis, panhypopituitarism and GH deficiency were diagnosed more often in the childhood-onset population (100 vs. 59%, p = 0.001; 100 vs. 52%, p = 0.003). Deficiencies of thyroid-stimulating and adrenocorticotropic hormone were the most frequent endocrine deficiencies in both groups. Comparing groups by histology, aCP related to higher prevalence of panhypopituitarism (p = 0.027) and diabetes insipidus (p = 0.026) after the initial treatment. After long-term follow-up, childhood-onset aCP patients experienced the highest rate of all hormone deficiencies, with GH deficiency, diabetes insipidus, and panhypopituitarism being more frequent in comparison to adult-onset pCP and aCP patients (p = 0.007, p = 0.02, and p = 0.009, respectively). When only comparing childhood- and adult-onset aCP patients, only frequency of GH deficiency remained statistically significant (p = 0.037).

Table 3.

Childhood- and adult-onset craniopharyngioma patients’ characteristics at the last follow-up compared by age at diagnosis

 Childhood- and adult-onset craniopharyngioma patients’ characteristics at the last follow-up compared by age at diagnosis
 Childhood- and adult-onset craniopharyngioma patients’ characteristics at the last follow-up compared by age at diagnosis
Table 4.

Comparison of long-term endocrine and metabolic complications based on age at diagnosis and histological subtype of craniopharyngioma

 Comparison of long-term endocrine and metabolic complications based on age at diagnosis and histological subtype of craniopharyngioma
 Comparison of long-term endocrine and metabolic complications based on age at diagnosis and histological subtype of craniopharyngioma

In our cohort, despite high rates of GH deficiency, only 29% of these patients were receiving GH treatment (41% of childhood-onset and 14% of adult-onset CP patients) at the last follow-up. All childhood-onset patients with growth potential and GH deficiency were treated with human recombinant GH (hr-GH) until the end of linear growth. They were advised to continue receiving hr-GH in the adult dose until their transition to the adult endocrinologist. Treatment with hr-GH was also offered to the patients with adult-onset CP with GH deficiency in the studied time period. Possibly due to the reassuring data about its safety, these patients seem to start hr-GH more frequently in the last decade.

At the last follow-up, MetS was diagnosed in 80% of childhood-onset and 68% of adult-onset patients (p = 0.411). In the latter group it tended to be more frequent in aCP than pCP subtype (80 vs. 50%, p = 0.110). When determining specific components of the MetS, after long-term follow-up, increased BMI was observed in 80% of patients whose weight data were available at the time of diagnosis (Fig. 2). At the last follow-up 89% of childhood-onset and 96% of adult-onset CP patients were overweight, and approximately 50% of patients in both groups were obese. Obesity correlated with the presence of hydrocephalus at diagnosis, hypothalamic damage, and damage of the third ventricular floor seen on the latest MRI scan (p = 0.029, p = 0.038, and p = 0.026, respec­tively).

Fig. 2.

Comparison of BMI before diagnosis and at last follow-up in childhood- and adult-onset craniopharyngioma patients.

Fig. 2.

Comparison of BMI before diagnosis and at last follow-up in childhood- and adult-onset craniopharyngioma patients.

Close modal

When comparing groups by the age at diagnosis, ­hypertension was more frequently seen in the adult-onset (63 vs. 6%, p = 0.001) and prediabetes in the childhood-onset group (67 vs. 30%, p = 0.031). Type 2 diabetes was diagnosed in 11% of childhood-onset and 22% of adult-onset patients. Comparing groups by histology,visceral obesity was significantly more common in aCP (p = 0.033) and in male patients generally (p = 0.002). No other difference was found between genders. No endocrine deficiency risk factors for the development of MetS were identified in our cohort. There were no significant differences in the frequency of MetS and its components between treated and untreated patients for GH deficiency at their last follow-up.

Presenting features and long-term endocrine and metabolic comorbidities of childhood- and adult-onset CP from a nationally representative cohort were analyzed based on age-at disease, complemented with histology data. As previously described in the literature, childhood-onset patients presented more frequently with a headache, whereas visual impairment was more common in adult-onset cohorts [5, 7, 30‒32]. After long-term follow-up we observed higher rates of hormone deficits (panhypopituitarism and GH deficiency) in childhood-onset CP, corroborating the results of other studies [5, 7]. GH deficiency, diabetes insipidus, and panhypopituitarism were more frequent in childhood-onset aCP compared to adult-onset pCP. In our cohort, MetS developed in 80% of childhood-onset and 68% of adult-onset patients, which is considerably higher than recently reported by Wijnen et al. [6], who evaluated the prevalence of MetS in the largest cohort to date.

At presentation headache and nausea predominated in childhood-onset CP and visual impairment in the adult-onset CP patients. Headache is reported to be the most frequent presenting symptom in childhood-onset CP [5, 7, 30], and similarly a high prevalence of visual deficits at diagnosis is reported in studies on adult-onset CP [5, 7, 31, 32]. Although there are no specific symptoms related to both childhood- and adult-onset CP, a combination of headache, visual impairment, decreased growth velocity (in children), weight gain, and polydipsia and/or polyuria should arouse suspicion of CP [30, 33]. Earlier diagnosis should be beneficial for improving the prognosis of CP, although tumor size and hypothalamic involvement at the time of diagnosis – two characteristics that have a significant negative effect on the overall survival and functional outcome – are not correlated with the duration of symptoms before diagnosis [34]. In our cohort we did not observe any difference in presenting symptoms between aCP and pCP, irrespective of the age of disease onset.

Childhood-onset CP histology was exclusively adamantinomatous. pCP is described in children, but it is extremely rare [35]. In adult-onset CP, pCP was histologically confirmed in 40%, concordant with the previous reports, recognizing this subtype in 14–50% of adult-onset CP [36]. Although CP is histologically benign, malignant alterations are possible. Until 2018, 17 cases of malignant CP were described in the literature; in 3 of them a malignant component was found at the initial diagnosis, while in others the alteration was secondary and it occurred years after initial treatment (all of these patients underwent radiotherapy) [37]. We report on an additional case of malignant aCP.

Several other studies analyzed long-term health conditions between patients with childhood- and adult-onset CP [7, 38‒40]. Concordant with our results, Wijnen et al. [7] and Gautier et al. [38] reported a significantly higher prevalence of panhypopituitarism and GH deficiency in childhood-onset CP. On the other hand, Kendall-Taylor et al. [40] and Karavitaki et al. [39] observed a similar frequency of panhypopituitarism in both adult- and childhood-onset disease. Interestingly, in a recent study by Feng et al. [41], in contrast to our study, higher frequencies of long-term endocrine deficiencies and hypothalamic dysfunction (in terms of obesity, eating disorders, polydipsia and polyuria, sleep disorder, cognitive dysfunction and personality changes, imbalances in the regulation of body temperature, and memory loss) were reported after surgery in pCP compared to aCP subtype. We observed a higher prevalence of panhypopituitarism and diabetes insipidus in the aCP cohort when compared to pCP at the last follow-up visit. When we further divided groups according to the age of disease onset, childhood-onset aCP patients experienced more GH deficiency, diabetes insipidus, and panhypopituitarism in comparison to the adult aCP and pCP cohort. Our median follow-up period was comparable to that in previously published studies, being 12 years in childhood-onset and 14 years in adult-onset CP [7, 38‒40]. The shorter follow-up period in pCP patients could influence our results, yet it was determined that pituitary hormonal deficiency rarely appearsmore than 6 years after tumor diagnosis and treatment [42]. Therefore, we presume that the duration of follow-up could mostly affect the lower prevalence of metabolic, but not the endocrine, complications in pCP patients. Another factor that is important in comparing patient outcomes is the difference in the biology of CP histological subtypes. It has been shown that pCP, which is typically solid, well-circumscribed, and does not adhere to the adjacent structures, allows safer radical removal in most cases. A lower recurrence rate together with a higher rate of total tumor removal rate has been reported for pCP [22, 43]. Because of the nature of aCP (not well-circumscribed, adheres to the surroundings with finger-like tumor protrusion not visible on MRI scans), complete resection is often not feasible and causes more damage to the adjacent structures while attempting it [22, 43]. Another feature of aCP is its secretion of proinflammatory cytokines from the tumor cells and cytokine infiltration of the brain tissue close to the tumor [44, 45]. Inflammation is likely to produce greater tumor adherence to and infiltration of the adjacent brain. It has been recently associated with the development of GH deficiency in aCP, which might at least partly explain the observed differences in our cohort. Inflammation-related cross-talk between aCP cells and pericytes in the pituitary could be an essential factor in the formation of GH deficiency through IL-1α-induced pituitary fibrosis. Neutralization of IL-1α signaling might be a potential therapy for GH deficiency in aCP [46].

In our study, there was a higher rate of hypothalamic involvement in childhood-onset CP at diagnosis determined by available preoperative MRI scans. This is a known risk factor for worse long-term outcomes by itself in terms of survival, functional capacity, and risk of obesity [13, 47‒49]. Hypothalamus-sparing surgery in these patients is therefore crucial to prevent additional hypothalamic damage induced by therapy. Hydrocephalus at diagnosis has been more frequently observed in childhood-onset disease, especially in children under 10 years of age; however, this was not confirmed in our cohort [7, 38, 39]. Its effect on long-term prognosis remains unclear, with data supporting higher relapse and morbidity rates in these patients [38, 50, 51], but no difference in their overall survival and functional capacity was found [50]. In our series hydrocephalus at diagnosis was significantly correlated with long-term obesity, corroborating previous reports [50, 51]. In the last decades a shift towards partial resection in patients with initial hypothalamic tumor involvement – hypothalamus-sparing surgery – lowered the frequency of hypothalamic obesity; however, in spite of this approach nearly half of the patients are still morbidly obese [27, 52]. Hypothalamic involvement/damage results in disrupted sensitivity to feeding-related signals for leptin, insulin, and ghrelin as well as in autonomic nervous system dysfunction, leading to reductions in energy expenditure and basal metabolic rate, and affecting food intake [14, 49]. Furthermore, reduced levels of physical activity, reduced motivation, and suboptimal psychosocial development are also known consequences of hypothalamic damage [12] and may also have an additional negative effect on metabolic function.

We observed a noticeably higher prevalence of MetS in our cohort than recently reported by Wijnen et al. [6], who described MetS in 48% of childhood-onset patients and 45% of adult-onset patients in the largest cohort to date evaluating the prevalence of MetS in 178 CP patients with a median follow-up of 16 years. In our aCP subgroup, independent of age at diagnosis, 2 components of MetS – visceral obesity and reduced HDL – were more frequent. Visceral adipose tissue-induced insulin resistance is postulated to be the principal factor resulting in MetS and its components [53]. GH treatment has a known beneficial metabolic effect (reduced visceral obesity, improved insulin sensitivity, effects on lipoprotein metabolism). In a study by Profka et al. [54], this effect was interestingly less pronounced in patients with CP compared to patients with hypopituitarism due to pituitary adenoma.

Some limitations of our study should be considered. The results of our study are limited due to its retrospective analysis of patient records and relatively small sample size. Our data on surgical treatment were incomplete (especially before the year 2000) and did not allow evaluation of its effect on long-term endocrinological and metabolic outcomes.

In conclusion, the prevalence of long-term endocrine and metabolic complications was very high in this national cohort of childhood- and adult-onset CP patients of both histological subtypes. The risk of pituitary hormonal deficits was especially increased in childhood-onset patients. The prevalence of MetS was higher compared to that of the largest cohort previously reported. Presented results emphasize the importance of all measures pertinent to prevent any additional hypothalamic damage, starting with hypothalamus-sparing surgery. Immediate structured, multidisciplinary postsurgical and long-term follow-up of these patients is paramount for achieving better long-term outcomes. In the future, the development of molecularly targeted treatment, which is currently already used in some pCP patients [16‒19], might be an alternative path to better outcomes in all forms of CP, minimizing damage caused to the hypothalamus by current treatment modalities.

The authors would like to thank all the physicians and medical personnel involved in the treatment and follow-up care of patients with craniopharyngioma and to the patients and their families who participated in the study.

The study protocol was approved by the National Ethics Committee (No. 0120-364/2018/6). Written consent was obtained from the parents on behalf of the child.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

This research was in part financed by the Slovenian National Research Agency (grant No. P3-0343) and University Medical Centre Ljubljana (grant No. 20190098).

All authors participated in the study design, data collection, data analysis, literature search, and writing of the manuscript.

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