Despite decades of experience, the diagnosis of growth hormone deficiency (GHD) remains challenging, especially in peripubertal children. Failure to respond to GH stimulation tests (GHSTs) is needed to confirm GHD, but long-standing controversies regarding the number of tests needed and the interpretation of GH peaks are still a matter of debate worldwide. Diagnostic workup is even more problematic in short children with slow growth and delayed sexual development: they often exhibit low GH peaks under GHST, which often normalize as puberty progresses. Consequently, this transient suboptimal response to GHST may result in GH overtreatment, carrying both health and economic concerns. Considering the complex and bound link between GH axis and sex steroids, the use of sex steroid priming prior to GHST might be helpful in peripubertal setting. However, its use is still controversial. There is no consensus regarding patient selection, timing, dose, and preparation of sex steroids. In this review, we aim to overview the use of sex steroid priming in clinical practice, highlighting the need to develop appropriate guidelines in order to overcome diagnostic pitfalls in peripubertal age.

Introduction: The coronavirus disease 19 (COVID-19) pandemic has prompted the development of new vaccines to reduce the morbidity and mortality associated with this disease. Recognition and report of potential adverse effects of these novel vaccines (especially the urgent and life-threatening ones) is therefore essential.Case presentation: A 16-year-old boy presented to the Paediatric Emergency Department with polyuria, polydipsia and weight loss over the last four months. His past medical history was unremarkable. Onset of symptoms was referred to be few days after first dose of anti-COVID-19 BNT162b2 Comirnaty vaccine and then worsened after the second dose. The physical exam was normal, without neurological abnormalities. Auxological parameters were within normal limits. Daily fluid balance monitoring confirmed polyuria and polydipsia. Biochemistry laboratory analysis and urine culture were normal. Serum osmolality was 297 mOsm/Kg H₂O (285-305), whereas urine osmolality was 80 mOsm/Kg H₂O (100-1100), suggesting diabetes insipidus. Anterior pituitary function was preserved. Since parents refused to give consent to water deprivation test, treatment with Desmopressin was administered and confirmed ex juvantibus diagnosis of AVP deficiency (or central diabetes insipidus). Brain MRI revealed pituitary stalk thickening (4 mm) with contrast enhancement, and loss of posterior pituitary bright spot on T1 weighted imaging. Those signs were consistent with neuroinfundibulohypophysitis. Immunoglobulin levels were normal. Low doses of oral Desmopressin were sufficient to control patient’s symptoms, normalizing serum and urinary osmolality values and daily fluid balance at discharge. Brain MRI after 2 months showed stable thicken pituitary stalk and still undetectable posterior pituitary. Due to persistence of polyuria and polydipsia, therapy with Desmopressin was adjusted by increasing dosage and number of daily administrations. Clinical and neuroradiological follow-up is still ongoing.Conclusion: Hypophysitis is a rare disorder characterized by lymphocytic, granulomatous, plasmacytic, or xanthomatous infiltration of the pituitary gland and stalk. Common manifestations are headache, hypopituitarism, and diabetes insipidus. To date, only time correlation between SARS-CoV-2 infection and development of hypophysitis and subsequent hypopituitarism has been reported. Further studies will be needed to deepen a possible causal link between anti-COVID-19 vaccine and AVP deficiency.

Aims: This study analysed the clinical features of a cohort of children with intracranial germ cell tumours (IC‐GCTs). We retrospectively reviewed timelag between symptoms onset, clinic‐radiological findings, diagnosis and outcomes.Methods: Symptoms at diagnosis were divided into four groups: (1) raised intracranial pressure (RICP); (2) visual impairment; (3) endocrinopathies; (4) other. Total diagnostic interval (TDI), defined as the interval between symptom onset (including retrospective recall of symptoms) and definitive diagnosis of IC‐GCT, was calculated and compared to survival rates.Results: Our cohort included 55 children with median follow‐up of 78.9 months (0.5–249.9). The majority (63.6%) had germinomas and 10.9% were metastatic at diagnosis. IC‐GCTs were suprasellar (41.8%), pineal (36.4%), bifocal (12.7%) or in atypical sites (9.1%). The most common presenting symptoms were related to RICP (43.6%); however, by the time of tumour diagnosis, 50.9% of patients had developed endocrine dysfunctions. All pineal GCTs manifested with RICP or visual impairment. All suprasellar GCTs presented with endocrinopathies. TDI ranged between 0.25 and 58.5 months (median 4 months). Pineal GCTs had the shortest TDI (median TDI 1 month versus 24 months in suprasellar GCTs, p < .001). TDI > 6 months was observed in 47.3% of patients and was significantly associated with endocrine presenting symptoms. No statistically significant difference was found in progression‐free survival and overall survival between patients with TDI > 6 months and with TDI ≤ 6 months.Conclusion: Approximately half of the IC‐GCT patients in this cohort had TDI > 6 months. These presented mostly with endocrine deficits. TDI > 6 months was not associated with increased relapse or mortality rates.

The objective of this study was to identify clinical and/or metabolic predictive factors of genetic obesity. Subjects aged ≤ 18 years with obesity (BMI ≥ 97 th percentile) followed-up at the Paediatric Endocrinology Clinic of Maggiore Hospital in Novara, Italy were screened for genes associated with obesity by next-generation sequencing. Anamnestic, anthropometric, and biochemical data were collected, and parents completed two questionnaires, to screen for hyperphagia and daytime sleepiness, respectively. The study included 50 patients. Six genetic variants (6/50 patients,12%) were classified as pathogenic/likely pathogenic, three (3/50 patients,6%) as polygenic, and 16 (13/50 patients,26%) as variants of uncertain clinical significance (VUS). Eight patients carried > 1 variant. All pathogenic mutations were in genes implicated in the hypothalamic melanocortin pathway or responsible for syndromic obesity. All subjects with definitive genetic diagnosis developed obesity before five years of age. There were no statistically significant differences in auxological nor metabolic parameters between the three genetic patterns of absent genetic mutations, VUS, and pathogenic/likely pathogenic mutations. Finally, a Genetic Obesity Risk Score was developed using logistic regression analysis, selecting Hyperphagia Questionnaire score, age of onset of obesity, and family history as variables. Genetic screening of our cohort of children and adolescents with severe obesity revealed pathogenic/polygenic variants in 18% of cases, with PCSK1 the most frequently mutated gene and with a definitive genetic diagnosis in 3 patients. Identifying clinical, behavioral, and metabolic features predictive of genetic obesity would facilitate early diagnosis and tailored management.

Primary adrenal insufficiency (PAI) is a severe and potentially life-threatening condition characterised by the inability of the adrenal cortex to produce enough glucocorticoids and/or mineralocorticoids. The clinical signs of PAI are primarily due to deficient steroid hormone synthesis and include weight loss, orthostatic hypotension secondary to dehydration, hyponatremia, hyperkalaemia, and hypoglycaemia. In the paediatric population, PAI is most commonly associated with inherited monogenic disorders, particularly enzyme deficiencies. X-linked adrenal hypoplasia congenita (AHC) is a rare condition caused by deletions or single-nucleotide variants in the NR0B1 (DAX1) gene, which encodes the DAX1 protein expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. Although molecular genetics has significantly expanded our understanding of the aetiology of PAI, clinical diagnosis remains challenging when the initial hormonal findings are atypical, often delaying recognition and treatment. Pathogenic variants of DAX1 can lead to a spectrum of phenotypes, ranging from isolated adrenal insufficiency (AI) to complex syndromic presentations combining AI with hypogonadotropic hypogonadism and impaired spermatogenesis. Here, we report a case of a male patient with AI due to a de novo pathogenic variant in the NR0B1 gene. Furthermore, we provide a non-systematic review of the available literature on the diagnostic challenges facing and clinical variability in AHC, with a particular focus on the paediatric population. This case highlights the importance of a stepwise, comprehensive diagnostic approach to suspected PAI, particularly when initial biochemical and genetic testing is inconclusive. Considering rare causes—such as NR0B1 pathogenic variants in men—can be crucial for establishing a definitive diagnosis, with significant implications for the management of patients and their families.