Background: We present three patients who developed symptomatic hypercalcaemia following discontinuation of the Type II RAF inhibitor, Tovorafenib. Methods: We report three paediatric cases who had been enrolled in the phase 2 FIREFLY-1 (PNOC026; NCT04775485) Kilburn et al. (2024), which was investigating the safety and efficacy of Tovorafenib monotherapy in patients with relapsed or refractory paediatric low-grade glioma (pLGG) harbouring a KIAA-BRAFfusion or BRAF V600E mutation. Hypercalcaemia was detected within weeks after discontinuation of Tovorafenib. Results: Adjusted serum calcium concentrations at first presentation were 2.91 mmol/L at 21 days (Patient 1), 3.06 mmol/L at 14 days (Patient 2), and 3.58 mmol/L at 26 days (Patient 3) following cessation of Tovorafenib. Calcium concentrations normalised following treatment with additional fluid and, in two of the patients, a single dose of bisphosphonate. Conclusion: We suspect that the hypercalcaemia reflects a rebound increase in bone turnover following Tovorafenib discontinuation and recommend that monitoring bone biochemistry after treatment cessation be considered as part of management protocols.

Many paediatricians assess infants or children with a history of excessive fluid intake. Most patients will have primary polydipsia, but the differential diagnosis includes rare disorders requiring specialist input and lifelong treatment. This article will focus on conditions characterised by abnormal vasopressin (AVP) secretion by the posterior pituitary gland. We describe the clinical features and investigations that are useful in identifying the underlying pathology in these patients and explain why the water deprivation test may not be needed. We discuss why the term diabetes insipidus should be consigned to the history books and why the precise cause of AVP deficiency is still unclear in some instances. Two clinical cases will be used to highlight topics such as diagnostic uncertainty, assessing thirst objectively and the potential role of copeptin.

OBJECTIVE:To establish the incidence of adrenal crisis (AC) in patients treated with supraphysiological glucocorticoid (GC) for nephrotic syndrome (NS) or juvenile idiopathic arthritis (JIA) and hence at risk of adrenal suppression (AS). DESIGN:Retrospective observational single centre study. SETTING:Great North Children's Hospital, Newcastle upon Tyne. PATIENTS:Children aged 1 month-<16 years, who received supraphysiological GC for NS or JIA within a defined period. MAIN OUTCOME MEASURES:Monthly GC regimen and incidence of AC identified by reviewing: (1) clinic letters and emergency department attendance, (2) region wide electrolyte results, (3) clinical coding and (4) proactive discussion with respective clinical teams. RESULTS:97 patients were included, totalling 2363 patient months of follow-up. During GC weaning, all NS and 15% of JIA patients were switched to an alternate day GC regimen. A total of 974 patient months were observed following discontinuation of GC and no episodes of AC were identified. An assessment of AC events in other published cohorts indicated that the low incidence is not simply a reflection of poor sensitivity linked to sample size. CONCLUSIONS:This study suggests that supraphysiological GC administered for several weeks can potentially be weaned and stopped safely without formal biochemical assessment in patients with NS and JIA. Specialist teams provide families with rapid access to advice which supports safe practice. An alternate day weaning regimen following a modest period of daily supraphysiological GC may have reduced the likelihood of AS at critical times.

ObjectiveCentral congenital hypothyroidism (incidence ∼1:13,000) occurs in isolation (40% cases) or with additional pituitary hormone deficiencies. T4 ± TSH-based neonatal screening detects central congenital hypothyroidism within the first two weeks of life, permitting prompt treatment, but the UK TSH-based screening programme will not detect these cases. We delineated clinical characteristics, time-frame and pathway to diagnosis in clinically diagnosed individuals. MethodsRecords were reviewed for 118 cases diagnosed from 1996 to 2022, in four tertiary centres. ResultsMedian age at diagnosis was 68 days (range: 1–5,056). 96% had combined pituitary hormone deficiencies. Non-specific neonatal concerns (hypoglycaemia/jaundice/weight concerns, 83%) and significant neurodevelopmental defects (34%) occurred frequently. Compared with cases diagnosed late (>1 year, n = 42), early diagnosis (≤14 days n = 23) was associated with neonatal intensive care admission (78 vs 29%, P < 0.001) and ACTH deficiency (96 vs 40% P < 0.0001). Mean FT4 was moderately low at diagnosis (−2.7 ± 0.9 SDS), but initial thyroid function was within reported reference ranges in 31 cases. Treatment delays could be substantial, even following detection of subnormal FT4, especially in late-diagnosed cases (mean: 208 ± 486 days). ConclusionUK central congenital hypothyroidism cases are diagnosed later than screening-detected cases, and isolated TSH deficiency may evade detection entirely. ‘Sicker’ neonates are diagnosed earlier, but late diagnosis frequently occurs despite neonatal/childhood morbidity attributable to combined pituitary hormone deficiencies. Challenges include non-specific neonatal signs, requirement for bespoke age-specific FT4 reference ranges, lack of biomarkers for alternative diagnoses and masking by concomitant GH deficiency. Our findings mandate further studies to assess practicalities, costs and justification for introducing UK-wide central congenital hypothyroidism screening.

Congenital hypothyroidism (CHT) represents a clinical and biochemical spectrum with associated implications in terms of screening and management. Babies at the mild end of this spectrum are more heterogeneous in terms of etiology and the potential benefits arising from their detection and intervention with thyroid hormone are less clear cut. This uncertainty is reflected in differences in screening threshold selected by nations. Preterm delivery can have a profound impact on the hypothalamo-pituitary thyroid axis and introduces an additional layer of complexity when selecting babies who may benefit from intervention. Iodine status remains an important agenda item whenever thyroid dysfunction in the newborn is discussed.

What is normal? Reference standards are a core component of endocrine practice but they come with caveats. Lying below the 2nd or above the 98th centiles—or lying below or above two standard deviations outwith the mean—does not automatically mean that there is underlying pathology. The 'lines in the sand' associated with biochemical reference ranges can be helpful but clinicians will be aware that normal ranges do not encompass all healthy individuals. Many physiological processes are subject to a similar yes/no classification with the paediatrician deciding whether a child is in puberty or not on the basis of the clinical assessment. The onset of puberty reflects rising gonadotropin secretion with ovarian oestrogen production and subsequent breast development being the key clinical marker of pubertal onset in girls and testicular enlargement > 3mLs the key marker in boys. Breast development on average occurs before the attainment of the 4 mL 'pubertal' testicular volume (just over 11 years of age vs. 12 years) with the implication being that puberty begins earlier in girls than boys [1-3]. This matters from a clinical perspective because the earlier that puberty begins in advance of normal timing, the more likely it is that there is an underlying pathological explanation for this. Irrespective of the underlying mechanism, there are effective treatments, notably GnRH analogues, that can safely put puberty on hold. Pubertal assessment of girls can be complicated by an increased body mass index and a degree of associated lipomastia and there are complicating factors in boys as well. The prepubertal testicle will vary in size between healthy individuals—a normal continuum. Hence a testicular volume of 2.5 mLs in one individual can presumably equate to the same physiological stage of development as a 1.5 mL volume in someone else. Perhaps a 3.5 mL volume (pubertal) in one child will be equivalent from a developmental perspective to a 2.5 mL volume (prepubertal) in someone else. Then there are factors such as the means of assessment—for example clinical examination or ultrasonography—that need to be taken into account. It is not uncommon for my clinical assessment to be different to that of my colleagues, an observation reinforced by more objective data collection [4]. An assessment of pubertal stage of development can be bolstered by blood tests such as baseline gonadotropins, their response to LHRH stimulation and by measuring sex steroid concentrations but the results of these investigations also form a continuum rather than neatly separating pre-pubertal from pubertal. In this issue of Clinical Endocrinology Demir and colleagues from Finland [5] have investigated urinary luteinizing hormone (U-LH) gonadotropin production in a large cohort of boys and girls. The authors conclude that measuring U-LH concentrations is a useful approach to establishing whether a child is in puberty or not. Day to day variation in the first morning urine samples was substantial but did not prevent the investigators from categorising the majority of patients correctly into prepubertal verses 'highly likely' pubertal/pubertal. Interestingly, U-LH concentrations indicated that participants were in puberty 1–2 years in advance of the appearance of clinical signs. The authors conclude that U-LH can be used as a screening test to classify children into prepubertal, peri-pubertal and pubertal groups and hence the measurement of U-LH could potentially help to prevent more expensive, time consuming and potentially uncomfortable investigations. Nevertheless, when faced with a child in clinic with potential early or precocious puberty paediatricians may still prefer blood samples so that other markers of pubertal development can be assessed as well. The logistical issues associated with obtaining a pertinent urine sample at the time of the clinic appointment introduce an additional layer of complexity and it sounds as though the assay used by the investigators is now obsolete. Whether U-LH proves to be anything more than a research tool in the longer term remains to be seen. An interesting component of the paper by Demir and colleagues is the fact that it underlines how the onset of increased gonadotropin production at puberty actually occurs at a similar time in boys as girls. In this cohort the increase in mean total U-LH concentrations appeared shortly after the age of 10 years in males and females and so the sexes have more in common than was previously thought to be the case. Whilst the attainment of a 4 mL testicular volume in boys may occur later than the presence of clinical breast tissue in girls, the physiological process underpinning these changes will have started many months previously when the '4 mL' testicle was much smaller. Demir and colleagues show us that there will already be an incremental 'pubertal' background rise in LH production in some boys with a 1 mL testicular volume who from a more traditional clinical perspective are not yet in puberty. This study has helpfully educated biologists and health professionals about the events taking place before the > 3 mL testicular 'line in the sand'.

OBJECTIVE:To determine the incidence and describe the presentation and management of unexpected symptomatic glucocorticoid-induced adrenal suppression (AS) in children and young people aged 0-15 years. SETTING AND DESIGN:Surveillance study of symptomatic glucocorticoid (GC)-induced AS with supportive biochemical evidence or presenting as an adrenal crisis, reported via the British Paediatric Surveillance Unit (BPSU) from September 2020 to September 2022. RESULTS:Over a 25-month period, 190 reports of symptomatic GC-induced AS/adrenal crisis were made, of which 22 were confirmed cases: 18 AS and 4 adrenal crises. This translates to an incidence rate of 0.09 new cases of GC-induced AS per 100 000 children aged 0-15 per year in the UK. There was a broad range of underlying diagnoses requiring GC prescription (16) and GC preparations (13). Of the 22 patients, 7 had more than 1 type of GC prescribed. The administration of oral GC occurred in 19 of the cases, inhaled GC use in 7, topical use in 5 and 1 case occurred after a single intramuscular injection of GC. All patients were discussed with a paediatric endocrinology team. CONCLUSIONS:The incidence of AS from this UK-based BPSU study is lower than a similar Canadian study. This may indicate that paediatricians in the UK and Ireland are becoming more aware of the potential for GC-induced AS and thus are more proactive to prevent its occurrence. The clinical cases still highlight the need to educate families and healthcare professionals with a view to further reducing the morbidity and potential mortality associated with GC-induced AS.

We present the SARAO MeerKAT Galactic Plane Survey (SMGPS), a 1.3 GHz continuum survey of almost half of the Galactic Plane (251 degrees <= l <= 358 degrees and 2 degrees <= l <= 61. at vertical bar b vertical bar = 1 degrees.5). SMGPS is the largest, most sensitive, and highest angular resolution 1 GHz survey of the plane yet carried out, with an angular resolution of 8 arcsec and a broad-band root-mean-square sensitivity of similar to 10-20 mu Jy beam(-1). Here, we describe the first publicly available data release from SMGPS which comprises data cubes of frequency-resolved images over 908-1656 MHz, power-law fits to the images, and broad-band zeroth moment integrated intensity images. A thorough assessment of the data quality and guidance for future usage of the data products are given. Finally, we discuss the tremendous potential of SMGPS by showcasing highlights of the Galactic and extragalactic science that it permits. These highlights include the discovery of a new population of non-thermal radio filaments; identification of new candidate supernova remnants, pulsar wind nebulae and planetary nebulae; improved radio/mid-infrared classification of rare luminous blue variables and discovery of associated extended radio nebulae; new radio stars identified by Bayesian cross-matching techniques; the realization that many of the largest radio-quiet Wide-field Infrared Survey Explorer (WISE) H II region candidates are not true H II regions; and a large sample of previously undiscovered background H I galaxies in the Zone of Avoidance.

We read with great interest the recent paper by Hannema et al.1 that we found particularly illuminating in respect of our patient with 46XY gonadal dysgenesis, who continues to decline prophylactic gonadectomy. Disorders of sex development (DSD) are a group of rare disorders involving abnormalities in karyotype, steroidogenesis, androgen action or gonadal development, resulting in various phenotypic presentations.2 Among the genetic determinants of sex development, the SRY (sex-determining region of the Y chromosome) gene initiates development of the male urogenital primordia.2, 3 Loss-of-function variants result in congenital abnormalities of male-typical development. Swyer syndrome or 46, XY gonadal dysgenesis (46XY GD) presents with female external genitalia and absent puberty due to gonadal insufficiency (hypergonadotrophic hypogonadism). Amidst the potential genetic culprits, variants of the SRY gene account for up to 15% of cases, as specific encoded proteins (i.e.: sex-determining region Y protein HMG-box) bind to regions of deoxyribonucleic acid (DNA) that control male-typical development. Other associated gene loci include MAP3K1, DHH, NR5A1 and SOX9.3 With no male differentiation stimulus to the urogenital ridge, Sertoli and Leydig cells do not arise within the primitive gonad, resulting in deficiencies of Anti-Müllerian hormone (AMH) and testosterone, respectively. Hence, the development of Mullerian structures and the absence of external male sexual differentiation (Figure 1). A 17-year-old female was referred with primary amenorrhoea and absent puberty. Her past medical and family history was insignificant. She had not progressed into puberty (Tanner stage 1) and had normal female external genitalia. Biochemical evaluation revealed hypergonadotrophic hypogonadism (LH—33.7 IU/L, FSH—105.8 IU/L, Oestradiol <60 pmol/L), undetectable Sertoli cell markers and no elevation of tumour markers (AMH < 0.5 pmol/L, Inhibin B < 9.8 ng/L, alpha fetoprotein (AFP) < 1.0 kU/L, carcinoembryonic antigen (CEA) < 1.0 μg/L). Karyotype was 46 XY, indicating gonadal dysgenesis. Magnetic resonance imaging (MRI) scan showed a tiny anteverted uterus (2.9 × 0.6 × 2.0 cm), but no gonads were visualized. The diagnosis had a significant psychological impact on the patient, for which she was signposted to support groups for peer support. She was also referred to clinical psychology through her general practitioner. She was then started on transdermal Estradiol at a dose of 6.25 μg twice weekly, gradually up-titrated to achieve normal breast (Tanner 4) and sonographic uterine development, after which she was converted to continuous-combined hormone replacement therapy (currently Estradiol 4 mg plus Norethisterone 1.05 mg daily). Laparoscopic exploration and gonadectomy were also recommended considering the risk of gonadoblastoma, but she firmly declined the procedure and continued to do so over the course of subsequent clinic visits. She remained unconvinced of the need for the procedure as no tumour had yet developed over serial monitoring, despite the increased risk of gonadoblastoma in 46 XY GD having been carefully explained to her. Six years after her initial presentation (at 23 years of age), Sertoli cell hormones remained undetectable and a repeat pelvic MRI in 2023 confirmed a mature uterine configuration (62 × 25 × 37 mm), although gonads were again not visualized. The option of exploratory laparoscopy was revisited with input from a gynaecologist, but she remained extremely reluctant to undergo any surgical procedure. Phenotypic female patients with DSD have an increased risk of gonadal tumour development in conjunction with the presence of the GBY region of the Y-chromossome.4 46XY pure GD has one of the highest risks of neoplastic transformation in DSD, which is estimated to be around 15%–60%.2 Thus, in contrast to other DSDs, having lower neoplasia risk and a chance of undergoing spontaneous puberty, prompt prophylactic gonadectomy is recommended in 46XY GD. Although there is a consensus in the literature on the benefits of early bilateral prophylactic gonadectomy, no clear guidance is available regarding the options to pursue when the patient declines this.1, 4, 5 Gonadoblastoma is an initially benign tumour that occurs exclusively in dysgenetic gonads, and may then undergo transformation into dysgerminoma, or other malignancy in up to 60% of cases.3 Imaging alone, such as US or MRI, identified 40%–50% of gonads (if present), but failed to identify any of the gonadoblastomas present in 28% of the patients.5 Negative imaging was one of the reasons this patient declined the procedure. Clinicians can explain to such patients that imaging has poor sensitivity in identifying gonadoblastomas. Because such methods are not always successful in identifying these tumours, we then explored whether tumour markers and Sertoli cell markers had the potential to identify tumours among those who declined gonadectomy. Measurable levels of AMH and inhibin B are correlated with the presence of germ cells, and might therefore indicate a greater potential for tumour development and measurable levels of beta-hCG and AFP might correlate to the presence of some germ cell tumours. Nevertheless, as per the study by Hannema et al.,1 the absence of measurable levels of AMH and inhibin B does not exclude the presence of germ cells. They found that 27% of DSD cases with undetectable AMH and/or inhibin B nevertheless had germ cells present in the gonadectomy specimen (all had gonadoblastoma and/or dysgerminoma). Ninety-four percent of patients with detectable inhibin B or AMH presented with germ cells and 35% of them had abnormal germ cells. In conclusion, the balance of evidence continues to support prophylactic bilateral gonadectomy in females with 46XY GD, irrespective of Sertoli cell markers. For those women who—despite our best efforts—continue to decline the procedure, the measurement of Sertoli cell markers has poor negative predictive value to reliably exclude the presence of germ cells. Although detectable AMH and inhibin B levels significantly increase the possibility of the presence of germ cells, and hence the risk of gonadoblastoma development, we can counsel patients that their absence by no means precludes the risk. Hopefully this provides an opportunity for these women to re-evaluate their decision. Whereas the majority of affected patients will likely accept medical recommendation to undergo gonadectomy, those who do not should ideally be recruited to the iDSD registry (https://home.i-dsd.org/), so as to gather more data in this area.

The spectrum of thyroid disorders presenting to paediatricians is different to that seen by adult physicians. Referrals reflect cases detected by the neonatal screening programme for congenital hypothyroidism and many of the inherited defects of thyroid hormone generation or action will be manifest in early life. Autoimmune thyroid disease can be particularly challenging to manage in the young and the potential impact of thyroid status on neurodevelopment and schooling are key considerations throughout childhood and adolescence.

Objectives Infants presenting with life threatening hyponatraemia and hyperkalaemia present a diagnostic conundrum that can reflect abnormally low aldosterone production (e.g. congenital adrenal hyperplasia (CAH), renal resistance to aldosterone associated with infec ted urinary tract malformations or single gene disorders also associated with failure of the kidney to respond to aldosterone (pseudohypoaldosteronism). Although incidence figures for individual conditions exist, no overall data exists for presentation of this characteristic la boratory pattern and underlying causes. We aimed to report the incidence, aetiology and outcome of infants presenting with hyponatraemia and hyperkalaemia. Methods Population-based surveillance study July2021-June2023 (Wales population 3.1 million1 with 28,879 live births/year2). Cases were identified by paediatricians using the monthly electronic Welsh Paediatric Surveillance Unit(WPSU) reporting system.3 4 Hospital biochemists and tertiary specialists were recruited to optimise ascertainment. Inclusion criteria: term infants<12 months with sodium<130 mmol/L(<2.5 SD) AND Potassium>5.5 mmol/L(>2.5 SD). Results 13 notifications were reported with 2 additional cases identified by receiving subspecialists; 10 met the inclusion criteria. The incidence of hyponatraemia and hyperkalaemia was 1.7cases/10,000 infants per year. Eventual diagnoses were: 3 CAH, 4 transient pseudohypoaldosteronism (3 with underlying urinary infection and urinary tract malformation), 1 with maternal hyponatraemia, 2 transient electrolyte abnormalities on NNU. All 10 were white ethnicity infants with birth weights >3kg, (5/10 male). Infants presented at median 14 days old (1 hour to 3 months). 4 were shocked or with >10% weight loss. All received 0.9% normal saline fluid boluses with 1/10 receiving insulin for h yperkalemia. Serum sodium and potassium corrected by median one day after admission (range 0–3 and 0–2 days respectively). Electrolyte abnormalities led to diagnosis of urinary tract malformations in those with urinary infections. Patients were discharged after median 6 days (range 3–17). One infant represented after one week with a seizure with normal neuro -imaging and examination. No other sequelae were reported at one month follow up. No deaths occurred. Conclusion This is the first ever study of infants presenting with severe hyponatraemia and hyperkalaemia across a whole population. Severe hyponatraemia and hyperkalaemia is rare. Normalisation of biochemistry derangement was rapid and short-term outcome favourable. When faced with this unusual clinical picture remember CAH and renal causes; early ultrasound may help to delineate the cause. References www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration/populationestimates/bulletins/populationandhouseholdestimateswales/census2021 www.gov.wales/maternity-and-birth-statistics-2021-html Sibert JR, Morgan RJ, O'Connell HI, Lynn R, Guildea ZE, Palmer SR; Welsh Paediatric Society-WPSU study group. Short report: Is regional paediatric surveillance useful? Experience in Wales. Arch Dis Child. 2001 Jun;84(6):486–7. doi: 10.1136/adc.84.6.486. PMID: 11369563; PMCID: PMC1718781. https://www.welshpaediatrics.org.uk/wpsu.

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