Availability, usage and preferences of estradiol, and progestogen preparations for puberty induction from multicentral perspective.

INTRODUCTION: Natural oestrogen administration as oral or transdermal 17ß-estradiol is recommended for pubertal induction in girls with hypogonadism. However, suitable low-dose formulations are not consistently available globally. This questionnaire study aimed to identify the current availability of estrogen and progesterone preparations worldwide. METHODS: Endorsed by the ESPE Turner Syndrome Working Group, the questionnaire targeted pediatric endocrinologists. Questions focused on accessibility of oral/transdermal 17ß-estradiol and progestogen preparations. Responses were collected through a SurveyMonkey survey disseminated via ESPE channels, direct outreach, and conferences from June 2020 to December 2022. RESULTS: Participation included 229 healthcare professionals from 45 countries. Oral and transdermal 17ß-estradiol in adult dosage were highly accessible (86.5% and 84.3%), with transdermal administration the preferred form (62.8%). Most commonly available estradiol preparations included 50 µg patches (32 countries) and 1 or 2 mg tablets (65.8% and 71.1% countries). However, 0.5 mg 17ß-estradiol tablets were available in only 20% of respondents from 8 countries. Patches delivering 14 or 25 mcg/day of 17ß-estradiol were available in 3 and 20 countries, respectively. Oral progestogen had widespread availability (96.0%) and preference (87.0%), while transdermal usage was limited to 15.2% of respondents. CONCLUSION: This study highlights global challenges in accessing suitable hormone preparations for female pubertal induction. In most countries the lowest dose of the estradiol is 50µg for patches and 2 mg for tablets. Appropriate low dose 17ß-estradiol tablets are much less available than low-dose patches. Our survey underscores the importance of adapting guidelines to local availability, and the need for improved accessibility to address these global disparities.

A Single-Center, Observational Study of 607 Children and Young People Presenting With Differences of Sex Development (DSD).

Context: Differences of sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family, and developing a management plan are important. Objective: We aimed to better understand the presentation and prevalence of pediatric DSD. Methods: A retrospective, observational cohort study was undertaken in a single tertiary pediatric center of all children and young people (CYP) referred to a DSD multidisciplinary team over 25 years (1995-2019). In total, 607 CYP (520 regional referrals) were included. Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence. Results: Among the 3 major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45,X/46,XY mosaicism), 46,XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46,XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or hernias. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46,XY children, usually due to complex associated features (46,XY girls, 8.3%; 46,XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6347 births, and 1 in 5101 overall throughout childhood. Conclusion: DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care.

Variability of response to early puberty induction demonstrated by transverse uterine diameter measurement and a novel method of 3D breast imaging.

OBJECTIVE: Induction of puberty with exogenous oestrogen results in considerable variability in final uterine and breast volumes. We set out to quantify the variability of these two outcome measures with a view to establishing monitoring methods that could be used to individualise treatment protocols. DESIGN: A prospective observational study. PARTICIPANTS: Sixteen participants with pubertal delay and primary amenorrhoea, due to hypogonadism were recruited from paediatric gynaecology and endocrinology clinics at University College London Hospital. A standardised protocol of transdermal 17ß oestradiol (17ßE) was used (Evorel™), with a starting dose of 12.5 mcg increasing to 25 mcg (patch changed twice weekly) after 4 months. Follow up was every 2 months for a total of 8 months. MEASUREMENTS: Uterine dimensions using ultrasound, oestradiol concentrations and breast development assessed by both Tanner staging and 3D photographic imaging. RESULTS: After 8 months of treatment, the changes in oestradiol concentrations (0-174 pmol), uterine volume growth (4.4-16.4 ml) and breast volume (1.76-140.1 ml) varied greatly between individuals. Of uterine parameters, transverse uterine diameter was most closely associated with serum oestradiol levels at 8 months (beta standardised coefficient = 0.80, p = .001). Change in breast volume was associated with age of treatment initiation (beta standardised coefficient 0.55 p = .04). CONCLUSIONS: We demonstrate variation in response to exogenous oestrogen, emphasising the necessity for individualised dose titration. In the absence of sensitive oestradiol assays, uterine transverse measurements may be used as a surrogate marker of oestrogen sensitivity to guide early dose adjustment. 3D breast imaging may provide a quantitative assessment of breast development to complement Tanner breast staging.

Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency.

Primary ovarian insufficiency (POI) affects 1% of women and carries significant medical and psychosocial sequelae. Approximately 10% of POI has a defined genetic cause, with most implicated genes relating to biological processes involved in early fetal ovary development and function. Recently, Ythdc2, an RNA helicase and N6-methyladenosine reader, has emerged as a regulator of meiosis in mice. Here, we describe homozygous pathogenic variants in YTHDC2 in 3 women with early-onset POI from 2 families: c. 2567C>G, p.P856R in the helicase-associated (HA2) domain and c.1129G>T, p.E377*. We demonstrated that YTHDC2 is expressed in the developing human fetal ovary and is upregulated in meiotic germ cells, together with related meiosis-associated factors. The p.P856R variant resulted in a less flexible protein that likely disrupted downstream conformational kinetics of the HA2 domain, whereas the p.E377* variant truncated the helicase core. Taken together, our results reveal that YTHDC2 is a key regulator of meiosis in humans and pathogenic variants within this gene are associated with POI.

Treatment outcome with a selective RET tyrosine kinase inhibitor selpercatinib in children with multiple endocrine neoplasia type 2 and advanced medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) in the context of multiple endocrine neoplasia type 2 (MEN2) is caused by mutations in the RET proto-oncogene. Therefore, in children with MEN2 and advanced MTC, the RET tyrosine kinase (TK) pathway is a target for treatment with selpercatinib, a selective RET TK inhibitor. PATIENTS AND METHODS: A retrospective review of the clinical, genetic, biochemical (calcitonin and carcinoembryonic antigen [CEA]) and imaging data of six medically untreated children with MEN2 and recurrent and or progressive MTC. The main parameters were safety and objective treatment response to selpercatinib. RESULTS: Six children (three males and three females, aged 3-12 years), four with MEN2B and two MEN2A, are reported. All had initial total thyroidectomy and extensive neck dissections but subsequently developed recurrent and progressive disease. All experienced an improvement in clinical symptoms with a concomitant biochemical response evidenced by significant fall in serum calcitonin and CEA concentrations. The fall in serum calcitonin was evident within 2 weeks of the start of selpercatinib, and responses were ongoing at a median follow-up of 13 months (range, 11-22 months). Four children with measurable radiological disease had good volume reduction. The most common adverse effects were transient but reversible grade 1 or 2 increase in alanine aminotransferase, serum bilirubin and constipation. No child required a dose modification or had to discontinue selpercatinib because of a drug-related adverse event. CONCLUSION: Selpercatinib has shown excellent therapeutic efficacy with minimal toxicity in children with MEN2 and progressive metastatic RET-mutated MTC.

Treating papillary and follicular thyroid cancer in children and young people: Single UK-center experience between 2003 and 2018.

AIM: Differentiated thyroid cancer (DTC) in children and adolescents is rare and data about its presentation and management are not well known. The aim of this study was to provide evidence of the current practice in the United Kingdom before the launch of the Rare National Paediatric Endocrine Tumours Guidelines (to be published in 2020). METHODS: Seventy-two children and adolescents with DTC (<18 years) who were treated at our institution between 2003 and 2018 were identified and their presentation, treatment and outcomes were reviewed. RESULTS: Median age at presentation was 12.7 years [range: 1-18] and fifty-two (72%) were girls. Fifty (69.4%) children and adolescents presented with a thyroid nodule. Thirteen (18%) had cervical adenopathy and seven of them (54%) underwent an excision biopsy under GA. Eight patients (11%) had evidence of lung metastases at presentation. Twenty-four patients (33%) underwent a hemithyroidectomy and 22 of those had a completion thyroidectomy subsequently, ten (14%) a total thyroidectomy alone and 37 (51%) a total thyroidectomy with lymph nodes dissection. Seventy patients (97%) underwent adjuvant RAI at our institution. The median number of children and adolescents managed per year was five [range: 0-10]. After an overall median follow-up of 40 months, eight patients (11%) had developed recurrent disease. The 1- and 5-year recurrence-free-survival-rates were 93% and 87%, respectively. Overall survival was 100%, with eight children and adolescents (11%) being alive with disease. CONCLUSION: This study confirms that DTC in children and adolescents is uncommon, is frequently advanced at presentation and has considerable recurrence rates. Despite this, overall survival is excellent. Although the work-up was generally appropriate (image-guided cytology), open biopsy for the diagnosis of lymph node involvement was still employed. The introduction of a specific UK guideline for this age-group will likely result in more tailored-made treatment-pathways and thereby hopefully improve quality and outcomes even further. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level IV.

Late Recovery of Parathyroid Function after Total Thyroidectomy in Children and Adults: Is There a Difference?

BACKGROUND: Parathyroid failure after total thyroidectomy is the commonest adverse event amongst both children and adults. The phenomenon of late recovery of parathyroid function, especially in young patients with persistent hypoparathyroidism, is not well understood. This study investigated differences in rates of parathyroid recovery in children and adults and factors influencing this. METHODS: A joint dual-centre database of patients who underwent a total thyroidectomy between 1998 and 2018 was searched for patients with persistent hypoparathyroidism, defined as dependence on oral calcium and vitamin D supplementation at 6 months. Demographic, surgical, pathological, and biochemical data were collected and analysed. Parathyroid Glands Remaining in Situ (PGRIS) score was calculated. RESULTS: Out of 960 patients who had total thyroidectomy, 94 (9.8%) had persistent hypoparathyroidism at 6 months, 23 (24.5%) children with a median [range] age 10 [0-17], and 71 (75.5%) adults aged 55 [25-82] years, respectively. Both groups were comparable regarding sex, indication, extent of surgery, and PGRIS score. After a median follow-up of 20 months, the parathyroid recovery rate was identical for children and adults (11 [47.8%] vs. 34 [47.9%]; p = 0.92). Sex, extent, and indication for surgery had no effect on recovery (all p > 0.05). PGRIS score = 4 (HR = 0.48) and serum calcium >2.25 mmol/L (HR = 0.24) at 1 month were associated with a decreased risk of persistent hypoparathyroidism on multivariate analysis (p < 0.05). CONCLUSION: Almost half of patients recovered from persistent hypoparathyroidism after 6 months; therefore, the term persistent instead of permanent hypoparathyroidism should be used. Recovery rates of parathyroid function in children and adults were similar. Regardless of age, predictive factors for recovery were PGRIS score = 4 and a serum calcium >2.25 mmol/L at 1 month.

Children are at a high risk of hypocalcaemia and hypoparathyroidism after total thyroidectomy.

PURPOSE: Disruption of calcium homeostasis is the most common complication after total thyroidectomy in adults. We explored the incidence and risk factors of hypocalcaemia and hypoparathyroidism after total thyroidectomy in children (≤18 years of age). METHODS: One hundred six children underwent total thyroidectomy. Patient, operative and outcome data were collected and analyzed. RESULTS: The indication for surgery was Graves' disease in 52 children (49.1%), Multiple Endocrine Neoplasia type-2 in 36 (33.9%), multinodular goiter in 3 (2.8%) and follicular/papillary thyroid carcinoma in 15 (14.2%). Neck dissection was performed in 23 children (18.9%). In 14 children (13.2%), autotransplantation was performed; in 31 (29.2%), ≥1 glands were found in the specimen. Hypocalcaemia within 24 h of thyroidectomy was observed in 63 children (59.4%) and 52 (49.3%) were discharged on supplements. Hypoparathyroidism at 6 months persisted in 23 children (21.7%). The ratios of all forms of calcium-related-morbidity were larger among children with less than four parathyroid glands remaining in situ: hypocalcaemia within 24 h of thyroidectomy (54.0% versus 47.5%; p = 0.01), hypoparathyroidism on discharge (64.4% versus 37.7%; p = 0.004) and long-term hypoparathyroidism (31.1% versus 14.8%; p = 0.04). CONCLUSION: The incidence of postoperative hypocalcaemia and hypoparathyroidism among children undergoing total thyroidectomy is considerable. The inability to preserve the parathyroid glands in situ during surgery seems an important factor. For optimal outcomes, the parathyroid glands should be preserved in situ. TYPE OF STUDY: Prognosis Study. LEVEL OF EVIDENCE: Level IV.

Sudden sex hormone withdrawal and the effects on body composition in late pubertal adolescents with gender dysphoria.

Background Sex hormones initiate profound physical and physiological changes during the pubertal process, but to what extent are they responsible for continuing the body composition changes of late adolescence and what happens to body composition on sudden sex hormone withdrawal? Methods Thirty-six healthy, phenotypically and chromosomally normal late and post-pubertal individuals aged 15-17 years with gender dysphoria (transgirls - birth-registered males identifying as female n = 11; and transboys - birth-registered females identifying as male n = 25) underwent Tanita body composition analysis at 0, 6 and 12 months during reproductive hormone suppression with Triptorelin as part of the standard therapeutic protocol. Results and conclusions In the transgirl cohort, paired t-test analysis demonstrated a significant decrease in height and lean mass standard deviation scores over the 12-month period, going against an expected trajectory over that time. In contrast, oestrogen suppression appeared not to affect the body composition of transboys; their measurements were not significantly different at baseline and after 12 months of treatment. The withdrawal of sex hormone secretion does not appear to have a significant impact on female post-pubertal body composition, in contrast to that seen at the menopause. This suggests that other factors may preserve normal body balance in adolescents in the absence of sex steroids.

Testicular-Epididymal Dissociation: Vas and Vessels May "Lead up the Garden Path".

The vas deferens and spermatic vessels entering the inguinal canal through the internal inguinal ring is thought to exclude an intra-abdominal testis. We present a case of high bilateral intra-abdominal testes on a 46,XY boy despite the vas deferens and good-sized vessels passing through the deep rings. Data were collected from clinical records, radiology (ultrasound, magnetic resonance imaging [MRI]), and endocrine blood tests. This case underlines the importance of following the pathway of embryological descent of the testis cranially as well as caudally during diagnostic laparoscopy, to avoid missing this rare anatomical variant.

Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing.

Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with nonspecific features and can be difficult to diagnose. We undertook next generation sequencing in a cohort of children and young adults with PAI of unknown etiology from around the world and identified a heterozygous missense variant (rs6161, c.940G>A, p.Glu314Lys) in CYP11A1 in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort, 0.102 vs 0.0026 in the Genome Aggregation Database; P < 0.0001). Seventeen individuals harbored a second heterozygous rare disruptive variant in CYP11A1 and two had very rare synonymous changes in trans (c.990G>A, Thr330 = ; c.1173C>T, Ser391 =). Although p.Glu314Lys is predicted to be benign and showed no loss-of-function in an Escherichia coli assay system, in silico and in vitro studies revealed that the rs6161/c.940G>A variant, plus the c.990G>A and c.1173C>T changes, affected splicing and that p.Glu314Lys produces a nonfunctional protein in mammalian cells. Taken together, these findings show that compound heterozygosity involving a relatively common and predicted "benign" variant in CYP11A1 is a major contributor to PAI of unknown etiology, especially in European populations. These observations have implications for personalized management and demonstrate how variants that might be overlooked in standard analyses can be pathogenic when combined with other very rare disruptive changes.

Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study.

BACKGROUND: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. METHODS: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. FINDINGS: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs. INTERPRETATION: Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year. FUNDING: None.

Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

Management of Cushing syndrome in children and adolescents: experience of a single tertiary centre.

UNLABELLED: The diagnosis and management of paediatric Cushing syndrome (CS) is highly challenging. This study aims to characterise its presentation, diagnosis, management and outcome by a retrospective case review of 30 patients (14 females) followed at a single tertiary paediatric endocrinology centre over a 30-year period. At presentation, median age was 8.9 years (0.2-15.5) and the commonest manifestations were weight gain (23/30), hirsutism (17/30), acne (15/30) and hypertension (15/30). Growth retardation was present in 11/30. Median body mass index (BMI) was +2.1 standard deviation score (SDS) (-6.5 to +4.6). Urinary free cortisol (UFC) was abnormal in 17/18 (94 %), midnight cortisol in 27/27 (100 %) and low-dose dexamethasone suppression (LDDS) test in 20/20 (100 %). High-dose dexamethasone suppression (HDDS) test was abnormal in 6/6 (100 %) of adrenal tumours, 1/10 (10 %) of Cushing disease (CD) and 1/2 (50 %) of ectopic tumours. Bilateral inferior petrosal sinus sampling (IPSS) identified five CD cases and one ectopic tumour. All patients underwent surgery and subsequently required cortisol replacement. Final diagnoses were 16 CD, 11 adrenal disease, 2 ectopic ACTH-secreting lesions and 1 case of unidentified aetiology. One year post-diagnosis, median BMI was 0.5 SDS (-2.5 to +3.7), hypertension was present in 4/14 (28 %), and 43 % (12/30) of individuals were off hydrocortisone. CONCLUSION: The prevalence of the clinical manifestations differs from that reported in other series. Screening tests were highly sensitive, with UFC, midnight cortisol and LDDS performing well. One year post-treatment, BMI and BP normalised in the majority of patients and almost half of them were able to discontinue replacement hydrocortisone. WHAT IS KNOWN: •Cushing syndrome is an extremely rare entity in the paediatric and adolescent age groups, so not many cohort studies have been published in this population. •Several tests can be employed to firstly diagnose hypercortisolaemia and secondly identify the source of origin of it. The efficacy and safety of these tests in children is still uncertain. What is New: •This study includes cases due to the different aetiologies of endogenous hypercortisolaemia (pituitary, adrenal and ectopic hypercortisolaemia) allowing us to compare the differences in presentation, diagnosis, management and long-term outcome between the groups. •There is a difference in the prevalence of Cushing syndrome symptoms and in the performance of the tests in our cohort compared to previously published studies in the literature.

Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations.

OBJECTIVE: We have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing's syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype-phenotype correlation of their PRKACA amplification. DESIGN: This study is a case series. METHODS: Molecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS. RESULTS: Reinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entire PRKACA gene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient, PRKACA triplication was associated with a more severe phenotype. CONCLUSIONS: Constitutional chromosomal PRKACA gene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occur de novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication. PRKACA amplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.

Thyroid Surgery in Children: Clinical Outcomes.

AIM: The aim of this study was to review the outcomes of thyroid surgery in children operated for both benign and malignant conditions. PATIENTS AND METHOD: Demography, clinical features, and surgical outcomes were noted retrospectively for operations performed during the last 23 years. Results were analyzed using Fisher exact test and Woolf (logit) method with p value < 0.05 considered as significant. RESULTS: In total, 61 children (43 girls and 18 boys) underwent thyroidectomy for benign (70%) and malignant (30%) conditions. Median follow-up period was 1.4 years. In the benign group, 84% children had Graves disease and 16% had other conditions. In this study, 42% children had total, 22% had near-total, 27% had subtotal, and 9% had type 2 hemithyroidectomy. In the malignant group, 50% had multiple endocrine neoplasia, 33% had papillary, 11% had follicular cancer, and 6% had B-cell lymphoma. Fifty percent children had prophylactic thyroidectomy, 44% had total thyroidectomy plus lymphadenectomy, and 6% had hemithyroidectomy. At the time of surgery, children with benign conditions were older than those with malignancy (median, 12 vs. 7.5 years). There were no incidents of postoperative bleeding or infection. Hypocalcemia was significantly more frequent in the malignant group (39 vs. 9%, p value = 0.01). The type of recurrent laryngeal nerve (RLN) injury was more serious in the benign group (one bilateral and one unilateral permanent injury) than in the malignant group (transient hoarseness in three). Overall rate of complications was higher for operations for malignancy (56 vs. 28%, p value = 0.07). In Graves disease, the subtotal thyroidectomies had a recurrence of 30% but no recurrence was seen following total or near-total thyroidectomy group (p value = 0.01). There was no recurrence in the malignant group. Children operated after 2000 were younger than those operated before 2000 (median age, 9 vs. 14 years). Malignant conditions were more common in children operated after 2000 in comparison to before 2000 (55 vs. 10%). CONCLUSION: Benign conditions are commonest indications for thyroid surgery in children but the incidence of surgery for malignant conditions is rising. Overall rate of complications, especially hypocalcemia, is higher after surgery for malignancy but all cases of permanent RLN injury were in benign group. Total or near total thyroidectomy prevents recurrence of thyrotoxicosis and is an operation of choice for Graves disease.

Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcemia type 3 (ADH3).

CONTEXT: Autosomal dominant hypocalcemia (ADH) types 1 and 2 are due to calcium-sensing receptor (CASR) and G-protein subunit-α11 (GNA11) gain-of-function mutations, respectively, whereas CASR and GNA11 loss-of-function mutations result in familial hypocalciuric hypercalcemia (FHH) types 1 and 2, respectively. Loss-of-function mutations of adaptor protein-2 sigma subunit (AP2σ 2), encoded by AP2S1, cause FHH3, and we therefore sought for gain-of-function AP2S1 mutations that may cause an additional form of ADH, which we designated ADH3. OBJECTIVE: The objective of the study was to investigate the hypothesis that gain-of-function AP2S1 mutations may cause ADH3. DESIGN: The sample size required for the detection of at least one mutation with a greater than 95% likelihood was determined by binomial probability analysis. Nineteen patients (including six familial cases) with hypocalcemia in association with low or normal serum PTH concentrations, consistent with ADH, but who did not have CASR or GNA11 mutations, were ascertained. Leukocyte DNA was used for sequence and copy number variation analysis of AP2S1. RESULTS: Binomial probability analysis, using the assumption that AP2S1 mutations would occur in hypocalcemic patients at a prevalence of 20%, which is observed in FHH patients without CASR or GNA11 mutations, indicated that the likelihood of detecting at least one AP2S1 mutation was greater than 95% and greater than 98% in sample sizes of 14 and 19 hypocalcemic patients, respectively. AP2S1 mutations and copy number variations were not detected in the 19 hypocalcemic patients. CONCLUSION: The absence of AP2S1 abnormalities in hypocalcemic patients, suggests that ADH3 may not occur or otherwise represents a rare hypocalcemic disorder.

Cushing syndrome associated with an adrenal tumour.

Cushing syndrome (CS) in children is a rare disorder that is most frequently caused by an adrenal tumour or a pituitary corticotrophin-secreting adenoma. The management is challenging and requires an individualised approach and multidisciplinary care. We present the case of a 23-month-old female child with a history of excessive weight gain, growth failure, hirsutism, acne and behavioural difficulties. Investigations revealed elevated serum midnight cortisol and 24 h urinary free cortisol. Overnight dexamethasone suppression testing showed no suppression of cortisol levels. Abdominal imaging revealed a right-sided suprarenal mass. She underwent right adrenalectomy and the histology showed an adrenal cortical carcinoma. There was clinical improvement with catch-up growth and weight normalisation. Despite being rare in clinical practice, in a child with weight gain, hirsuitism and growth failure the diagnosis must be considered. The overall prognosis of CS in childhood is good, but challenges remain to ensure normal growth and body composition.

Severe resistance to weight gain, lack of stored triglycerides in adipose tissue, hypoglycaemia, and increased energy expenditure: a novel disorder of energy homeostasis.

BACKGROUND: Growth during childhood is a consequence of the equilibrium of energy balance. Obesity results from a shift of the equilibrium towards increased energy intake over expenditure. A clinical description of extreme leanness and failure to thrive secondary to a shift of the equilibrium towards increased energy expenditure over energy intake has not been previously described in the medical literature. SUBJECTS AND METHODS: We report the case of a female child born premature with a birth weight of 1.1 kg who presented with extreme failure to thrive, persistent hypoglycaemia, paucity of fat in the adipose tissue with increased brown fat and increased resting energy expenditure. RESULTS: Complete cessation of weight and height was noted between 3 months to 3.5 years of age. Hypoglycaemia was secondary to depleted energy stores and increased insulin sensitivity. Increased resting energy expenditure was demonstrated on indirect calorimetric assessment. Biopsy of adipose tissue demonstrated paucity of stored fat with increase in brown fat. No gain in weight and height was demonstrated despite high calorie intake of enteral and parenteral feeds. CONCLUSION: We describe a unique case of extreme failure to thrive with increased energy expenditure and severe hypoglycaemia. Unravelling the molecular basis of this novel disorder has the potential to provide insights into the prevention of obesity.