RESUMO
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.
Assuntos
Puberdade Precoce , Útero , Criança , Estradiol , Estrogênios , Feminino , Humanos , Puberdade/fisiologia , Útero/diagnóstico por imagemRESUMO
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.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Fenótipo , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Fácies , Feminino , Estudos de Associação Genética/métodos , Humanos , Lactente , Padrões de Herança , Masculino , Polimorfismo de Nucleotídeo Único , Síndrome , Adulto JovemRESUMO
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: â¢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. â¢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: â¢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. â¢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.
Assuntos
Síndrome de Cushing/diagnóstico , Glucocorticoides/uso terapêutico , Adolescente , Criança , Pré-Escolar , Síndrome de Cushing/terapia , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos RetrospectivosRESUMO
The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that has an extracellular bilobed venus flytrap domain (VFTD) predicted to contain five calcium (Ca(2+))-binding sites. To elucidate the structure-function relationships of the VFTD, we investigated 294 unrelated probands with familial hypocalciuric hypercalcaemia (FHH), neonatal severe primary hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemic hypercalciuria (ADHH) for CaSR mutations and performed in vitro functional expression studies and three-dimensional modelling of mutations involving the VFTD. A total of 70 different CaSR mutations were identified: 35 in FHH, 10 in NSHPT and 25 in ADHH patients. Furthermore, a CaSR variant (Glu250Lys) was identified in FHH and ADHH probands and demonstrated to represent a functionally neutral polymorphism. NSHPT was associated with a large proportion of truncating CaSR mutations that occurred in the homozygous or compound heterozygous state. Thirty-four VFTD missense mutations were identified, and 18 mutations were located within 10 Å of one or more of the predicted Ca(2+)-binding sites, particularly at the VFTD cleft, which is the principal site of Ca(2+) binding. Mutations of residues 173 and 221, which are located at the entrance to the VFTD cleft binding site, were associated with both receptor activation (Leu173Phe and Pro221Leu) and inactivation (Leu173Pro and Pro221Gln), thereby highlighting the importance of these residues for entry and binding of Ca(2+) by the CaSR. Thus, these studies of disease-associated CaSR mutations have further elucidated the role of the VFTD cleft region in Ca(2+) binding and the function of the CaSR.
Assuntos
Hipercalcemia/genética , Hipocalcemia/genética , Mutação , Receptores de Detecção de Cálcio/genética , Sítios de Ligação/genética , Cálcio/química , Cálcio/metabolismo , Genótipo , Células HEK293 , Humanos , Hiperparatireoidismo , Recém-Nascido , Modelos Moleculares , Taxa de Mutação , Mutação de Sentido Incorreto , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores de Detecção de Cálcio/química , Receptores de Detecção de Cálcio/metabolismoRESUMO
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 oestrogen and progesterone preparations worldwide. METHODS: Endorsed by the ESPE Turner Syndrome Working Group, the questionnaire targeted paediatric 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 was 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 µg/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 50 µg 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.
RESUMO
GCMB is a member of the small transcription factor family GCM (glial cells missing), which are important regulators of development, present in vertebrates and some invertebrates. In man, GCMB encodes a 506 amino acid parathyroid gland-specific protein, mutations of which have been reported to cause both autosomal dominant and autosomal recessive hypoparathyroidism. We ascertained 18 affected individuals from 12 families with autosomal recessive hypoparathyroidism and have investigated them for GCMB abnormalities. Four different homozygous germline mutations were identified in eight families that originate from the Indian Subcontinent. These consisted of a novel nonsense mutation R39X; a missense mutation, R47L in two families; a novel missense mutation, R110W; and a novel frameshifting deletion, I298fsX307 in four families. Haplotype analysis, using polymorphic microsatellites from chromosome 6p23-24, revealed that R47L and I298fsX307 mutations arose either as ancient founders, or recurrent de novo mutations. Functional studies including: subcellular localization studies, EMSAs and luciferase-reporter assays, were undertaken and these demonstrated that: the R39X mutant failed to localize to the nucleus; the R47L and R110W mutants both lost DNA-binding ability; and the I298fsX307 mutant had reduced transactivational ability. In order to gain further insights, we undertook 3D-modeling of the GCMB DNA-binding domain, which revealed that the R110 residue is likely important for the structural integrity of helix 2, which forms part of the GCMB/DNA binding interface. Thus, our results, which expand the spectrum of hypoparathyroidism-associated GCMB mutations, help elucidate the molecular mechanisms underlying DNA-binding and transactivation that are required for this parathyroid-specific transcription factor.
Assuntos
Genes Recessivos/genética , Hipoparatireoidismo/genética , Mutação/genética , Proteínas Nucleares/genética , Glândulas Paratireoides/patologia , Fatores de Transcrição/genética , Sequência de Aminoácidos , Sequência de Bases , Núcleo Celular/metabolismo , DNA/metabolismo , Ensaios Enzimáticos , Família , Feminino , Genes Reporter , Humanos , Luciferases/metabolismo , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Mutantes/química , Proteínas Nucleares/química , Especificidade de Órgãos/genética , Glândulas Paratireoides/metabolismo , Linhagem , Ligação Proteica , Transporte Proteico , Fatores de Transcrição/químicaRESUMO
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.
Assuntos
Insuficiência Ovariana Primária , RNA Helicases , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/metabolismo , Feminino , Humanos , Meiose , Insuficiência Ovariana Primária/genética , RNA Helicases/genéticaRESUMO
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.
RESUMO
We investigated playmate and play style preference in children with congenital adrenal hyperplasia (CAH) (26 females, 31 males) and their unaffected siblings (26 females, 17 males) using the Playmate and Play Style Preferences Structured Interview (PPPSI). Both unaffected boys and girls preferred same-sex playmates and sex-typical play styles. In the conflict condition where children chose between a same-sex playmate engaged in an other-sex activity or an other-sex playmate engaged in a same-sex activity, boys (both CAH and unaffected brothers) almost exclusively chose playmates based on the preferred play style of the playmate as opposed to the preferred gender label of the playmate. By contrast, unaffected girls used play style and gender label about equally when choosing playmates. Girls with CAH showed a pattern similar to that of boys: their playmate selections were more masculine than unaffected girls, they preferred a boy-typical play style and, in the conflict condition, chose playmates engaged in a masculine activity. These findings suggest that prenatal androgen exposure contributes to sex differences in playmate selection observed in typically developing children and that, among boys and girls exposed to high levels of androgens prenatally, play style preferences drive sex segregation in play.
Assuntos
Hiperplasia Suprarrenal Congênita/psicologia , Comportamento Infantil/psicologia , Relações Interpessoais , Jogos e Brinquedos/psicologia , Caracteres Sexuais , Comportamento Social , Análise de Variância , Criança , Desenvolvimento Infantil , Pré-Escolar , Comportamento de Escolha , Feminino , Humanos , Masculino , Grupo AssociadoRESUMO
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.
RESUMO
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.
Assuntos
Adenocarcinoma Folicular , Carcinoma Papilar , Neoplasias da Glândula Tireoide , Adenocarcinoma Folicular/cirurgia , Adolescente , Carcinoma Papilar/cirurgia , Criança , Feminino , Humanos , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Reino Unido/epidemiologiaRESUMO
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.
Assuntos
Composição Corporal , Disforia de Gênero/tratamento farmacológico , Disforia de Gênero/fisiopatologia , Hormônios Esteroides Gonadais/administração & dosagem , Hormônio Liberador de Gonadotropina/agonistas , Maturidade Sexual/efeitos dos fármacos , Suspensão de Tratamento/estatística & dados numéricos , Adolescente , Índice de Massa Corporal , Feminino , Humanos , MasculinoRESUMO
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.
Assuntos
Hipoparatireoidismo/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Recuperação de Função Fisiológica , Tireoidectomia/efeitos adversos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Hipoparatireoidismo/etiologia , Lactente , Londres/epidemiologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Espanha/epidemiologia , Tireoidectomia/reabilitaçãoRESUMO
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 (≤18â¯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 24â¯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 24â¯h of thyroidectomy (54.0% versus 47.5%; pâ¯=â¯0.01), hypoparathyroidism on discharge (64.4% versus 37.7%; pâ¯=â¯0.004) and long-term hypoparathyroidism (31.1% versus 14.8%; pâ¯=â¯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.
Assuntos
Hipocalcemia/etiologia , Hipoparatireoidismo/etiologia , Complicações Pós-Operatórias/etiologia , Doenças da Glândula Tireoide/cirurgia , Tireoidectomia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Hipocalcemia/diagnóstico , Hipocalcemia/epidemiologia , Hipoparatireoidismo/diagnóstico , Hipoparatireoidismo/epidemiologia , Incidência , Lactente , Recém-Nascido , Masculino , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Tireoidectomia/métodos , Resultado do TratamentoRESUMO
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.
RESUMO
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.
Assuntos
Neoplasias das Glândulas Suprarrenais/mortalidade , Carcinoma Neuroendócrino/mortalidade , Neoplasia Endócrina Múltipla Tipo 2b/mortalidade , Feocromocitoma/mortalidade , Neoplasias da Glândula Tireoide/mortalidade , Tireoidectomia/mortalidade , Adolescente , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Adulto , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2b/patologia , Neoplasia Endócrina Múltipla Tipo 2b/cirurgia , Feocromocitoma/patologia , Feocromocitoma/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Adulto JovemRESUMO
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.
RESUMO
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.
Assuntos
Doenças da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Hipocalcemia/etiologia , Masculino , Complicações Pós-Operatórias , Recidiva , Traumatismos do Nervo Laríngeo Recorrente/etiologia , Estudos Retrospectivos , Tireoidectomia/efeitos adversosRESUMO
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.
Assuntos
Glândulas Suprarrenais/patologia , Síndrome de Cushing/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Amplificação de Genes/genética , Glândulas Suprarrenais/fisiopatologia , Glândulas Suprarrenais/cirurgia , Adrenalectomia , Adulto , Criança , Pré-Escolar , Síndrome de Cushing/patologia , Síndrome de Cushing/fisiopatologia , Variações do Número de Cópias de DNA , Feminino , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Hiperplasia/fisiopatologia , Masculino , Fenótipo , Adulto JovemRESUMO
To determine the value of the TRH test, we analyzed the unstimulated serum T(4) and TSH concentrations in 54 children with central hypothyroidism. A TRH test was performed in 30 patients. Midline brain defects (septo-optic dysplasia, 28; holoprosencephaly, 2) and combined pituitary hormone deficiencies were present in 30 and 52 patients, respectively. The mean serum free T(4), total T(4), and basal TSH concentrations were 0.6 ng/dl, 4.0 microg/dl, and 2.8 microU/ml, respectively. Five patients demonstrated elevated basal serum TSH concentrations. A normal TRH test [increase (delta) in TSH, 4.5-17.8], based on data from 30 controls, was documented in 23.3% of patients. Brisk (deltaTSH, >17.8), absent/blunted (deltaTSH, <4.5), and delayed responses were documented in 16.7%, 30%, and 30% of patients, respectively. The mean age at diagnosis was 2.8 yr, with 8 patients evolving into TSH deficiency. It was not possible to differentiate patients as having pituitary or hypothalamic disease based solely on the TRH test results. Patients with septo-optic dysplasia were diagnosed earlier and had elevated basal serum TSH and PRL concentrations, diabetes insipidus, and evolving disease. Although full pituitary function assessment is mandatory to identify combined pituitary hormone deficiencies, a TRH test is not essential, and the diagnosis should be made by serial T(4) measurements.