Differentiated Thyroid Cancer in Children and Adolescents: 12-year Experience in a Single Center.

Objective: Differentiated thyroid cancer (DTC) is the most common pediatric endocrine cancer but studies are scarce. Latest recommendations advocate for an individualized risk-based approach to select patients for additional therapy. Lymphovascular invasion is not considered, despite being a well-known risk factor in the adult population. The aim of our study was to describe the outcomes of a cohort of DTC patients diagnosed at pediatric age and to evaluate the impact of lymphovascular invasion on the risk of persistence/recurrence. Methods: We conducted a retrospective study of patients diagnosed with DTC at pediatric age from 2010 to 2022 at our center. All patients had total thyroidectomy. Radioactive iodine therapy (RAI) was used in selected patients. The response to therapy and occurrence of persistent/recurrent disease were evaluated. Results: A total of 21 DTC were diagnosed, mostly papillary thyroid carcinoma (PTC) (81.0%, 17). Six patients (28.6%) had nodal involvement and one (4.8%) had lung metastasis at the time of the diagnosis. Lymphovascular invasion was present in 11 patients (52.4%). After surgery, 13 patients (61.9%) were submitted to RAI. The mean follow-up time was 5.7 ± 3.1 years. Overall, 6 patients (31.6%) experienced persistent/recurrent disease during the follow-up time. Among PTC patients, persistent/recurrent disease was more frequent in the presence of lymphovascular invasion [55.6% (5/9) vs 0.0% (0/6), p=0.031]. Conclusion: An individualized risk-based approach is recommended. Our study suggests that lymphovascular invasion may be associated with a higher risk of persistence/recurrence and should therefore be considered for decision making in children and adolescents with PTC.

Hyperthyroidism in McCune-Albright Syndrome - a case report.

OBJECTIVES: We intend to describe a case of McCune-Albright Syndrome (MAS), a rare disease characterized by fibrous dysplasia (FD), cutaneous hyperpigmentation and hyperfunctioning endocrinopathies (HFE). CASE PRESENTATION: We report the case of a 13-year-old male child who presented with a café-au-lait macule in the lumbosacral region and disabling polyostotic FD, requiring several surgical interventions and bisphosphonates from the age of 3 years (Y) + 9 months (M) due to persistent and severe pain. Hyperthyroidism (HT) became apparent at 5 Y + 1 M with a T3/T4 ratio greater than 20. Treatment with anti-thyroid drugs (ATD) was carried out for 7 Y and there was a progressive improvement in pain complaints 8 M after starting ATD, allowing treatment with pamidronate to be discontinued. Total thyroidectomy was performed at 12 Y + 5 M. CONCLUSIONS: This is a case of MAS-associated HT that reflects the deleterious effect of thyroid hormone excess on FD, reinforcing the need of having a low threshold for suspicion of HFE that may arise.

A serious and unusual presentation of congenital isolated ACTH deficiency due to TBX19 mutation, beyond the neonatal period.

Summary: Congenital isolated adrenocorticotrophic hormone (ACTH) deficiency due to T-box transcription factor-19 (TBX19 mutation) (MIM 201400; ORPHA 199296) usually presents in the neonatal period with severe hypoglycemia, seizures, and sometimes prolonged cholestatic jaundice. We report a case with an unusual presentation that delayed the diagnosis. A 9-month-old female patient with no relevant personal history was admitted to the emergency department due to a hypoglycemic seizure in the context of acute gastroenteritis. There was rapid recovery after glucose administration. At age 4, she presented with tonic-clonic seizures, fever, and gastrointestinal symptoms and came to need support in an intensive care unit. Low serum cortisol was documented and hydrocortisone was initiated. After normalization of inflammatory parameters, the patient was discharged with hydrocortisone. The genetic investigation was requested and compound heterozygous mutations in TBX19 were detected. This is a rare case of presentation of TBX19 mutation outside the neonatal period and in the setting of acute disease, which presented a diagnostic challenge. Learning points: Congenital isolated adrenocorticotrophic hormone deficiency due to TBX19 mutation usually presents with neonatal hypoglycemia and prolonged cholestatic jaundice. An uneventful neonatal period, however, does not exclude the diagnosis as the disease may be asymptomatic at this stage. In the context of idiopathic hypoglycemia, even in the context of acute disease, hypocortisolism must always be excluded. Genetic evaluation should be performed in cases of congenital central hypocortisolism to allow proper counselling.

A variant in the CASR gene (c.368T>C) causing hypocalcemia refractory to standard medical therapy.

SUMMARY: Hypoparathyroidism is characterized by low or inappropriately normal parathormone production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. Current treatments for ADH type 1 include supplementation with calcium and active vitamin D. We report a case of hypoparathyroidism in an adolescent affected by syncope without prodrome. The genetic testing revealed a variant in the CASR gene. Due to standard therapy ineffectiveness, the patient was treated with recombinant human parathyroid hormone (1-34), magnesium aspartate and calcitriol. He remained asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to achieve clinical stability. LEARNING POINTS: Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. The variant c.368T>C (p.Leu123Ser) in heterozygosity in the CASR gene is likely pathogenic and suggests the diagnosis of ADH type 1. Teriparatide (recombinant human parathyroid hormone 1-34) may be a valid treatment option to achieve clinical stability for those individuals whose condition is poorly controlled by current standard therapy.

Neonates Born to Mothers with Graves' Disease: 15 Year Experience of a Pediatric Endocrinology Department.

INTRODUCTION: Graves disease is characterized by the existence of autoantibodies directed to the thyrotropin receptor, which can have a stimulatory/inhibitory action, in women with the condition, their fetus or neonate. Our aim was to review the case series of these neonates in order to establish neonatal thyroid function predictors. MATERIAL AND METHODS: Retrospective cohort study of the database of the Department of Pediatric Endocrinology, including patients born to mothers with Graves' disease, between 2002 and 2017. Clinical and biochemical data were collected from mothers and offspring. RESULTS: Fifty newborns, from 46 women with a median of 3.5 years after diagnosis, were included. During all trimesters of pregnancy, more than half of women had positive autoantibodies directed to the thyrotropin receptor. Not every woman had a complete thyroid function evaluation every trimester. In 32 newborns, cord blood screening was done. During the neonatal period, there were three cases of hypothyroidism and two of hyperthyroidism. The mothers of these five newborns had higher levels of free thyroid hormones during the second trimester (p = 0.03). The level of antibodies directed to the thyrotropin receptor was significantly higher in the cord blood (p = 0.03) and in the first neonatal test (p = 0.03) of these dysthyroid newborns. DISCUSSION: Our results reinforce the need for every pregnant woman with Graves' disease to be subject to thyroid function and autoantibodies evaluation during every trimester, as well as the importance of evaluating these antibodies in cord blood. CONCLUSION: High levels of free thyroid hormones during the second trimester of pregnancy and antibodies directed to the thyrotropin receptor value in cord blood are predictors of dysthyroidism in neonates born from women with Grave's disease.

Introdução: A doença de Graves é caraterizada pela existência de autoanticorpos dirigidos ao recetor da tirotrofina, que podem ter uma ação estimuladora/inibitória, ao nível da mulher com a doença, bem como do seu feto ou recém-nascido. Quisemos rever a nossa série de casos de filhos de mães com doença de Graves de forma a estabelecer preditores da função tiroideia neonatal. Material e Métodos: Estudo retrospetivo de uma coorte da base de dados da Unidade de Endocrinologia Pediátrica, composta por filhos de mães com doença de Graves, seguidos entre 2002 e 2017. Foram recolhidos dados clínicos e laboratoriais dos processos clínicos das progenitoras e seus filhos. Resultados: Foram incluídos 50 recém-nascidos, de 46 mulheres com uma mediana de 3,5 anos de diagnóstico. Em todos os trimestres de gravidez, mais de metade das mulheres tinham autoanticorpos dirigidos ao recetor da tirotrofina positivos. Nem todas fizeram uma avaliação trimestral completa da função tiroideia. O rastreio no sangue do cordão foi realizado em trinta e dois recémnascidos. Durante o período neonatal houve três casos de hipotiroidismo e dois de hipertiroidismo. As mães destes recém-nascidos tinham valores mais elevados das frações livres das hormonas tiroideias no segundo trimestre (p = 0,03). O valor dos anticorpos dirigidos ao recetor da tirotrofina no sangue do cordão e na primeira avaliação neonatal foi significativamente mais elevado (p = 0,03 em ambos) nos recém-nascidos distiroideus. Discussão: Os nossos resultados sublinham a importância de todas as mulheres grávidas, com doença de Graves, fazerem a avaliação da função tiroideia e autoanticorpos dirigidos ao recetor da tirotrofina em cada trimestre, bem como da avaliação destes anticorpos no sangue do cordão. Conclusão: Valores elevados das frações livres das hormonas tiroideias no segundo trimestre de gravidez e de anticorpos dirigidos ao recetor da tirotrofina no sangue do cordão são preditores de distiroidismo nos recém-nascidos filhos de mães com doença de Graves.

Type 1 diabetes and GAD65 limbic encephalitis: a case report of a 10-year-old girl.

Limbic encephalitis is a rare neurological disorder that may be difficult to recognize. Clinical features include memory impairment, temporal lobe seizures and affective disturbance. We report the case of a 10-year-old girl with type 1 diabetes mellitus that presented with seizures, depressed mood and memory changes. The diagnosis of glutamic acid decarboxylase 65 (GAD65) mediated limbic encephalitis relied on cerebral magnetic resonance imaging lesions and high serological and cerebrospinal fluid GAD65-antibodies titers. High-dose steroidal therapy was started with clinical improvement. Relapse led to a second high-dose steroid treatment followed by rituximab with remission. A correlation between serum GAD65-antibodies levels and symptoms was found, demonstrating GAD65-antibodies titers may be useful for clinical follow-up and immunotherapy guidance. This report raises awareness of this serious neurological condition that may be associated with type 1 diabetes, underlining the importance of an early diagnosis and prompt treatment for a better prognosis.

Autoimmune alternating hyper- and hypo-thyroidism: a rare condition in pediatrics.

UNLABELLED: Alternating between hyper- and hypo-thyroidism may be explained by the simultaneous presence of both types of TSH receptor autoantibodies (TRAbs) - thyroid stimulating autoantibodies (TSAbs) and TSH blocking autoantibodies (TBAbs). It is a very rare condition, particulary in the pediatric age. The clinical state of these patients is determined by the balance between TSAbs and TBAbs and can change over time. Many mechanisms may be involved in fluctuating thyroid function: hormonal supplementation, antithyroid drugs and levels of TSAbs and TBAbs. Frequent dose adjustments are needed in order to achieve euthyroidism. A definitive therapy may be necessary to avoid switches in thyroid function and frequent need of therapeutic changes. We describe an immune-mediated case of oscillating thyroid function in a 13-year-old adolescent. After a short period of levothyroxine treatment, the patient switched to a hyperthyroid state that was only controlled by adding an antithyroid drug. LEARNING POINTS: Autoimmune alternating hypo- and hyper-thyroidism is a highly uncommon condition in the pediatric age.It may be due to the simultaneous presence of both TSAbs and TBAbs, whose activity may be estimated in vitro through bioassays.The clinical state of these patients is determined by the balance between TSAbs and TBAbs and can change over time.The management of this condition is challenging, and three therapeutic options could be considered: I-131 ablation, thyroidectomy or pharmacological treatment (single or double therapy).Therapeutic decisions should be taken according to clinical manifestations and thyroid function tests, independent of the bioassays results.A definitive treatment might be considered due to the frequent switches in thyroid function and the need for close monitoring of pharmacological treatment. A definitive treatment might be considered due to the frequent switches in thyroid function and the need for close monitoring of pharmacological treatment.

Autosomal recessive axonal neuropathy with neuromyotonia: a rare entity.

BACKGROUND: Autosomal recessive axonal neuropathy with neuromyotonia is a recently described entity associated to the HINT1 gene, encoding histidine triad nucleotide-binding protein 1. PATIENT: The authors report a Portuguese 16-year-old girl of Roma ethnicity, descendant of consanguineous parents, with progressive distal muscular atrophy and weakness, beginning at age 6. After several years of extensive investigation with inconclusive results, clinical myotonia was identified. Electrophysiologic studies revealed neuromyotonia associated with a severe chronic predominantly motor axonal neuropathy and homozygous mutation (c.334 C > A, p.H112 N) in HINT1 was detected. CONCLUSION: This report emphasizes the late onset of clinical myotonia essential to the diagnosis.

[S. Pyogenes invasive disease in a paediatric hospital: 1996-2009]. / Doença invasiva por Streptococcus pyogenes num hospital pediátrico - 1996-2009.

INTRODUCTION: S. pyogenes is among the most common bacteria in Pediatrics, and is associated with a wide variety of infections and large range of severity. AIMS: The aim was to evaluate trends of Group A Streptococcal invasive disease in a paediatric tertiary hospital. METHODS: Retrospective analyses of the medical records of all children with group A streptococcal invasive disease (positive culture obtained from sterile sites), from January 1996 to December 2009 (14 years). RESULTS: There were 24 cases, with a maximum of four cases/year. Eighteen cases (75%) ocurred in the second half of the study. Sixty-seven percent were boys and the median age was three years. The most frequent clinical manifestations were fever (79%), rash (54%) and arthalgia/limbs' pain (46%). The diagnoses were bacteriemia (six), osteoarticular infection (five), celulitis (three), pyomyositis, mastoiditis, surgical wound infection, toxic shock syndrome (two each), necrotizing fasciitis and pneumonia (one each). Four cases occurred during the course of varicella. Other risk factors were present in six cases. Median neutrophyl count was 10.690 x 105/L (2.013-19.180 x 105/L) and median C reactive protein was 146 mg/L (3-425 mg/L). Bacteria were isolated mainly from blood (71%). The outcome was good for most cases but there were two deaths due to toxic shock syndrome. M typing and the presence of virulence factors genes were not assessed. CONCLUSION: Although the number is small, there was an increase of S. pyogenes invasive disease in the second half of the study. Several cases occurred in the course of varicela or in the presence of other risk factors. Fatal outcome was associated with two toxic shock syndrome cases. Microbiological investigation is essential to understand which M types or virulence factors genes are involved.