Apoptosis through Death Receptors in Temporal Lobe Epilepsy-Associated Hippocampal Sclerosis.

Seizure models have demonstrated that neuroinflammation and neurodegeneration are preponderant characteristics of epilepsy. Considering the lack of clinical studies, our aim is to investigate the extrinsic pathway of apoptosis in pharmacoresistant temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) patients, TLE(HS). By a specific death receptor-mediated apoptosis array plate, 31 upregulated targets were revealed in the sclerotic hippocampus from TLE(HS) patients. Amongst them are the encoding genes for ligands (FASLG, TNF, and TNFSF10) and death receptors (FAS, TNFRSF1A, TNFRSF10A, and TNFRSF10B). In addition, we evaluated the hippocampal relative mRNA expression of the two TNF receptors, TNFRSF1A and TNFRSF1B, in patients, being both upregulated (n = 14; P < 0.01 and P < 0.04, resp.) when compared to the post mortem control group (n = 4). Our results have clearly suggested that three different death receptor apoptotic systems may be associated with the maintenance and progression of TLE-associated HS: (1) TNF-TNFRSF1A, (2) FASLG-FAS, and (3) TNFSF10-TNFRSF10A/B. Their effects on epilepsy are still scarcely comprehended. Our study points out to TNF and TNF receptor superfamily pathways as important targets for pharmacological studies regarding the benefits of an anti-inflammatory therapy in these patients.

Developmental impairment in children exposed during pregnancy to maternal SARS-COV2: A Brazilian cohort study.

OBJECTIVES: To determine the effects of in-utero exposure to maternal SARS-CoV-2 infection on offspring's neurodevelopment during the first year of life. METHODS: We performed a prospective cohort of babies exposed to SARS-CoV-2 during pregnancy, and a control group (CG) of unexposed babies in a low-income area in Brazil. Children's neurodevelopment was assessed using the guide for Monitoring Child Development in the Integrated Management of Childhood Illness context for both groups (at 1,2,3,4,5,6, 9, and 12 months), and the Ages & Stages Questionnaire (ASQ-3) for the exposed group (EG) (at 4, 6 and 12 months). RESULTS: We followed 137 children for 1 year, 69 in the COVID-19-EG, and 68 in the CG. All mothers were unvaccinated at the time of cohort inclusion, and maternal demographics were similar in the two groups. 20.3% of EG children and 5.9% of the CG received a diagnosis of neurodevelopmental delay within 12 months of life (P = 0.013, relative risk = 3.44; 95% confidence interval, 1.19- 9.95). For the EG, the prevalence of neurodevelopment impairment using Ages & Stages Questionnaire was 35.7% at 4 months, 7% at 6 months, and 32.1% at 12 months. CONCLUSION: SARS-CoV-2 exposure was associated with neurodevelopmental impairment, and specific guidelines are needed for the follow-up of these high-risk children to mitigate the long-term effects on children's health.

Hippocampal gene expression dysregulation of Klotho, nuclear factor kappa B and tumor necrosis factor in temporal lobe epilepsy patients.

BACKGROUND: Previous research in animal seizure models indicates that the pleiotropic cytokine TNF is an important effector/mediator of neuroinflammation and cell death. Recently, it has been demonstrated that TNF downregulates Klotho (KL) through the nuclear factor kappa B (NFkB) system in animal models of chronic kidney disease and colitis. KL function in the brain is unclear, although Klotho knockout (Kl-/-) mice exhibit neural degeneration and a reduction of hippocampal synapses. Our aim was to verify if the triad KL-NFKB1-TNF is also dysregulated in temporal lobe epilepsy associated with hippocampal sclerosis (TLE(HS)) patients. FINDINGS: We evaluated TNF, NFKB1 and KL relative mRNA expression levels by reverse transcription quantitative PCR (RT-qPCR) in resected hippocampal tissue samples from 14 TLE(HS) patients and compared them to five post mortem controls. Four reference genes were used: GAPDH, HPRT1, ENO2 and TBP. We found that TNF expression was dramatically upregulated in TLE(HS) patients (P <0.005). NFKB1 expression was also increased (P <0.03) while KL was significantly downregulated (P <0.03) in TLE(HS) patients. Hippocampal KL expression had an inverse correlation with NFKB1 and TNF. CONCLUSIONS: Our data suggest that, similar to other inflammatory diseases, TNF downregulates KL through NFkB in TLE(HS) patients. The remarkable TNF upregulation in patients is a strong indication of hippocampal chronic inflammation. Our finding of hippocampal KL downregulation has wide implications not only for TLE(HS) but also for other neuronal disorders related to neurodegeneration associated with inflammation.

Perspective of pediatricians and adolescent patients on the transition process in a university hospital.

OBJECTIVE: To map the transition process from the perspective of pediatricians and their adolescent patients, and to suggest a transition protocol. METHODS: This is a descriptive, cross-sectional study conducted in a pediatric outpatient clinic of a public tertiary hospital. Pediatricians answered a questionnaire about the transition process, and that was evaluated in a descriptive manner. The Transition Readiness Assessment Questionnaire (TRAQ) on health autonomy was answered by the adolescents and the analysis was performed using the χ2 and Mann-Whitney tests. p<0.05 were considered significant. RESULTS: 31 pediatricians (16 residents, 15 supervisors) were enrolled, with a mean age of 40.1 (±16.9), 87% women, with years working in Pediatrics ranging from 2 to 45 years (median of 5 years). Most doctors agreed that there was no transition plan, but they stimulated the patient's autonomy and talked to the patient and family members about any existing chronic diseases. A total of 102 adolescent patients participated, with a median age of 15; 56% were female. The TRAQ median was 58, with similar scores between females and males, and higher scores in those older than 16 years of age (Mann-Whitney U test, p=0.01). The patients reported ease in face-to-face communication with their doctors, but great difficulty in talking about health issues over the phone. CONCLUSIONS: Even without a transition protocol, adolescents developed several self-care skills as they aged. The lack of a transitional protocol led to conflicting opinions, which reinforces the need for improvement. We suggest a flowchart and transition protocol.

Maternal and Neonatal Outcomes Associated with Mild COVID-19 Infection in an Obstetric Cohort in Brazil.

Previous coronavirus epidemics were associated with increased maternal morbidity, mortality, and adverse obstetric outcomes. Reports for SARS-CoV-2 indicate that the obstetric population is at increased risk for severe illness, although there are still limited data on mild COVID-19 infection during pregnancy. To determine the association between mild COVID-19 infection during pregnancy, and maternal and neonatal outcomes, we performed a prospective cohort study among pregnant women with COVID-19 and a control group. Postnatal depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale. We recruited 84 pregnant women with mild COVID-19 and 88 pregnant women without COVID-19. All participants were unvaccinated. The most common acute COVID-19 symptoms were headache (82.1%), loss of smell (81%), and asthenia (77.4%). The median duration of long COVID symptoms was 60 days (interquartile range, 130). Pregnant women with a COVID-19 diagnosis were at greater risk for obstetric ultrasound abnormalities-mainly, fetal growth restriction (relative risk [RR], 12.40; 95% CI, 1.66-92.5), premature birth (RR, 2.62; 95% CI, 1.07-6.43), and postpartum depression (RR, 2.28; 95% CI, 1.24-4.21). Our results alert clinicians to the consequences of COVID-19 during pregnancy, even in mild cases, given the increased risk of ultrasound abnormalities, premature birth, long COVID symptoms, and postpartum depression. National guidelines on preventive measures and treatments should be based on scientific evidence, including attention to the impact on health and family needs during and after the COVID-19 pandemic.

Adaptation of the Youth Connectedness to Provider scale to assess the relationship between health professionals and adolescent and young adult patients.

OBJECTIVE: The aim was to adapt an instrument that evaluates the relationship between young individuals and health professionals to the Brazilian population, which will be called the Escala de Avaliação de Vínculo entre Jovens e Profissionais de Saúde (Youth Connectedness to Provider scale). METHOD: The questionnaire known as the Youth Connectedness to Provider scale consists of seven Likert-like questions. The translation, back-translation, evaluation by ten specialists, and pre-test with 43 adolescents and young adults aged between 10 and 24 years were performed to assess the clarity and reliability of meanings. The content validity index was calculated for each question. Subsequently, the clinical validation was performed with 83 patients aged 10-24 years old and Cronbach's alpha coefficient was calculated. RESULTS: A content validity index >0.8 (considered satisfactory) was obtained for all items analyzed by experts and adolescents. At the clinical validation, it showed a high internal consistency (Cronbach's alpha=0.76). The questions showed a good correlation, except for the question about judgment (Spearman's rho=0.03-0.19). CONCLUSIONS: The scale adaptation showed an adequate agreement rate at the translation evaluation and a good reliability index in the questions. This instrument provides information on strengths and topics that require more attention from professionals to improve the relationship with their patients; it can be a valuable parameter in assessing the medical consultation quality.

Impairment in anthropometric parameters and body composition in females with classical 21-hydroxylase deficiency.

The aim of this study was to evaluate the physical measurements and body composition of female patients with the classic form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Twenty-eight girls with CAH were classified according to both hormonal control (well or not well controlled) and the clinical form of the disease (simple virilizing or salt-wasting). In the control group, 112 healthy individuals were included, divided into two subgroups (male and female). Both patients and controls were subdivided by age into three groups according to pubertal stage: < or =10 years (prepubertal), 11-15 years (pubertal), and > or =15 years (postpubertal). Anthropometrical evaluations and bioelectrical impedance were used to obtain the physical measurement and body composition data. The patients with the simple virilizing form presented higher values for BMI, waist, arm fat area, and fat mass percentage. The not well controlled group presented shorter leg length. Values obtained for BMI as well as for arm fat area, brachial circumference, waist, hip, bi-iliac diameter and fat mass percentage were significantly higher in the patients than in the controls, whereas leg length, hand size and the percentages of water and lean mass were lower. Alterations in body composition were observed in all age groups, mainly by increase of fat mass with age. After puberty, impairments in limb measurements (leg, hand and foot) were more evident. Patients with CAH presented differences in anthropometric parameters but mainly in body composition. Hence, more comprehensive and careful anthropometric evaluation during monitoring of patients with CAH is recommended.

Neonatal screening: 9% of children with filter paper thyroid-stimulating hormone levels between 5 and 10µIU/mL have congenital hypothyroidism.

OBJECTIVES: To determine the prevalence of congenital hypothyroidism in children with filter-paper blood-spot TSH (b-TSH) between 5 and 10µIU/mL in the neonatal screening. METHODS: This was a retrospective study including children screened from 2003 to 2010, with b-TSH levels between 5 and 10µIU/mL, who were followed-up during the first two years of life when there was no serum TSH normalization. The diagnosis of congenital hypothyroidism was defined as serum TSH ≥10µIU/mL and start of levothyroxine treatment up to 2 years of age. RESULTS: Of the 380,741 live births, 3713 (1.04%) had filter paper TSH levels between 5 and 10µIU/mL and, of these, 339 (9.13%) had congenital hypothyroidism. Of these, 76.11% of the cases were diagnosed in the first three months of life and 7.96% between 1 and 2 years of age. CONCLUSION: The study showed that 9.13% of the children with b-TSH levels between 5 and 10µIU/mL developed hypothyroidism and that in approximately one-quarter of them, the diagnosis was confirmed only after the third month of life. Based on these findings, the authors suggest the use of a 5µIU/mL cutoff for b-TSH levels and long-term follow-up of infants whose serum TSH has not normalized to rule out congenital hypothyroidism.

The calcium-sensing receptor and related diseases.

The calcium-sensing receptor (CASR) adjusts the extracellular calcium set point regulating PTH secretion and renal calcium excretion. The receptor is expressed in several tissues and is also involved in other cellular functions such as proliferation, differentiation and other hormonal secretion. High extracellular calcium levels activate the receptor resulting in modulation of several signaling pathways depending on the target tissues. Mutations in the CASR gene can result in gain or loss of receptor function. Gain of function mutations are associated to Autossomal dominant hypocalcemia and Bartter syndrome type V, while loss of function mutations are associated to Familial hypocalciuric hypercalcemia and Neonatal severe hyperparathyroidism. More than one hundred mutations were described in this gene. In addition to calcium, the receptor also interacts with several ions and polyamines. The CASR is a potential therapeutic target to treatment of diseases including hyperparathyroidism and osteoporosis, since its interaction with pharmacological compounds results in modulation of PTH secretion.

Polyclonality of Parathyroid Tumors in Neonatal Severe Hyperparathyroidism.

Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder characterized by major hypercalcemia, elevated parathyroid hormone levels, and marked enlargement of multiple parathyroid glands, usually associated with germline mutations in the calcium receptor gene CASR. However, little is known about the outgrowth of parathyroid tumors in NSHPT, including whether they represent monoclonal or polyclonal expansions. We sought to examine the clonality of parathyroid tissues resected from a patient with NSHPT and biallelic CASR mutations. DNA from two distinct parathyroid tumors resected from a girl with NSHPT, plus polyclonal/monoclonal control samples, were subjected to analyses of clonality by two independent methods, X-chromosome inactivation analysis at the androgen receptor locus (HUMARA) and BAC array comparative genomic hybridization (CGH). Both parathyroid tumor samples revealed polyclonal patterns by X-inactivation analysis, with polyclonal and monoclonal controls yielding the expected patterns. Similarly, by BAC array CGH, neither parathyroid sample contained monoclonal copy number changes and both appeared identical to the patient-matched polyclonal controls. Our observations provide direct experimental evidence that the markedly enlarged parathyroid tumors in the setting of NSHPT constitute polyclonal, generalized hyperplastic growths rather than monoclonal neoplasms.

BTK mutations selectively regulate BTK expression and upregulate monocyte XBP1 mRNA in XLA patients.

Mutations in the Bruton agammaglobulinemia tyrosine kinase (BTK) gene are responsible for X-linked agammaglobulinemia (XLA). Unfolded or misfolded proteins can trigger stress pathways in the endoplasmic reticulum (ER), known as unfolded protein response (UPR). The aim was to clarify the involvement of UPR in XLA pathophysiology. By reverse transcription-quantitative PCR, we evaluated the expression of BTK and 12 UPR-related genes in eight patients. Moreover, we assessed the BTK protein expression and pattern in the patients' monocytes by flow cytometry and fluorescence immunocytochemistry. We found a reduced BTK expression in patients with stop codon mutations (P < 0.02). However, missense mutations did not affect BTK expression. Flow cytometry showed a reduction of BTK in patients which was corroborated by an absent or nonfunctional protein synthesis revealed by immunocytochemistry. In contrast with the other UPR-related genes, X-box binding protein 1 (XBP1) was markedly upregulated in the patients (P < 0.01), suggesting Toll-like receptor (TLR) activation since BTK directly interacts with TLRs as a negative regulator and XBP1 can be activated in direct response to TLR ligation. Different BTK mutations can be identified by the BTK expression. Inasmuch as UPR-related genes were downregulated or unaltered in patients, we speculate the involvement of the TLRs-XBP1 axis in the XLA pathophysiology. Such data could be the basis for further studies of this novel pathomechanism concerning XLA.

CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.

Familial hypocalciuric hypercalcemia (FHH) is caused by heterozygous loss-of-function mutations in the calcium-sensing receptor (CASR), in which the lifelong hypercalcemia is generally asymptomatic. Homozygous loss-of-function CASR mutations manifest as neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism, which occur in infancy. Activating mutations in the CASR gene have been identified in several families with autosomal dominant hypocalcemia (ADH), autosomal dominant hypoparathyroidism, or hypocalcemic hypercalciuria. Individuals with ADH may have mild hypocalcemia and relatively few symptoms. However, in some cases seizures can occur, especially in younger patients, and these often happen during febrile episodes due to intercurrent infection. Thus far, 112 naturally-occurring mutations in the human CASR gene have been reported, of which 80 are unique and 32 are recurrent. To better understand the mutations causing defects in the CASR gene and to define specific regions relevant for ligand-receptor interaction and other receptor functions, the data on mutations were collected and the information was centralized in the CASRdb (www.casrdb.mcgill.ca), which is easily and quickly accessible by search engines for retrieval of specific information. The information can be searched by mutation, genotype-phenotype, clinical data, in vitro analyses, and authors of publications describing the mutations. CASRdb is regularly updated for new mutations and it also provides a mutation submission form to ensure up-to-date information. The home page of this database provides links to different web pages that are relevant to the CASR, as well as disease clinical pages, sequence of the CASR gene exons, and position of mutations in the CASR. The CASRdb will help researchers to better understand and analyze the mutations, and aid in structure-function analyses.

Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia.

Familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism (NSHPT), and autosomal dominant hypocalcemia (ADH), in which calcium homeostasis is disordered, are associated with mutations in the calcium-sensing receptor (CASR). Six unrelated kindreds with FHH and/or NSHPT and two unrelated kindreds with ADH were studied. Direct sequence analysis of the exons of the CASR gene identified heterozygous mutations in six of the kindreds with FHH and in one of those with ADH. We performed functional analyses on the novel missense and insertion/frameshift mutants by transiently transfecting wild-type and mutant CASRs tagged with a c-Myc epitope in human embryonic kidney (HEK293) cells. All mutant receptors were expressed at a similar level to that of the wild type; however, whereas mutants R220W and A835T (the ADH mutant) were fully glycosylated and were visualized on the cell surface, glycosylation of mutants G549R and C850-851 ins/fs was impaired, resulting in reduced cell surface staining. In fura-2-loaded HEK293 cells expressing the wild-type or mutant receptors, the inactivating R220W mutant produced a significant shift to the right relative to the wild-type CASR in the cytosolic calcium response to increasing extracellular calcium concentrations and the G549R and C850-851 ins/fs mutants were without detectable activity. The activating A835T mutation resulted in a shift to the left in the cytosolic calcium response to extracellular calcium concentrations relative to the wild type. Our studies have identified novel CASR mutations that alter the function of the CASR in several different ways.

Maternal activating mutation of the calcium-sensing receptor: implications for calcium metabolism in the neonate.

Two infants were studied born of a mother with autosomal dominant hypocalcemia who is heterozygous for an activating mutation in the calcium-sensing receptor gene. Both infants had serum calcium levels in the low-normal range and parathyroid hormone levels in the high-normal range and were healthy. The mother's hypocalcemia had been treated with calcium carbonate and calcitriol and she has nephrocalcinosis and mild renal insufficiency. By genetic testing, both infants were shown to have normal calcium-sensing receptor gene alleles, i.e., they had not inherited the activating mutation from their mother. This provided reassurance to the family and ensured that treatment to correct apparent hypocalcemia would not be necessary. The fact that the infants had high normal parathyroid hormone levels with normal calcium may be due to the fact that with a normal calcium-sensing receptor their parathyroid glands responded in utero to the maternal hypocalcemia with an increase in parathyroid hormone.

Prader-Willi syndrome: a case report with atypical developmental features.

OBJECTIVE: To describe the case of a male Prader-Willi syndrome (PWS) patient with atypical development features. DESCRIPTION: We report the case of a male adolescent with confirmed diagnosis of PWS which presents atypical phenotype. The patient progressed with spontaneous and complete pubertal development, stature in the normal range, and weight control without any pharmacological treatment, except metformin. COMMENTS: PWS is an imprinting paternally inherited disorder of 15q11-13 characterized by hypotonia in infant age, hyperphagia, varied degrees of mental retardation, behavior problems, hypogonadism, short stature, and other less common findings.

Comparison of cervical length in adult and adolescent nulliparae at mid-gestation.

STUDY OBJECTIVE: To compare cervical lengths of adolescents and adults in mid-gestation. DESIGN: An analytical, observational, and cross-sectional study. SETTING: Public health system in the city of Blumenau, Brazil. PARTICIPANTS: Primigravidae adolescents under the age of 16 and adults over age 20 (n = 40/group) were systematically sampled. INTERVENTIONS: Cervical measurements were performed between 21 and 24 weeks of gestation through transvaginal ultrasonography using a previously validated method. MAIN OUTCOME MEASURES: Mean cervical length (Mann-Whitney test) and percentage of cervices below 25 mm (Fisher exact test). RESULTS: For adolescents and adults, average uterine cervix lengths were 28 ± 6.6 mm 33 ± 4.1 mm (P < .0001), respectively, and the proportion of cervixes below 25 mm were 27.5% and 7.5% (P < .02), respectively. In addition, adolescents had significantly lower gynecologic age, education, and family income than adults. CONCLUSION: Primigravida adolescents under the age of 16 have shorter cervices than adults, and a higher percentage of adolescents have cervices shorter than 25 mm. This may be associated with the higher risk of preterm birth observed in adolescents and suggests that this population requires special attention in prenatal care.

Quantitative changes in human epithelial cancers and osteogenesis imperfecta disease detected using nonlinear multicontrast microscopy.

We show that combined multimodal nonlinear optical (NLO) microscopies, including two-photon excitation fluorescence, second-harmonic generation (SHG), third harmonic generation, and fluorescence lifetime imaging microscopy (FLIM) can be used to detect morphological and metabolic changes associated with stroma and epithelial transformation during the progression of cancer and osteogenesis imperfecta (OI) disease. NLO microscopes provide complementary information about tissue microstructure, showing distinctive patterns for different types of human breast cancer, mucinous ovarian tumors, and skin dermis of patients with OI. Using a set of scoring methods (anisotropy, correlation, uniformity, entropy, and lifetime components), we found significant differences in the content, distribution and organization of collagen fibrils in the stroma of breast and ovary as well as in the dermis of skin. We suggest that our results provide a framework for using NLO techniques as a clinical diagnostic tool for human cancer and OI. We further suggest that the SHG and FLIM metrics described could be applied to other connective or epithelial tissue disorders that are characterized by abnormal cells proliferation and collagen assembly.

Turner syndrome and metabolic derangements: another example of fetal programming.

BACKGROUND AND AIM: Turner syndrome (TS) patients have an increased risk of weight gain and metabolic syndrome. To date, it is unknown what factors are involved in this metabolic process, even though it is recognized that TS patients are frequently born small-for-gestational age. The aim of this study was to evaluate the correlation between lipid and glucose profiles with being overweight and birth weight and length in TS patients. STUDY DESIGN: This was a cross-sectional study. SUBJECTS AND OUTCOME MEASURES: Serum glucose, insulin (HOMA-IR), total cholesterol, and triglycerides were measured in 64 patients with TS. Data regarding birth weight and length and current body mass index (BMI) were also evaluated. RESULTS: Total cholesterol showed a significant negative correlation with birth weight and a positive correlation with BMI; triglycerides showed significant negative correlation with birth weight and length and a positive correlation with BMI; and HOMA-IR showed a significant negative correlation with birth weight and length. Low birth weight and a high BMI were predictive for 28% of total cholesterol and triglycerides; and low birth weight for 22% of HOMA-IR. CONCLUSIONS: Lipid profile was correlated with a high current BMI and low birth weight and length in TS patients and glucose profile only with low birth weight. Thus far, growth retardation may play a role in metabolic derangements in this group of patients, being considered another example of fetal programming.

Neonatal screening: 9% of children with filter paper thyroid-stimulating hormone levels between 5 and 10 µIU/mL have congenital hypothyroidism / Triagem neonatal: 9% das crianças com TSH em papel filtro entre 5 e 10 µUI/mL têm hipotireoidismo congênito

Abstract Objectives: To determine the prevalence of congenital hypothyroidism in children with filter-paper blood-spot TSH (b-TSH) between 5 and 10 µIU/mL in the neonatal screening. Methods: This was a retrospective study including children screened from 2003 to 2010, with b-TSH levels between 5 and 10 µIU/mL, who were followed-up during the first two years of life when there was no serum TSH normalization. The diagnosis of congenital hypothyroidism was defined as serum TSH ≥10 µIU/mL and start of levothyroxine treatment up to 2 years of age. Results: Of the 380,741 live births, 3713 (1.04%) had filter paper TSH levels between 5 and 10 µIU/mL and, of these, 339 (9.13%) had congenital hypothyroidism. Of these, 76.11% of the cases were diagnosed in the first three months of life and 7.96% between 1 and 2 years of age. Conclusion: The study showed that 9.13% of the children with b-TSH levels between 5 and 10 µIU/mL developed hypothyroidism and that in approximately one-quarter of them, the diagnosis was confirmed only after the third month of life. Based on these findings, the authors suggest the use of a 5 µIU/mL cutoff for b-TSH levels and long-term follow-up of infants whose serum TSH has not normalized to rule out congenital hypothyroidism.

Resumo Objetivos: Determinar a prevalência de hipotireoidismo congênito em crianças com TSH em papel filtro (TSH-f) entre 5 e 10 µUI/mL na triagem neonatal. Métodos: Estudo retrospectivo que incluiu crianças triadas de 2003 a 2010, com TSH-f entre 5 e 10 µUI/mL, acompanhadas nos dois primeiros anos de vida quando não houve normalização do TSH sérico. O diagnóstico de hipotireoidismo congênito foi definido como TSH sérico igual ou superior a 10 µUI/mL e início de tratamento com levotiroxina até os dois anos. Resultados: Dos 380.741 nascidos vivos triados, 3.713 (1,04%) apresentaram TSH-f entre 5 e 10 µUI/mL e, desses, 339 (9,13%) tinham hipotireoidismo congênito. Desses, 76,11% dos casos foram diagnosticados nos primeiros três meses de vida e 7,96% entre um e dois anos. Conclusão: O estudo mostra que 9,13% das crianças com TSH-f entre 5 e 10 µUI/mL desenvolveram hipotireoidismo e que em cerca de um quarto delas o diagnóstico só se confirmou após o terceiro mês de vida. Com base nesses achados, sugere-se, para descartar o hipotireoidismo congênito, o uso do ponto de corte de TSH-f de 5 µUI/mL e o acompanhamento em longo prazo dos lactentes cujo TSH sérico não tenha se normalizado.

46,XX DSD and Antley-Bixler syndrome due to novel mutations in the cytochrome P450 oxidoreductase gene.

Deficiency of the enzyme P450 oxidoreductase is a rare form of congenital adrenal hyperplasia with characteristics of combined and partial impairments in steroidogenic enzyme activities, as P450 oxidoreductase transfers electrons to CYP21A2, CYP17A1, and CYP19A1. It results in disorders of sex development and skeletal malformations similar to Antley-Bixley syndrome. We report the case of a 9-year-old girl who was born with virilized genitalia (Prader stage V), absence of palpable gonads, 46,XX karyotype, and hypergonadotropic hypogonadism. During the first year of life, ovarian cyst, partial adrenal insufficiency, and osteoarticular changes, such as mild craniosynostosis, carpal and tarsal synostosis, and limited forearm pronosupination were observed. Her mother presented severe virilization during pregnancy. The molecular analysis of P450 oxidoreductase gene revealed compound heterozygosis for the nonsense p.Arg223*, and the novel missense p.Met408Lys, inherited from the father and the mother, respectively.