Hamilton Cabral de Menezes Filho

Hypophosphatemic rickets and osteomalacia

The hypophosphatemic conditions that interfere in bone mineralization comprise many hereditary or acquired diseases, all of them sharing the same pathophysiologic mechanism: reduction in the phosphate reabsorption by the renal tubuli. This process leads to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of calcitriol, causing osteomalacia or rickets in children and osteomalacia in adults. X-linked hypophosphatemic rickets, autosomal-dominant hypophosphatemic rickets, and tumor-induced osteomalacia are the main syndromes involved in the hypophosphatemic rickets. Although these conditions exhibit different etiologies, there is a common link among them: increased activity of a phosphaturic factor, being the fibroblast growth factor 23 (FGF-23) the most studied one and to which is attributed a central role in the pathophysiology of the hyperphosphaturic disturbances. Activating mutations of FGF-23 and inactivating mutations in the PHEX gene (a gene on the X chromosome that codes for a Zn-metaloendopeptidase proteolytic enzyme which regulates the phosphate) involved in the regulation of FGF-23 have been identified and have been implicated in the pathogenesis of these disturbances. Genetic studies tend to show that the phosphorus homeostasis depends on a complex osteo-renal metabolic axis, whose mechanisms of interaction have been poorly understood so far. This paper reviews the current knowledge status concerning the pathophysiology of phosphate metabolism regulation and the pathophysiologic basis of hypophosphatemic rickets. It also analyzes the clinical picture and the therapeutic aspects of these conditions as well.

Síndrome metabólica em crianças e adolescentes: dúvidas na terminologia, mas não nos riscos cardiometabólicos

Metabolic syndrome (MS) has been a condition involved in considerable controversy, starting with the terminology. Gerald Reaven himself, the author who proposed the term MS, advised against the use of this terminology because the definition implies in at least three metabolic alterations, and it is never clear to which group of alterations we are referring to when we say that a patient has MS. In children, the problem is even more complicated, since there are many different adaptations to the criteria used in adults. On the other hand, independent of the terminology, cardiovascular risks are well-established and it is very clear that even children may present metabolic disturbances which predict future metabolic problems. The role of the pediatric endocrinologist or the general pediatrician is to investigate, especially in overweight/obese children, conditions that if treated early, may prevent future complications that today, unfortunately, are being diagnosed only in adult life. In this review, we discuss problems on the definition, epidemiology, pathophysiology, and complications of MS in children and adolescents.

Efeito fundador da mutação E180splice no gene do receptor de hormônio de crescimento identificada em pacientes brasileiros com insensibilidade ao GH

We studied the growth hormone receptor (GHR) gene in 6 patients with Laron syndrome (LS) from 4 unrelated families. Exons 2 to 10 were amplified by PCR using specific intronic pairs of primers. The PCR products were directly sequenced. Our results showed that all 6 patients carried a homozygous GAG>GAA mutation in codon 180 of exon 6. This mutation did not change the translated amino acid, but created an abnormal splice site deleting 8 amino acids from the extracellular domain of GHR. Members of all 4 kindreds with the E180splice mutation were genotyped for 4 polymorphic intragenic sites: The retention or exclusion of exon 3, single nucleotide polymorphisms present in exons 6 and 10, and intron 9 polymorphic site. All 6 patients presented the same haplotype. The E180splice mutation was first described in a population of Spanish descendants from the Andes of Southern Ecuador. This mutation was also found in oriental Jewish patients from Israel. Our families share the same intron-9 haplotype observed in Ecuadorian and Israeli patients. We conclude that the E180splice mutation is an important cause of LS in Brazil and there is probably a founder effect since our patients, Ecuadorian and Israeli patients share the same haplotype in intron 9.

Novel mutation in MCT8 gene in a Brazilian boy with thyroid hormone resistance and severe neurologic abnormalities

MCT8 is a cellular transporter of thyroid hormones important in their action and metabolization. We report a male patient with the novel inactivating mutation 630insG in the coding region in exon 1 of MCT8. He was characterized clinically by severe neurologic impairment (initially with global hypotonia, later evolving with generalized hypertonia), normal growth during infancy, reduced weight gain, and absence of typical signs and symptoms of hypothyroidism, while the laboratory evaluation disclosed elevated T3, low total and free T4, and mildly elevated TSH serum levels. Treatment with levothyroxine improved thyroid hormone profile but was not able to alter the clinical picture of the patient. These data reinforce the concept that the role of MCT8 is tissue-dependent: while neurons are highly dependent on MCT8, bone tissue, adipose tissue, muscle, and liver are less dependent on MCT8 and, therefore, may suffer the consequences of the exposition to high serum T3 levels.

A novel DAX1/NR0B1 mutation in a patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism

We report a case of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to a novel DAX1 mutation. A 19-month-old boy with hyperpigmentation and failure to thrive came to our service for investigation. Three brothers of the patient had died due to adrenal failure, and a maternal cousin had adrenal insufficiency. Adrenoleukodystrophy was excluded. MRI showed normal pituitary and hypothalamus. Plasma hormone evaluation revealed high ACTH (up to 2,790 pg/mL), and low levels of androstenedione, DHEA-S, 11-deoxycortisol, and cortisol. At 14 years of age the patient was still prepubescent, his weight was 43.6 kg (SDS: -0.87) and his height was 161 cm (SDS: -0.36), with normal body proportions. In the GnRH test, basal and maximum values of LH and FSH were respectively 0.6/2.1 and < 1.0/< 1.0 U/L. Molecular investigation identified a novel mutation that consists of a deletion of codon 372 (AAC; asparagine) in exon 1 of DAX1. This mutation was not found in a study of 200 alleles from normal individuals. Prediction site analysis indicated that this alteration, located in the DAX1 ligand-binding domain, may damage DAX1 protein. We hypothesize that the novel (p.Asp372del) DAX1 mutation might be able to cause a disruption of DAX1 function, and is probably involved in the development of AHC and HH in this patient.

Pesquisa de tecido prostático em pacientes 46, XX portadoras da forma clássica de hiperplasia congênita das suprarrenais

ABSTRACT Objectives: To describe the presence of prostatic tissue in 46,XX patients with the classical form of congenital adrenal hyperplasia (CAH); to evaluate the sensitivity and specificity of prostatic specific antigen (PSA) measured in congenital adrenal hyperplasia patients with regard to the detection of prostatic tissue in pelvic MRI. Methods: We studied 52 children and adolescents, 32 with the classical form of congenital adrenal hyperplasia, 10 boys and 10 girls without CAH. Pelvic MRI was performed in all patients to detect prostatic tissue. Prosta-te specific antigen, testosterone and dihydrotestosterone were measured in all patients. We used Receiver Operating Characteristic Curve for PSA discrimination capacity. Results: Five girls with congenital adrenal hyperplasia showed image of prostatic tissue on pelvic MRI. Prostate specific antigen showed sensitivity and specificity of 100% and 88.9%, respectively, taking 0.1 ng/mL as the cutoff level. Conclusions: The incidence of prostatic tissue in 46,XX patients with the classical form of congenital adrenal hyperplasia was 15.6%. PSA demons-trated to be a good marker of prostatic tissue in these patients and should be used to screen patients to be submitted to image studies.

Identification and functional analysis of a novel inactivating mutation (A804D) of the calcium-sensing receptor gene.

Relatively little is known about patients’ understanding of thyrotoxicosis and its treatment. Lincoln et al . (2000) found that patient knowledge of the disorder was limited, in an endocrine clinic with no routine provision of printed material or formal education programme. Thyrotoxic patients need to be aware of the symptomatology associated with the condition as well as potential side-effects of antithyroid drugs. Agranulocytosis, although rare (Cooper, 2003), is potentially fatal, and patients with suggestive symptoms should stop their medication immediately, and seek urgent medical advice. In this endocrine clinic, patients with thyrotoxicosis receive written information sheets detailing the major symptoms, treatment options and potential side-effects, and also have personal and telephone access to an endocrine specialist nurse. The aim of this study was to determine the level of knowledge of thyrotoxicosis and its treatment among patients attending the clinic who had been treated with antithyroid drugs. Consecutive patients were asked to respond to a postal questionnaire relating to information contained within the information sheets. Ethical approval was obtained. Responders were asked to identify thyrotoxic symptoms from a list. The correct course of action to be taken in the event of a sore throat developing on antithyroid medication was also selected from a list in a two-part question. A ‘total knowledge score’ was calculated for each patient, the maximum achievable score being 16. A subscore was also calculated for questions relating to antithyroid treatment (the ‘treatment score’), with a maximum achievable value of 8. Patients were asked to rate their perception of the adequacy of information received. Questionnaires were posted to 162 patients [median age 42 years (range 21–86), 84% female] and 57 completed questionnaires were returned. The majority of individuals (98%) had had at least three attendances at the endocrine clinic prior to completing the questionnaire. Only 30% of responders were aware of all six thyrotoxic symptoms listed. The most commonly recognized symptoms were weight loss (84% of responders), heat intolerance (83%) and palpitations (83%). The median knowledge score was 12·1 (range 2–16). There was a negative correlation between total score and age ( ρ = − 0·47, P < 0·001). Sixty-nine per cent of individuals perceived themselves to have received adequate information about thyroid disease. However, median knowledge scores were identical regardless of whether patients felt they had received adequate information or not. Only 42% of individuals identified a ‘drop in blood count’ as a potential side-effect of antithyroid medication. Overall, 51% of responders knew the correct course of action to take should a sore throat develop while on antithyroid drugs. Of the 40 patients (74% of responders) who perceived that they had received adequate information about antithyroid medications, 40% were unaware of the correct action required. The median treatment score was 6 (range 0–8), and worsened with age ( ρ = − 0·42, P = 0·001). Patients who felt they had received adequate information about treatment had better treatment scores [6·0 (0– 8) vs. 3·5 (0–6); P = 0·006]. We have demonstrated that understanding of key issues pertaining to thyrotoxicosis is disappointing. Less than half of the responders were aware of agranulocytosis as a potential sideeffect of antithyroid drugs. Only half knew the correct course of action to take in the face of suspected agranulocytosis, despite the fact that a much greater proportion of individuals felt they had received adequate information about treatment. This level of knowledge is particularly poor in view of the provision of information sheets and contact with an endocrine specialist nurse throughout this study. The influence of patient age on consultations was demonstrated by Callahan et al . (2000), who reported that although older patients reported greater satisfaction during consultations, they were given less health education and asked fewer questions. Lincoln et al . (2000) found that knowledge of thyrotoxicosis among patients was limited. Patients’ knowledge and satisfaction improved whether they received information leaflets alone or together with group education. In our study, patients were already receiving information sheets, but still demonstrated inadequate knowledge. The present study demonstrates that we need to be more active in providing education about key aspects of thyrotoxicosis and its treatment during every consultation. Furthermore, we need to check patients’ understanding of the information we have imparted, as there is a discrepancy between patient perception of adequacy of education and actual knowledge gained.

Fatores que interferem no crescimento e na altura final de pacientes com hiperplasia congênita das supra-renais por deficiência da 21-hidroxilase

Congenital adrenal hyperplasia (CAH) represents a group of genetic diseases where the synthesis of cortisol is compromised by deficiency in one of the enzymes involved in adrenal steroidogenesis. In CAH owing to 21-hydroxylase deficiency (21OHD), responsible for more than 90% of all cases, the adrenal androgen secretion is increased. The classic form of 21OHD is treated with glucocorticoids, and mineralocorticoid is replaced if necessary. The chronic use of corticosteroids may compromise growth by different means. Otherwise, the excessive adrenocortical secretion of sex steroids reduces the duration of growth, by both accelerating bone age and the possible induction of central precocious puberty. The associated effects of prolonged glucocorticoid therapy and excessive amounts of sex steroids upon growth render children with CAH specially at risk for short stature. Therefore their growth and pubertal evolution must be carefully evaluated and monitored. It is also important to use glucocorticoids with less growth suppressive potential. Thus, we believe that the best therapeutic option for children with CAH is the use of hydrocortisone ou cortisone acetate in physiologic doses, the larger dose given in the morning.