ABSTRACT BACKGROUND: Knowledge of clinical and laboratory differences between chromosomal and undefined causes aids etiological research on non-obstructive azoospermia. OBJECTIVE: Compare clinical and laboratory differences between men with non-obstructive azoospermia due to chromosomal anomalies versus undefined causes DESIGN AND SETTING: A cross-sectional retrospective study conducted at a public university hospital in Campinas (Brazil) METHODS: All men aged 20–40 years with non-obstructive azoospermia were included in the analysis. RESULTS: The 107 cases included 14 with Klinefelter syndrome (KS) (13%), 1 with mosaic KS, 4 with sex development disorders (2 testicular XX, 1 NR5A1 gene mutation, and 1 mild androgen insensitivity syndrome) (4%), 9 with other non-obstructive azoospermia etiologies (8%), and 79 with undefined causes. The 22 chromosomal anomaly cases (14 KS, 1 mosaic KS, 2 testicular XX, 4 sex chromosome anomalies, and 1 autosomal anomaly) were compared with the 79 undefined cause cases. The KS group had lower average testicular volume, shorter penile length, and lower total testosterone levels but greater height, arm span, serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, and gynecomastia frequency (absent in the undefined group and affecting more than half of the KS group). Patients with testicular XX DSD had LH, FSH, and penile length data intermediate between the KS and undefined cause groups, testicular volume similar to the KS group, and other data similar to the undefined group. CONCLUSION: Clinical and laboratory data differentiate men with non-obstructive azoospermia and chromosomal anomalies, particularly KS and testicular XX, from those with undefined causes or other chromosomal anomalies. BACKGROUND nonobstructive non obstructive OBJECTIVE SETTING crosssectional cross sectional Brazil (Brazil METHODS 2040 20 40 20–4 analysis RESULTS 10 (KS 13%, 13 13% , (13%) ( NRA NR NR5A mutation 4%, 4% (4%) 8%, 8 8% (8%) 7 (1 height span LH (LH FSH (FSH absent . group) groups CONCLUSION 204 20– (13% (4% (8% (13 (4 (8

Abstract BACKGROUND: Because normal male sexual differentiation is more complex than normal female sexual differentiation, there are more cases of disorders of sex development (DSDs) with 46,XY karyotype that have unclear etiology. However, Leydig and Sertoli cell markers are rarely used in distinguishing such individuals. OBJECTIVES: To evaluate the function of Leydig and Sertoli cells in individuals with genital ambiguity, 46,XY karyotype, palpable gonads and normal testosterone secretion. STUDY DESIGN AND SETTING: Case-control study with 77 patients, including eight with partial androgen insensitivity syndrome, eight with 5α-reductase deficiency type 2 (5ARD2) and 19 with idiopathic 46,XY DSD, and 42 healthy controls, from the Interdisciplinary Study Group for Sex Determination and Differentiation (GIEDDS), at the State University of Campinas (UNICAMP), Campinas, Brazil. METHODS: Baseline levels of gonadotropins, anti-Müllerian hormone (AMH), inhibin B, insulin-like 3 (INSL3), testosterone and dihydrotestosterone in cases, and AMH, inhibin B, and INSL3 levels in controls, were assessed. RESULTS: There was no significant difference in age between cases and controls (P = 0.595). AMH and inhibin B levels were significantly lower in cases than in controls (P = 0.031 and P < 0.001, respectively). INSL3 levels were significantly higher in cases than in controls (P = 0.003). Inhibin B levels were lower in 5ARD2 patients (P = 0.045) and idiopathic patients (P = 0.001), in separate comparisons with the controls. CONCLUSION: According to our findings, we can speculate that inhibin B levels may be used to differentiate among DSD cases.

ABSTRACT BACKGROUND: Knowledge of clinical and laboratory differences between chromosomal and undefined causes aids etiological research on non-obstructive azoospermia. OBJECTIVE: Compare clinical and laboratory differences between men with non-obstructive azoospermia due to chromosomal anomalies versus undefined causes DESIGN AND SETTING: A cross-sectional retrospective study conducted at a public university hospital in Campinas (Brazil) METHODS: All men aged 20–40 years with non-obstructive azoospermia were included in the analysis. RESULTS: The 107 cases included 14 with Klinefelter syndrome (KS) (13%), 1 with mosaic KS, 4 with sex development disorders (2 testicular XX, 1 NR5A1 gene mutation, and 1 mild androgen insensitivity syndrome) (4%), 9 with other non-obstructive azoospermia etiologies (8%), and 79 with undefined causes. The 22 chromosomal anomaly cases (14 KS, 1 mosaic KS, 2 testicular XX, 4 sex chromosome anomalies, and 1 autosomal anomaly) were compared with the 79 undefined cause cases. The KS group had lower average testicular volume, shorter penile length, and lower total testosterone levels but greater height, arm span, serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, and gynecomastia frequency (absent in the undefined group and affecting more than half of the KS group). Patients with testicular XX DSD had LH, FSH, and penile length data intermediate between the KS and undefined cause groups, testicular volume similar to the KS group, and other data similar to the undefined group. CONCLUSION: Clinical and laboratory data differentiate men with non-obstructive azoospermia and chromosomal anomalies, particularly KS and testicular XX, from those with undefined causes or other chromosomal anomalies. BACKGROUND nonobstructive non obstructive OBJECTIVE SETTING crosssectional cross sectional Brazil (Brazil METHODS 2040 20 40 20–4 analysis RESULTS 10 (KS 13%, 13 13% , (13%) ( NRA NR NR5A mutation 4%, 4% (4%) 8%, 8 8% (8%) 7 (1 height span LH (LH FSH (FSH absent . group) groups CONCLUSION 204 20– (13% (4% (8% (13 (4 (8

Os distúrbios do desenvolvimento sexual (DDS) envolvem várias condições que resultam de anormalidades que podem acontecer tanto na determinação como durante a diferenciação gonadal. Algumas dessas doenças podem se manifestar ao nascimento principalmente por genitália ambígua, outras são diagnosticadas apenas na puberdade por atraso no aparecimento de características sexuais secundárias. A determinação e a diferenciação do sexo em seres humanos são processos que envolvem interações entre vários genes nas vias testicular, tais como NR5A1, NR0B1, WT1, SOX9, entre outros, e ovariana, tais como WNT4, DAX1, FOXL2 e RSPO1. Uma das principais proteínas na diferenciação gonadal de mamíferos é o fator esteroidogênico e receptor nuclear 1 (SF1). Esta revisão cobrirá alguns dos dados mais recentes sobre os papéis funcionais de SF1 e as últimas descobertas relacionadas a mutações em seu gene, NR5A1.

Disorders of sex development (DSD) involve several conditions that result from abnormalities during gonadal determination and differentiation. Some of these disorders may manifest at birth by ambiguous genitalia; others are diagnosed only at puberty, by the delayed onset of secondary sexual characteristics. Sex determination and differentiation in humans are processes that involve the interaction of several genes such as WT1, NR5A1, NR0B1, SOX9, among others, in the testicular pathway, and WNT4, DAX1, FOXL2 and RSPO1, in the ovarian pathway. One of the major proteins in mammalian gonadal differentiation is the steroidogenic nuclear receptor factor 1 (SF1). This review will cover some of the most recent data on SF1 functional roles and findings related to mutations in its coding gene, NR5A1.

OBJETIVO: Avaliar a presença de resistência insulínica e dislipidemia em mulheres com hiperplasia adrenal congênita (HAC) por deficiência da 21-hidroxilase (21OHD) e investigar a associação com índice de massa corporal (IMC) e dose de glicocorticoide prescrita. PACIENTES E MÉTODOS: Em 18 mulheres jovens (média ± DP, 19,3 ± 3,0 anos), avaliamos IMC, circunferência abdominal, dose de glicocorticoide, glicemia, insulinemia e perfil lipídico. RESULTADOS: O IMC foi normal em 12 pacientes; 5 apresentavam sobrepeso e 1 apresentou obesidade. Circunferência abdominal estava aumentada em 7 pacientes. Insulinemia de jejum e HOMA-IR estavam elevados em 7 e 8 pacientes, respectivamente. Apenas 2 pacientes apresentaram aumento de colesterol total ou de triglicérides e 4, diminuição dos níveis de HDL-colesterol. Resistência insulínica não apresentou associação com IMC, circunferência abdominal ou dose de glicocorticoide prescrita. CONCLUSÃO: Mulheres jovens com CAH 21OHD apresentaram pouca dislipidemia, mas tiveram alta prevalência de resistência insulínica e obesidade central, independentemente do IMC e da dose de glicocorticoide prescrita.

OBJECTIVE: To evaluate insulin resistance and lipid profile in women with congenital adrenal hyperplasia (CAH) caused by classical 21-hydroxylase deficiency (21OHD), and their association with body mass index (BMI) and corticosteroid dosage. SUBJECTS AND METHODS: We assessed BMI, waist circumference, current glucocorticoid dosage, glucose, insulin and lipid profile in eighteen young women (mean ± SD, 19.3 ± 3.0 years) with 21OHD CAH. RESULTS: BMI was normal in 12 patients, 5 of them were overweight, and 1 was obese. Waist circumference was high in 7 patients. Fasting insulin and HOMA-IR were elevated in seven and eight patients, respectively. Total cholesterol and triglycerides were high in only two patients, and HDL-cholesterol was low in four. Insulin resistance was not associated with BMI, waist circumference or glucocorticoid dose. CONCLUSIONS: Young women with 21OHD CAH had infrequent dyslipidemia, but had a higher prevalence of insulin resistance and central obesity, that were independent of BMI or corticosteroid dosage.

A neoplasia endócrina múltipla tipo 1 (NEM1) é uma doença hereditária autossômica dominante, caracterizada principalmente por tumores de paratireoide, enteropancreáticos e adeno-hipofisários. Apresentamos o caso de um menino com 8 anos encaminhado por crises de hipoglicemia. Seu diagnóstico foi insulinoma pancreático. Sua avó paterna faleceu por úlceras gastroduodenais de repetição e a tia paterna tinha as mesmas manifestações. Na primeira avaliação, o pai apresentou apenas úlcera gástrica, porém com a evolução desenvolveu hiperparatireoidismo e tumor carcinoide pulmonar. Durante cerca de 15 anos de seguimento, os três irmãos e o caso índice desenvolveram hiperparatireoidismo e hiperprolactinemia. O estudo molecular mostrou a substituição G por A no intron 4, a nove nucleotídeos do sítio aceptor de splicing, criando um novo sítio de splicing. Todos os membros da família afetados e estudados tinham a mesma mutação. A NEM1 é uma condição rara que requer assistência médica permanente. As identificações clínicas e genéticas precoces são essenciais para o tratamento e aconselhamento genético.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary cancer syndrome characterized mostly by parathyroid, enteropancreatic, and anterior pituitary tumors. We present a case of an 8-year-old boy referred because of hypoglycemic attacks. His diagnosis was pancreatic insulinoma. Paternal grandmother died due to repeated gastroduodenal ulcerations and a paternal aunt presented similar manifestations. At a first evaluation, the father presented only gastric ulceration but subsequently developed hyperparathyroidism and lung carcinoid tumor. During almost 15 years of follow-up, three brothers and the index case presented hyperparathyroidism and hyperprolactinemia. Molecular study showed a G to A substitution in intron 4, at nine nucleotides upstream of the splicing acceptor site, causing a splicing mutation. All affected members of the family have the same mutation. Paternal grandmother and aunt were not studied and the mother does not carry any mutation. MEN1 is a rare condition that requires permanent medical assistance. Early clinical and genetic identification of affected individuals is essential for their own surveillance and also for genetic counseling.

A síndrome do homem XX é uma condição rara na qual o fenótipo da genitália externa pode variar de uma genitália ambígua até uma genitália masculina normal. Este estudo tem por objetivo relatar a avaliação hormonal, molecular e citogenética de um menino com essa síndrome. 0 O exame da genitália externa na idade de 16 meses mostrava: pênis medindo 3,5 cm, hipospadia proximal e testículos tópicos. A ultrassonografia pélvica não visualizou estruturas mullerianas. Cariótipo foi 46,XX. A testosterona sérica não se elevou após o teste de estímulo com gonadotrofina. Biópsias gonadais mostraram túbulos seminíferos, sem evidência de células de Leydig. Estudos moleculares revelaram ausência dos genes SRY, TSPY e DYZ3, bem como ausência de deleção ou duplicação das regiões SOX9, NR5A1, WNT4 e NROB1. A criança era heterozigótica para todos os microssatélites da região 9p, incluindo o gene DMRT1. Apenas 10% dos pacientes com a síndrome do homem 46,XX são SRY-negativos. Nesses casos, a genitália geralmente é ambígua, como corroborado pelo paciente do presente relato. A masculinização incompleta sugere ganho de mutação funcional em um ou mais genes a jusante do gene SRY.

The XX male syndrome - Testicular Disorder of Sexual Differentiation (DSD) is a rare condition characterized by a spectrum of clinical presentations, ranging from ambiguous to normal male genitalia. We report hormonal, molecular and cytogenetic evaluations of a boy presenting with this syndrome. Examination of the genitalia at age of 16 months, showed: penis of 3.5 cm, proximal hypospadia and scrotal testes. Pelvic ultrasound did not demonstrate Mullerian duct structures. Karyotype was 46,XX. Gonadotrophin stimulation test yielded insufficient testosterone production. Gonadal biopsy showed seminiferous tubules without evidence of Leydig cells. Molecular studies revealed that SRY and TSPY genes and also DYZ3 sequences were absent. In addition, the lack of deletions or duplications of SOX9, NR5A1, WNT4 and NROB1 regions was verified. The infant was heterozygous for all microsatellites at the 9p region, including DMRT1 gene, investigated. Only 10% of the patients are SRY-negative and usually they have ambiguous genitalia, as the aforementioned patient. The incomplete masculinization suggests gain of function mutation in one or more genes downstream to SRY gene.

O gene SRY, localizado no cromossomo Y, codifica uma proteína testículo-específica contendo um domínio HMG (grupo de alta mobilidade) de ligação ao DNA. No entanto, mutações no gene SRY não são frequentes, especialmente nos casos de disgenesia gonadal parcial em indivíduos 46,XY. São atualmente conhecidos vários genes que participam do processo de diferenciação gonadal, tanto para o desenvolvimento testicular quanto para o ovariano. Além disso, pequenas deleções heterozigotas em 9p podem causar disgenesia gonadal XY completa ou parcial, sem outros sintomas associados. O gene DMRT1 humano, que está localizado em 9p24.3, é expresso no testículo e ovário no período fetal e tem sido considerado um dos genes autossômicos envolvido na etiologia das disgenesias gonadais. Neste trabalho, descrevemos a inserção de um nucleotídeo em 3'UTR do gene DMRT1 em um paciente 46,XY com disgenesia gonadal parcial. A mutação 3'UTR+11insT está localizada dentro de um motivo conservado importante para a estabilização do mRNA.

The Y-chromosome-located SRY gene encodes a small testis-specific protein containing a DNA-binding motif known as the HMG (high mobility group) box. However, mutations in SRY are not frequent especially in cases of 46,XY partial gonadal dysgenesis. Several sex-determining genes direct the fate of the bipotential gonad to either testis or ovary. In addition, heterozygous small deletions in 9p can cause complete and partial XY gonadal dysgenesis without other symptoms. Human DMRT1 gene, which is located at 9p24.3, is expressed in testis and ovary and has been considered, among others, a candidate autosomal gene responsible for gonadal dysgenesis. In this report we describe a nucleotide insertion in DMRT1 3'UTR in a patient of XY partial gonadal dygenesis. The 3'UTR+11insT is located within a conserved motif important for mRNA stabilization.

A enzima 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase do tipo 2 (3β-HSD2), codificada pelo gene HSD3B2, é importante na biossíntese de todas as classes de hormônios esteroides. As mutações no gene HSD3B2 podem causar deficiência da 3β-HSD2 da forma clássica. É de herança autossômica recessiva e uma das causas mais raras de hiperplasia congênita da adrenal (HCA). A deficiência dessa enzima leva frequentemente à ambiguidade genital e à insuficiência da adrenal em recém-nascidos com vários níveis de perda de sal. Neste trabalho, foi feito o estudo estrutural e molecular do gene HSD3B2 gene em um paciente 46,XY, filho de pais consanguíneos, com ambiguidade genital e perda de sal. O paciente é homozigoto para a troca nucleotídica c.665C>A no éxon 4, que putativamente leva à substituição de uma prolina do códon 222 por uma glutamina. A modelagem molecular por homologia das enzimas 3β-HSD2 normal e mutantes ressaltou que a prolina no códon 222 é um resíduo importante no enovelamento da enzima e validou um modelo adequado para avaliações de novas mutações.

Type II 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3β-HSD2), encoded by the HSD3B2 gene, is a key enzyme involved in the biosynthesis of all the classes of steroid hormones. Deleterious mutations in the HSD3B2 gene cause the classical deficiency of 3β-HSD2, which is a rare autosomal recessive disease that leads to congenital adrenal hyperplasia (CAH). CAH is the most frequent cause of ambiguous genitalia and adrenal insufficiency in newborn infants with variable degrees of salt losing. Here we report the molecular and structural analysis of the HSD3B2 gene in a 46,XY child, who was born from consanguineous parents, and presented with ambiguous genitalia and salt losing. The patient carries a homozygous nucleotide c.665C>A change in exon 4 that putatively substitutes the proline at codon 222 for glutamine. Molecular homology modeling of normal and mutant 3β-HSD2 enzymes emphasizes codon 222 as an important residue for the folding pattern of the enzyme and validates a suitable model for analysis of new mutations.

Em 2004, segundo Costa-Santos e cols., p.W406R e p.R362C correspondiam a 50% e 32% dos alelos mutantes do gene CYP17A1, respectivamente, em 24 pacientes de 19 famílias brasileiras com deficiência da 17α-hidroxilase. Apresentamos os dados clνnicos e moleculares de seis pacientes de três famílias consanguíneas brasileiras com deficiência da 17α-hidroxilase. Todas as pacientes apresentavam hipogonadismo, amenorreia e hipertensão ao diagnóstico. Duas irmãs tinham cariótipo 46,XY, ambas com gônadas palpáveis na região inguinal. Todas tinham hipogonadismo hipergonadotrófico, com nível aumentado de ACTH (> 104 ng/mL), atividade de renina plasmática suprimida, baixos níveis de potássio (< 2,8 mEq/L) e progesterona aumentada (> 4,4 ng/mL). Três delas, incluindo duas irmãs, apresentaram homozigose para a mutação p.W406R e as outras três (duas irmãs e uma prima) foram homozigotas para a mutação p.R362C. A recorrência das mutações p.W406R e p.R362C no gene CYP17A1 aqui relatada em famílias adicionais confirma que essas são as mais frequentes causadoras do fenótipo completo da deficiência combinada de 17α-hidroxilase/17,20-liase em pacientes brasileiros.

In 2004, Costa-Santos and cols. reported 24 patients from 19 Brazilian families with 17α-hydroxylase deficiency and showed that p.W406R and p.R362C corresponded to 50% and 32% of CYP17A1 mutant alleles, respectively. The present report describes clinical and molecular data of six patients from three inbred Brazilian families with 17α-hydroxlyse deficiency. All patients had hypogonadism, amenorrhea and hypertension at diagnosis. Two sisters were found to be 46,XY with both gonads palpable in the inguinal region. All patients presented hypergonadotrophic hypogonadism, with high levels of ACTH (> 104 ng/mL), suppressed plasmatic renin activity, low levels of potassium (< 2.8 mEq/L) and elevated progesterone levels (> 4.4 ng/mL). Three of them, including two sisters, were homozygous for p.W406R mutation and the other three (two sisters and one cousin) were homozygous for p.R362C. The finding of p.W406R and p.R362C in the CYP17A1 gene here reported in additional families, confirms them as the most frequent mutations causing complete combined 17α-hydroxylase/17,20-lyase deficiency in Brazilian patients.

OBJETIVO: Estimar a composição corporal avaliada pela espessura de dobras cutâneas (EDC) e pela impedância bioelétrica (BIA) em um grupo de mulheres com hiperplasia adrenal congênita, forma clássica por deficiência da enzima 21-hidroxilase (HAC-C-D21OH) e em relação ao um grupo controle. PACIENTES E MÉTODOS: Foram avaliadas 16 pacientes com HAC-C-D21OH e 26 controles, todas do sexo feminino, com idades de 8 a 18 anos. Foram estimadas as massas gorda (MG) e magra (MM) utilizando EDC e BIA. Os dados das MG e MM foram analisados de forma relativa (%), absoluta (kg) e em relação à estatura (IMG e IMM). RESULTADOS: Não foram encontradas diferenças significativas entre os dois métodos em cada grupo avaliado. Em relação ao grupo controle, as pacientes com HAC-C-D21OH apresentaram valores maiores de MG (%) BIA, IMG BIA e IMM EDC e menores de MM (%) BIA. Foi verificada correlação positiva e alta em todos os parâmetros analisados. CONCLUSÃO: Os resultados observados pelos métodos de EDC e BIA foram semelhantes nesta amostra de mulheres com HAC-CD21OH, porém controversos em relação ao grupo controle, sugerindo que se tenha cautela no uso desses métodos de avaliação da composição corporal nessa população.

OBJECTIVE: To estimate body composition by evaluating skinfold thickness (ST) and electric bioimpedance (EB) in a group of women with congenital adrenal hyperplasia due to classical 21-hydroxylase deficiency (CAH-C-21OHD) in relation to a control group. SUBJECTS AND METHODS: Sixteen patients and 26 controls were evaluated, all female, with age varying from 8 to 18 years. Fat (FM) and lean (LM) masses were evaluated by ST and EB. FM and LM data were analyzed in relative (%) and absolute (kg) values, and in relation to stature (FMI and LMI). RESULTS: There were no observed significant differences between the two methods in each group. In relation to the control group, CAH-C-21OHD patients showed higher values for FM (%) EB, FMI EB and LMI ST but lower values for FM (%) EB. Positive and high correlation values were observed for all parameters analyzed. CONCLUSION: ST and EB results observed were similar in this sample of females with CAH-C-21OHD, but controversial in relation to the control group, suggesting caution when using these methods to evaluate body composition in this population.

A síndrome de Morning Glory (SMG) é uma displasia óptica congênita associada a anomalias craniofaciais, principalmente encefalocele basal e hipopituitarismo. Os sinais clínicos são variados e muitas vezes ocultos. O gene PAX6 está envolvido na morfogênese ocular e se expressa em vários tecidos oculares durante o desenvolvimento do sistema nervoso central. O objetivo deste estudo foi avaliar o gene PAX6 na SMG associada com deficiência isolada de hormônio de crescimento. Foram relatados três pacientes pré-púberes (A, B e C) com SMG e baixa estatura por deficiência de hormônio de crescimento tratados com hormônio de crescimento recombinante humano. As seqüências codificadoras e não-codificadoras correspondentes ao PAX6 em diferentes transcritos foram analisadas por seqüenciamento direto. Variações nucleotídeas com trocas pontuais de aminoácidos não foram encontradas. O paciente A apresentou uma transição nova IVS2+9G>A, enquanto os pacientes A e C foram heterozigotos para um polimorfismo (SNP) no íntron 4. Ainda, dois SNPs em heterozigose nos íntrons 9 e 13 foram observados no paciente C. O seqüenciamento também mostrou várias variações nucleotídeas no paciente B. Dois SNPs conhecidos com a alteração nucleotídea nova C>A no íntron 4 foram observados em heterozigose. Este paciente também apresentou um baixo número de repetições TG no íntron 9 e uma nova transversão IVS11+33A>T. A regulação e a transcrição do gene PAX6 são um processo complexo; existem 2 isoformas principais da proteína, PAX6(-5a) e PAX6(+5a) e 9 transcritos descritos. Considerando que nem a distribuição de SNPs no PAX6 e nem as suas ligações com as doenças foram relatadas, um defeito funcional devido às alterações descritas não pode ser descartado.

Morning glory syndrome (MGS) is a congenital optic disc dysplasia often associated with craniofacial anomalies, especially basal encephalocele and hypopituitarism. Clinical signs are varied and often occult. The PAX6 gene is involved in ocular morphogenesis and is expressed in numerous ocular tissues during development especially in the developing central nervous system. The aim of the present study is to evaluate PAX6 in MGS associated with isolated growth hormone deficiency. Three pre-pubertal males (A, B and C) with MGS and short stature due to growth hormone deficiency, treated with recombinant human growth hormone with limited response, were reported. Two of them had basal encephalocele. Coding and non-coding sequences corresponding of PAX6 different transcripts were analyzed by direct sequencing. Nucleotide variations causing putative aminoacid change were not observed. Patient A presented the new IVS2+9G>A transition, whereas patients A and C were heterozygous for known single nucleotide polymorphisms (SNP) within the intron 4. In addition, two SNP heterozygoses were observed for patient C in both intron 9 and 13. Sequencing also revealed several nucleotide variations in patient B. Two heterozygoses for known polymorphisms were identified along with a novel C>A nucleotide change in intron 4. This patient also presented a low number on the TG repeat in intron 9 and a new IVS11+33A>T transversion. Gene regulation and transcription of PAX6 are complex processes; there are two major protein isoforms, PAX6(-5a) and PAX6(+5a), and nine transcripts described. Furthermore, extra transcription regulatory elements have been postulated within PAX6 introns. Considering that neither population distributions on PAX6 polymorphism nor their linkeages with diseases have been reported, a functional effect due to alterations described here cannot be discarded.

OBJETIVO: Descrever a variabilidade fenotípica das anomalias relacionadas ao WT1. MÉTODOS: Descrição das características clínicas e genéticas de cinco pacientes 46,XY com anomalias no WT1. RESULTADOS: Paciente 1: Recém-nascido com ambigüidade genital desenvolveu tumor de Wilms (TW) e insuficiência renal crônica (IRC), com óbito aos 10 meses. Detectada a mutação 1186G>A em heterozigose, compatível com síndrome de Denys-Drash. Pacientes 2 e 3: Adolescentes com IRC, amenorréia primária e hipogonadismo hipergonadotrófico; a paciente 2 apresentava gonadoblastoma. Ambas apresentavam mutação IVS9+4, C>T em heterozigose, característica da síndrome de Frasier. Paciente 4: Idade 9 anos, aniridia, ambigüidade genital, dismorfismos e deficiência mental; deleção 11p, compatível com síndrome WAGR foi encontrada em heterozigose. Paciente 5: Dois meses, mesmo diagnóstico do paciente 4, desenvolveu TW aos 8 meses. CONCLUSÕES: Alterações constitucionais do WT1 determinam anomalias gonadais, renais e predisposição a neoplasias; devem ser pesquisadas em casos de ambigüidade genital associada a IRC e(ou) TW; de amenorréia primária com IRC; e aniridia, ambigüidade genital e dismorfismos.

AIM: To present phenotypic variability of WT1-related disorders. METHODS: Description of clinical and genetic features of five 46,XY patients with WT1 anomalies. RESULTS: Patient 1: newborn with genital ambiguity; he developed Wilms tumor (WT) and chronic renal disease and died at the age of 10 months; the heterozygous 1186G>A mutation compatible with Denys-Drash syndrome was detected in this child. Patients 2 and 3: adolescents with chronic renal disease, primary amenorrhea and hypergonadotrophic hypogonadism; patient 2 had a gonadoblastoma. The heterozygous IVS9+4, C>T mutation, compatible with Frasier syndrome was detected. Patient 4: 9-year-old boy with aniridia, genital ambiguity, dysmorphisms and mental deficiency; a heterozygous 11p deletion, compatible with WAGR syndrome was detected. Patient 5: 2 months old, same diagnosis of patient 4; he developed WT at the age of 8 months. CONCLUSIONS: Constitutional abnormalities of WT1 cause gonadal and renal anomalies and predisposition to neoplasia and must be investigated in patients with ambiguous genitalia, chronic renal disease and(or) Wilms tumors; primary amenorrhea with chronic renal disease; and aniridia, genital ambiguity and dysmorphisms.

We report on a girl presenting Léri-Weill dyschondrosteosis (LWD) due to deletion of the SHOX gene. Her family included individuals with short stature alone or with both short stature and mesomelia or Madelung's deformity. The deletion was demonstrated through detection of hemizygosity for microsatellite markers SHOX-CA repeat, DXYS10092, DXYS10093 and DXYS10091 localized around the SHOX gene, with retention of paternal alleles in the proband and three of her sisters who had short stature as the only clinical feature. Hemizygosity for these loci was also observed in their mother, who had short stature too. The deletion in the proband was however larger, including locus DXY10083. The proband's only sister with normal height did not carry the deletion. Family history suggests transmission of the deletion from the proband's maternal great-grandfather to her grandfather via the Y chromosome, and from the grandfather to the proband's mother via the X chromosome after crossing-over in the pseudoautosomal region proximal to the SHOX gene.

OBJETIVO: Avaliar o padrão de crescimento de pacientes com hiperplasia adrenal congênita com a forma clássica da deficiência da 21-hidroxilase (21-OH), em relação ao controle hormonal e ao uso de corticóide no tratamento. MÉTODOS: Análise retrospectiva dos prontuários de 45 pacientes. Como padrão de crescimento, foi utilizado o ganho ou não de altura, avaliando-se a diferença entre o escore Z da estatura na última consulta (para idade óssea) em relação ao escore Z da estatura no início do tratamento (para a idade cronológica). Foram avaliadas todas as concentrações de 17-OH progesterona (17-OHP), androstenediona e renina, sendo considerados bem controlados os pacientes com 50% ou mais das dosagens normais. Em relação ao corticóide, foram analisados o tipo e a dose. RESULTADOS: A idade na última consulta variou de 2,8 a 26,6 anos (12,6+5,8 anos), sendo 31 do sexo feminino, 30 com a forma perdedora de sal; 62% foram considerados bem controlados para 17-OHP, 75% para androstenediona e 78% para renina. A hidrocortisona foi usada por 41 pacientes (20,2+2,6 mg/m²/dia) e, por 40, em associação com a 9a-fludrocortisona. Encontrou-se 14 pacientes com ganho, 20 com manutenção e 11 com perda estatural. Os pacientes perdedores de sal (p=0,01) e os bem controlados (p=0,0005) para 17-OHP e androstenediona apresentaram associação significativa com o ganho de estatura. CONCLUSÕES: Nesta amostra de pacientes com a forma clássica da deficiência da 21-OHD, o melhor crescimento apresentou associação com o bom controle laboratorial da 17-OHP e da androstenediona e com a forma perdedora de sal.

OBJECTIVE: To verify the growth pattern of patients with congenital adrenal hyperplasia (CAH) due to classical 21hydroxylase (21-OH) deficiency in relation to hormonal control and use of corticoid during the treatment. METHODS: Retrospective analysis of data from 45 patients. The growth pattern was analyzed according to height gain or not, using the difference between height Z score (for bone age) at the last visit in relation to the height Z score (for chronological age) in the first visit. Concentrations of 17-OH progesterone (17-OHP), androstenedione and rennin were evaluated, and the patients were considered well-controlled when 50% or more of the dosages were normal. Corticoid therapy was analyzed according to type and dose. RESULTS: The age at last visit ranged from 2.8 to 26.6 years (12.6+5.8 years), 31 were females, 30 with salt wasting form; 62% were considered well-controlled for 17-OHP, 75% for androstenedione and 78% for renin. Hidrocortisone was used in 41 patients (20.2+2.6 mg/m²/day) and 40 in association with 9a-fludrocortisone. There were 14 patients with height gain, 20 with maintenance and 11 with loss. Height gain was associated with salt wasting patients (p=0.01) and with patients well-controlled for 17OHP (p=0,0005) and androstenedione (p=0,02). CONCLUSIONS: In this sample of patients with CAH due to classical 21-OH deficiency, better height gain was associated with a good control of 17-OHP and androstenedione and with salt wasting clinical form of the disease.