Maternal Hypomethylation of KvDMR in a Monozygotic Male Twin Pair Discordant for Beckwith-Wiedemann Syndrome.

Beckwith-Wiedemann syndrome (BWS; OMIM 130650) is a heterogeneous overgrowth syndrome characterized by visceromegaly, macroglossia, tumor predisposition, and other congenital abnormalities. BWS is usually associated with abnormalities of chromosome 11p15, including (epi)genetic changes, paternal disomy and point mutations. A number of identical twin pairs, mostly female, have been reported to be clinically discordant for BWS. Studies of monozygotic twins discordant for BWS provide more information about failure in the DNA methylation maintenance machinery during very early embryonic development. Here, we report a case of monozygotic male twins discordant for BWS phenotype. Methylation analysis of the 2 imprinted domains at 11p15.5 (H19DMR and KvDMR) was performed by methylation-specific MLPA and pyrosequencing of DNA extracted from peripheral blood and buccal swabs of both twins. Hypomethylation at KvDMR was identified in both cell types of the affected twin, whereas his healthy brother presented hypomethylation only in blood cells and a normal methylation profile in buccal swab. For diagnostic purposes, it is important to remember that twins can share fetal circulation and possibly share hematopoietic stem cells early in development; therefore, the affected and unaffected twins can share an epigenotype that will resemble partial hypomethylation. If a patient is a twin, it is valuable to obtain a sample from a tissue other than blood.

Diferente expresividad de la mutacion Asn264LysfsX35 del gen GNAS en una familia afecta de pseudohipoparatiroidismo / Different expression of the Asn264LysfsX35 mutation of the GNAS gene in a family with pseudohypoparathyroidism

El pseudohipoparatiroidismo (PHP) comprende un grupo heterogéneo de enfermedades endocrinológicas que se caracterizan por la existencia de hipocalcemia, hiperfosfatemia y resistencia tisular a la hormona paratiroidea. Se distinguen diferentes formas de PHP. El PHP-Ia es la forma más frecuente y asocia resistencia hormonal múltiple, signos clínicos de osteodistrofia hereditaria de Albright (OHA) y mutaciones en el gen GNAS codificador de la proteína Gsα. El pseudoPHP (PPHP) asocia igualmente mutaciones en el gen GNAS pero cursa con OHA aislada sin anomalías endocrinas. Se presenta una familia con madre afecta de PPHP y dos hijas con PHP-Ia que comparten la misma mutación inactivadora en heterocigosis en el gen GNAS (Asn264LysfsX35). Se discute la diferente expresividad clínica así como el modelo de herencia dominante con impronta genética en el que el fenotipo de la descendencia está deteminado por el sexo del progenitor afecto (AU)

Pseudohypoparathyroidism (PHP) is a heterogeneous group of endocrine diseases characterised by hypocalcaemia, hyperphosphataemia and resistance to PTH. There are different forms of PHP. PHP-Ia is the most frequent form and shows multi-hormonal resistance, GNAS (Gsα) mutations and signs of Albright́s hereditary osteodystrophy (AHO). PseudoPHP (PPHP) have isolated AHO without hormonal resistance and it is also caused by GNAS mutations. We present a family that share the same inactivating GNAS mutation (Asn264LysfsX35); the mother being affected with PPHP and the two daughters with PHP-Ia. We discuss the different clinical phenotypes and the dominant mode of inheritance with genetic imprinting where the phenotype of the offspring depends on the sex of the parent affected (AU)

[Different expression of the Asn264LysfsX35 mutation of the GNAS gene in a family with pseudohypoparathyroidism.]. / Diferente expresividad de la mutacion Asn264LysfsX35 del gen GNAS en una familia afecta de pseudohipoparatiroidismo.

Pseudohypoparathyroidism (PHP) is a heterogeneous group of endocrine diseases characterised by hypocalcaemia, hyperphosphataemia and resistance to PTH. There are different forms of PHP. PHP-Ia is the most frequent form and shows multi-hormonal resistance, GNAS (Gs(α)) mutations and signs of Albright́s hereditary osteodystrophy (AHO). PseudoPHP (PPHP) have isolated AHO without hormonal resistance and it is also caused by GNAS mutations. We present a family that share the same inactivating GNAS mutation (Asn264LysfsX35); the mother being affected with PPHP and the two daughters with PHP-Ia. We discuss the different clinical phenotypes and the dominant mode of inheritance with genetic imprinting where the phenotype of the offspring depends on the sex of the parent affected.

Coexistence of two different pseudohypoparathyroidism subtypes (Ia and Ib) in the same kindred with independent Gs{alpha} coding mutations and GNAS imprinting defects.

BACKGROUND: Pseudohypoparathyroidism (PHP) defines a rare group of disorders whose common feature is resistance to the parathyroid hormone. Patients with PHP-Ia display additional hormone resistance, Albright hereditary osteodystrophy (AHO) and reduced Gsalpha activity in easily accessible cells. This form of PHP is associated with heterozygous inactivating mutations in Gsalpha-coding exons of GNAS, an imprinted gene locus on chromosome 20q13.3. Patients with PHP-Ib typically have isolated parathyroid hormone resistance, lack AHO features and demonstrate normal erythrocyte Gsalpha activity. Instead of coding Gsalpha mutations, patients with PHP-Ib display imprinting defects of GNAS, caused, at least in some cases, by genetic mutations within or nearby this gene. PATIENTS: Two unrelated PHP families, each of which includes at least one patient with a Gsalpha coding mutation and another with GNAS loss of imprinting, are reported here. RESULTS: One of the patients with GNAS imprinting defects has paternal uniparental isodisomy of chromosome 20q, explaining the observed imprinting abnormalities. The identified Gsalpha coding mutations include a tetranucleotide deletion in exon 7, which is frequently found in PHP-Ia, and a novel single nucleotide change at the acceptor splice junction of intron 11. CONCLUSIONS: These molecular data reveal an interesting mixture, in the same family, of both genetic and epigenetic mutations of the same gene.

Diabetes neonatal: defectos genéticos en la función de la célula B pancreática. Enfoque diagnóstico y tratamiento / Neonatal diabetes: genetic defects in the pancreatic B cell function. Diagnostic and treatment approach

La diabetes neonatal es una enfermedad rara y se inicia en los 3-6 meses de la vida. Al igual que la diabetes MODY, no tiene componente autoinmune y es una enfermedad monogénica. Las formas clínicas de diabetes neonatal más frecuentes se asocian a mutaciones en los genes que codifican para las subunidades Kir6.2 y SUR1 de los canales KATP (gen ABCC8 y gen KCNJ11, respectivamente), en el gen de la insulina o a alteraciones en la región 6q24 (isodisomía, duplicación o pérdida de metilación). Cada una de estas alteraciones genéticas conocidas se manifiesta con fenotipos de diabetes neonatal moderadamente diferentes. Así, las alteraciones en la región 6q24 se presentan al nacimiento con un retraso del crecimiento marcado (reflejo del déficit de insulina intraútero), la diabetes es de comienzo muy precoz (primera semana de vida) y remite en los primeros años precoz (primera semana de vida) y remite en los primeros años (diabetes neonatal transitoria), aunque después recidiva en la 2ª y 3ª década de la vida. Requiere insulina para su tratamiento. Las alteraciones en el gen de la insulina y en los genes que codifican para las subunidades SUR1 y Kir6.2 de los canales KATP responden al tratamiento con Sulfonilureas. Existen otras formas más raras de diabetes neonatal asociadas con mutaciones en otros genes implicados en la diferenciación y en la función de la célula B pancreática (genes GCK, IPF1, GLIS3, etc). Asimismo, otras alteraciones genéticas dan cuadros sindrómicos más complejos además de la diabetes neonatal, como el síndrome IPEX (gen FOXP3) en el que hay una inmunodeficiencia asociada o el síndrome de Wolcott-Rallison (gen EIF2AK•) (AU)

Neonatal diabetes is a rare disease developing in the first 3-6 months of life. Similar to MODY, it seems to be unrelated to autoimmunity in most instances and is a monogenic disease,. Most patients with PNDM have activating mutations in KC-NJ11 or ABCC8, the genes enconding the potassium ATP-sensitive (KATP) channel subunits Kir6.2 and SUR 1, or heterozygous mutations in the preproinsulin (INS) gene. In contrast abnormalities in chromosome 6q24 (isodsomy, paternal duplication or loss of maternal methylation) are the most common cause of TNDM. Each of the genetic alteration is associated to slightly different neonatal diabetes phenotypes. For example, patients with alterations at 6q24 band are more likely to have intrauterine growth retardation, develop diabetes in the first few weeks of life but go into remission in a few months, with possible relapse to a permanent diabetes state usually around adolescence or as adults. Insulin in the required treatment. Patients with alterations at INS or KCNJ11 and ABCC8 genes, encoding the Kir6.2 and SUR1 subunit of the pancreatic KATP channel are diagnosed later on (after 3-4 weeks of life), perinatal data show intrauterine growth retardation, with a normal ponderal index, and even transient forms are detected, they are usually associated to the permanent form. Patients with alterations at the coding K ATP channel genes can be transferred from insulin therapy to sulfonylureas. The other known genetic causes of neonatal diabetes are rare and are attributed to mutations in the genes that encode glucokinase, insulin promoter factor, pancreas transcription factor 1 α, FOXP3 or the eukaryotic translation initiation factor 2-alpha kinase 3. Clinical features, such as pancreatic aplasia or extra pancreatic features, and knowledge of consanguinity can be very helpful when deciding whether to test for other genetic subtypes (AU)

Pseudohipoparatiroidismo: diagnóstico genético / No disponible

El pseudohipoparatiroidismo (PHP) está caracterizado por hipocalcemia e hiperfosfatemia debidas a resistencia a la hormona paratiroidea (PTH). Pacientes con PHP-Ia, generalmente, presentan otras resistencias hormonales y muestran un fenotipo característico que se conoce como osteodistrofi a hereditaria de Albright (AHO). Este mismo fenotipo también está presente en pacientes diagnosticados de pseudopseudohipoparatiroidismo (PPHP), que no tienen resistencia hormonal. Por otra parte, los pacientes con PHP-Ib, presentan, preferentemente, resistencia a la PTH y no tienen fenotipo de Albright. Desde el punto de vista genético, el PHP-I está causado por alteraciones en el gen GNAS o en la región 5 de este complejo locus, así, los pacientes con PHP-Ia presentan mutaciones en heterozigosis en cualquiera de los 13 exones codificantes de la proteína Gs, mientras que el PHP-Ib se debe a alteraciones en el patrón de metilación del locus GNAS. En algunos casos, esas pérdidas de metilación se asocian con microdeleciones en regiones situadas 5 al gen GNAS y que son transmitidas por la madre. El locus GNAS está sometido al fenómeno de imprinting y este hecho tiene consecuencias importantes a la hora de establecer un patrón de herencia y un adecuado consejo genético (AU)

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Neonatal diabetes with end-stage nephropathy: pancreas transplantation decision.

OBJECTIVE: To describe the diagnosis of a patient with neonatal diabetes who had been misdiagnosed with type 1 diabetes and referred to our hospital for pancreas and kidney transplantation because of end-stage renal disease. RESEARCH DESIGN AND METHODS: A diagnosis of neonatal diabetes was made after a molecular genetic study revealed a mutation in exon 34 of the ABCC8 gene. Pancreas transplantation was ill-advised. RESULTS: The patient was switched from insulin to glibenclamide 4 months after kidney transplantation, confirming that pancreas transplantation would not have been a good decision. CONCLUSIONS: This is the first report of a patient with neonatal diabetes who developed diabetic nephropathy that progressed to end-stage renal disease. This report illustrates that careful endocrinological evaluation, including molecular genetic studies, if necessary, is mandatory before a decision to perform a pancreas transplant is made.

Diabetes monogénica neonatal y en la edad pediátrica / Monogenic diabetes during the neonatal period and in the pediatric patient

La diabetes neonatal (DN) es una entidad rara cuya incidencia se sitúa aproximadamente en un caso por cada 300.000-400.000 recién nacidos vivos. Si bien la enfermedad se desarrolla en los primeros días o semanas de vida, en el 50% de los niños remite en los primeros años (diabetes neonatal transitoria [DNT]), mientras que en otros casos la diabetes requerirá tratamiento a lo largo de toda la vida (diabetes neonatal permanente [DNP]). Algunos pacientes con DNT en remisión recidivan con posterioridad, principalmente en la pubertad o durante el embarazo. Si comparamos los pacientes con DNT frente a aquellos con DNP, es más probable que los primeros presenten mayor retraso en el crecimiento intrauterino, se diagnostiquen más tempranamente, no presenten cetoacidosis y sus requerimientos iniciales de insulina sean menores. Sin embargo, teniendo en cuenta que existe un gran solapamiento entre ambas patologías, no es posible distinguirlas completamente utilizando exclusivamente el criterio clínico. La DN parece no relacionarse con alteraciones autoinmunes en la mayoría de los casos. Asimismo, se han descrito algunos síndromes asociados -principalmente a DNP- que sólo pueden ser caracterizados a nivel molecular; así, por ejemplo, se han identificado alteraciones en los genes KCNJ11 y ABCC8, que codifican para las subunidades Kir6.2 y SUR1 de los canales pancreáticos de potasio sensibles al ATP (KATP) implicados en la regulación de la secreción insulínica, en un 33-50% de los pacientes con DNP. Los estudios moleculares de las anomalías en el cromosoma 6 (observadas en más de un 60% de las DNT) y de los genes KCNJ11 y ABCC8 son una buena herramienta para distinguir las DNT y las DNP en el periodo neonatal. Este aspecto tiene asimismo una gran importancia terapéutica, dado que los pacientes con mutaciones en los genes KCNJ11 y ABCC8 pueden sustituir el tratamiento con insulina por sulfonilureas. Teniendo en cuenta que es muy frecuente la recurrencia de los pacientes diagnosticados de diabetes neonatal «transitoria», es imprescindible su seguimiento a lo largo de la vida

Neonatal diabetes is a rare condition occurring in one per 300,000-400,000 live births. The disease develops in the fi rst days/weeks of life, although 50% of the cases go into remission in a matter of a few years (transient neonatal diabetes [TND]). However, in other cases, diabetes persists and requires lifelong treatment (permanent neonatal diabetes [PND]). Some patients with TND in remission relapse later on to a state of permanent diabetes at times of metabolic stress, such as puberty or pregnancy. Compared to patients with PND, those with TND are more likely to have intrauterine growth retardation, are diagnosed earlier and are less likely to develop ketoacidosis. Moreover, their initial insulin requirements are lower. However, there is considerable overlap between the two groups and, thus, TND cannot be distinguished from PND on the basis of clinical features alone. Very early onset of diabetes mellitus seems to be unrelated to autoimmunity in most instances. A number of conditions are associated with PND, some of which have been characterized only at the molecular level. Among these, the very recently described mutations in the KCNJ11 and ABCC8 genes, encoding the Kir6.2 and SUR1 subunit of the pancreatic KATP channel involved in regulation of insulin secretion, have been identifi ed in one third to one half of the patients with PND. Molecular analysis of chromosome 6 anomalies (found in more than 60% of the cases of TND) and the KCNJ11 and ABCC8 genes provides a tool to differentiate between TND and PND during the neonatal period. This analysis also has potentially important therapeutic consequences, since those patients with mutations in the KCNJ11 and ABCC8 genes can be switched from insulin therapy to sulfonylureas. Recurrent diabetes is common in patients with "ransient" neonatal diabetes mellitus and, consequently, prolonged follow-up is imperative

The majority of cases of neonatal diabetes in Spain can be explained by known genetic abnormalities.

BACKGROUND: Neonatal diabetes is a rare disease characterized by hyperglycaemia within the first 3 months of life and requiring insulin treatment; it can either be transient (TNDM) or permanent (PNDM). Alterations at band 6q24 and heterozygous activating mutations in KCNJ11, the gene encoding the pore-forming subunit of the KATP channel, can cause neonatal diabetes. Aims We screened the 6q24 region, KCNJ11, GCK, FOXP3 and IPF1 genes for mutations in families with PNDM or TNDM to establish a phenotype-genotype correlation. METHODS: Twenty-two patients with neonatal diabetes were recruited. Inclusion criteria were insulin-treated diabetes diagnosed within the first 3 months and insulin treatment for at least 15 days. Clinical data were recorded in a questionnaire. RESULTS: We identified 17 genetic alterations in our patients: six alterations at the 6q24 band associated with TNDM and nine mutations in KCNJ11, five of which were novel. The analysis for a phenotype-genotype correlation showed that patients with 6q24 alterations had a lower birth weight and were diagnosed earlier than patients with KCNJ11 mutations. At follow-up of the TNDM patients with genetic alterations, 43% developed diabetes or impaired glucose tolerance in later life (one with 6q24 duplication and two with N48D and E227K mutations at KCNJ11 gene). Furthermore, half the first-degree relatives who carried a genetic alteration but who had not suffered from neonatal diabetes were diagnosed with diabetes or impaired glucose tolerance before the age of 30 years. CONCLUSIONS: KCNJ11 mutations are common in both TNDM and PNDM and are associated with a higher birth weight compared with patients with 6q24 abnormalities. Patients with TNDM should be screened for abnormalities in glucose metabolism in adult life.

Panhypopituitarism: genetic versus acquired etiological factors.

OBJECTIVE: Mutations in the genes encoding pituitary transcription factors (mainly PROP1, POUF1 and HESX1) are responsible for familial combined pituitary hormone deficiency (CPHD) and septo-optic dysplasia (SOD) while only a low percentage of mutations are the cause of sporadic forms. Indeed, it has been suggested that environmental rather than genetic factors could be important in the pathogenesis of CPHD. PATIENTS AND METHODS: Thirty-six sporadic patients diagnosed with CPHD or SOD were included in the study. All coding exons and intron-exon boundary regions of PROP1, POUF1 and HESX1 were amplified by PCR and subsequently sequenced. RESULTS: Two novel missense mutations in the HESX1 gene (Q117P, K176T) were identified in two patients. Polymorphisms in PIT1 and PROP1 were also detected. A higher percentage of breech delivery in male patients with CPHD versus females was observed. CONCLUSIONS: The low percentage of mutations found in the most common transcription factors involved in CPHD show that a better characterization of hormonal and morphological phenotypes is necessary for patients with CPHD included in genetic studies, and other genetic or non-genetic factors have to be taken into account.

Association of KIR2DL5B gene with celiac disease supports the susceptibility locus on 19q13.4.

Genome-wide scans have detected linkage to celiac disease (CD) in several genomic locations, including 19q13.4. Killer immunoglobulin-like receptor (KIR) genes map to the region and encode receptors of natural killer (NK) cells and certain T cells that modulate cytolitic activity through interactions with HLA class I ligands, participating in the innate immune response. We performed KIR genotyping in a group of 70 CD patients of Basque origin and compared gene content, genotype and haplotype frequencies to ethnically matched blood-donors. The frequency of gene combination KIR2DL5B(+)/KIR2DL5A(-) was significantly higher in the disease group, and this result was confirmed in a second group of 343 CD patients and 160 controls of Spanish origin, suggesting an implication of this 'unexpressed' gene with increased susceptibility to CD (combined OR of 3.63 (95% CI: 1.76-7.51; P=0.0004)), possibly due to the lack of an efficient inhibitory signal. Our results support the role of the KIR gene cluster in celiac disease and replicate the CD-susceptibility locus at 19q13.4.

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease.

The major susceptibility locus for type 1 diabetes mellitus (T1D) maps to the human lymphocyte antigen (HLA) class II region in the major histocompatibility complex on chromosome 6p21. In southern European populations, like the Basques, the greatest risk to T1D is associated with DR3 homo- and heterozygosity and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD) is another DR3-associated autoimmune disorder showing certain overlap with T1D that has been explained by the involvement of common genetic determinants, a situation more frequent in DR3-rich populations, like the Basques. As both T1D- and CD-associated HLA alleles are part of conserved extended haplotypes (CEH), we compared DR3-homozygous T1D and CD patients to determine whether CEHs were equally distributed between both disorders or there was a differential contribution of different haplotypes. We observed a very pronounced distribution bias (P<10(-5)) of the two major DR3 CEHs, with DR3-B18 predominating in T1D and DR3-B8 in CD. Additionally, high-density single nucleotide polymorphism (SNP) analysis of the complete CEH [A*30-B*18-MICA*4-F1C30-DRB1*0301-DQB1*0201-DPB1*0202] revealed extraordinary conservation throughout the 4.9 Mbp analyzed supporting the existence of additional diabetogenic variants (other than HLA-DRB1*0301-DQB1*0201), conserved within the DR3-B18 CEH (but not in other DR3 haplotypes) that could explain its enhanced diabetogenicity.

Disgenesias gonadales y pseudohermafroditismo masculino / No disponible

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Heterogeneity of vitamin D receptor gene association with celiac disease and type 1 diabetes mellitus.

OBJECTIVE: Vitamin D has been shown to exert multiple immunomodulatory effects and is known to suppress T-cell activation by binding to the vitamin D receptor (VDR). To determine whether VDR gene polymorphisms are related to the susceptibility to celiac disease, we investigated its implication as a candidate gene in the Basque population. Because celiac disease and type 1 diabetes share common susceptibility loci, we also analyzed families with type 1 diabetes mellitus. METHODS: A total of 37 families with celiac disease and 64 type 1 diabetic families of Basque origin with at least one affected offspring were genotyped for four VDR restriction-site polymorphisms (Fok I, Bsm I, Apa I and Taq I). The AFBAC approach was used to test for association. RESULTS: Comparison of VDR genotypes of the patients with those of 88 healthy individuals identified "ff" as a risk genotype for celiac disease [p = 0.01; OR = 3.45 (1.12-10.79)]. On the other hand, a significantly higher frequency of haplotype "fBAt" was observed in the type 1 diabetic group [p(c) = 0.02; OR = 4.4 (1.5-15.3)]. CONCLUSION: Our findings suggest that polymorphisms within the vitamin D receptor gene are markers of susceptibility to or protection from autoimmune diseases, although, at least in the Basque population, association of VDR variants with celiac disease and type 1 diabetes seems to be heterogeneous.

Neoplasia endocrina múltiple: estudio genético / Multiple endocrine neoplasia: genetic approach

Las neoplasias endocrinas múltiples (MEN) son síndromes de herencia autosómica dominante caracterizados por la asociación de lesiones en distintas glándulas presentes en varios miembros de una misma familia. Las principales características de MEN tipo 1 incluyen hiperparatiroidismo primario, tumores pancreáticos y adenomas hipofisarios; con menos frecuencia pueden aparecer adenomas suprarrenales, tumores tímicos y bronquiales, lipomas y varias lesiones cutáneas. Los síndromes tipo 2 (MEN 2A y 2B, y carcinoma medular de tiroides familiar) se caracterizan por alta penetrancia de carcinoma medular de tiroides y difieren en su expresión variable de feocromocitoma, hiperparatiroidismo y otros rasgos clínicos. El gen supresor de tumores MEN1 codifica para una proteína nuclear, la menina, que interactúa con diferentes factores de transcripción. Los síndromes MEN 2 se producen por mutaciones en línea germinal en el protooncogén RET, que codifica para un receptor tirosincinasa. El estudio genético de mutaciones en estos 2 genes permite la identificación de individuos con predisposición a la enfermedad, el diagnóstico temprano y el adecuado tratamiento clínico y terapéutico (AU)

Multiple endocrine neoplasias (MEN) are inherited autosomal dominant syndromes characterized by the association of distinct glandular lesions in several members of the same kindred. The main clinical features of MEN1 include primary hyperparathyroidism, pancreatic islet cell tumors and pituitary adenomas; less common features are adrenal adenomas, thymic and bronchial carcinoid tumors, lipomas and various cutaneous lesions. The MEN2 syndromes (MEN2A, MEN2B and familial medullary thyroid carcinomas) are characterized by a high penetrance of medullary thyroid carcinoma and differ in their variable expression of pheochromocytoma, hyperparathyroidism and other clinical features. The MEN1 tumor suppressor gene encodes a nuclear protein, menin, which interacts with distinct transcription factors. The MEN2 syndromes are caused by germ-line which encodes a tyrosine kinase transmembrane receptor. Genetic testing for mutmutations of the RET proto-oncogene, ations in these two genes allows identification of individuals predisposed to the disease, and their early diagnosis, and appropriate clinical and therapeutic management (AU)

Molecular analysis of Frasier syndrome: mutation in the WT1 gene in a girl with gonadal dysgenesis and nephronophthisis.

The Wilms' tumor gene (WT1) encodes a protein that is believed to exert transcriptional and tumor-suppressor activities. Mutations in this gene have occasionally been associated with Wilms' tumor (<15% patients) and, more consistently, with three syndromes characterized by urogenital abnormalities (WAGR, Denys-Drash and Frasier syndromes). We report 17 years follow-up of a 29 year-old phenotypic female with 46,XY karyotype, gonadal dysgenesis and nephronophthisis in order to identify possible germline alterations of the WT1 gene. Frasier syndrome was suspected and confirmed by genetic analysis. Sequence analysis permitted the identification of an A40-->G mutation in position +5 in the donor splice site of intron 9. During surgery for streak gonads extirpation, a microscopic gonadoblastoma was found, a typical complication of Frasier syndrome.

Importancia de la genética en pediatría. A propósito de la diabetes / Importance of genetics in pediatrics. Based on diabetes

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Familial hypercalcemia and hypercalciuria: no mutations in the Ca2+-sensing receptor gene.

A 6-year-old boy presented with persistent hypercalcemia, hypercalciuria and nephrocalcinosis from early infancy. His 40-year-old father also had hypercalcemia and hypercalciuria. In both individuals serum values of intact parathyroid hormone (PTH) were repeatedly normal. Although these findings suggest a functional abnormality of the calcium-sensing receptor (CaR), no mutations in coding regions of the CaR gene could be demonstrated.