Genetics: Is LADA just late onset type 1 diabetes?

Background: There is a controversy regarding Latent Autoimmune Diabetes in Adults (LADA) classification and whether it should be considered a slowly progressing form of type 1 (T1) diabetes (DM) or a distinct type of DM altogether. Methods: This cross-sectional study assessed major genes associated with T1DM (class II HLA, PTPN22 [rs2476601] and INS [rs689]) in patients with LADA, as compared with participants with T1DM (stratified according to age of diagnosis before or after 30) and T2DM. HLA genotyping of the DRB1, DQA1 and DQB1 loci was performed by reverse PCR sequence-specific oligonucleotides. HLA haplotypes were assigned according to those most frequently described in the European population. INS and PTPN22 SNPs were genotyped by real-time PCR. Results: A total of 578 participants were included: 248 with T1DM (70 diagnosed after the age of 30), 256 with T2DM and 74 with LADA. High risk HLA alleles were significantly more frequent in LADA than in T2DM, whereas the opposite was true for protective alleles. We found a lower frequency of the high-risk DRB1*04-DQB1*03:02-DQA1*03:01 haplotype in LADA (21.1%) than in the overall T1DM (34.7%) (p<0.05), whereas no differences were found between these groups for DRB1*03-DQB1*02:01-DQA1*05:01 or for protective alleles. Only 12% the overall T1DM group had no risk alleles vs 30% of LADA (p<0.0005). However, HLA allele distribution was similar in LADA and T1DM diagnosed after the age of 30. A total of 506 individuals (195 with T1DM [21 diagnosed after age 30] 253 with T2DM and 58 with LADA) were genotyped for the PTPN22 and INS SNPs. The G/A genotype of the PTPN22 rs2476601 was more frequent and the T/T genotype of the INS SNP rs689 was less frequent in T1DM compared to LADA. We did not find any significant differences in the frequency of the mentioned SNPs between LADA and T2DM, or between LADA and T1DM diagnosed after the age of 30. Conclusion: In this relatively small cross-sectional study, the genetic profile of subjects with LADA showed a similar T1DM-related risk allele distribution as in participants with T1DM diagnosed after the age of 30, but fewer risk alleles than those diagnosed before 30. Differences were present for HLA, as well as PTPN22 and INS genes.

Disgenesia gonadal completa 46 XY: forma atípica con talla baja / Complete gonadal dysgenesis 46 XY: atypical form with short stature

La disgenesia gonadal completa 46 XY (46, XY CGD) es un trastorno del desarrollo sexual. Se caracteriza por el cariotipo 46 XY, genitales externos femeninos normales, presencia de estructuras müllerianas y gónadas sin desarrollar. Es un síndrome infrecuente, cuyos pacientes tienen un fenotipo femenino normal y una talla normal o alta, por lo que se diagnostican por retraso puberal o amenorrea primaria. La mayoría de los pacientes con 46, XY CGD muestran un gen SRY normal. Asociado a la presencia de un cromosoma Y, existe un riesgo marcado de tumores gonadales, especialmente después de la pubertad. El gonadoblastoma es el tumor más frecuente y tiene un alto riesgo de malignización hacia disgerminoma. Presentamos el caso de una niña que consulta a los 8 años de edad por talla baja. A la exploración la paciente presenta un fenotipo femenino normal, genitales externos femeninos, con estadio de Tanner I, peso de 21,6 kg (DE -1,43) y talla de 115,4 cm (DE -3,1). El laboratorio reveló test de estimulación con gonadotropina coriónica humana sin respuesta de testosterona y hormona antimülleriana <1 pmol/L. El cariotipo en sangre periférica es informado como 46 XY, con presencia del gen SRY. La resonancia magnética abdominal mostró la presencia de vagina, útero hipoplásico y ausencia de gónadas. Se realiza gonadectomía bilateral laparoscópica. El análisis anatomopatológico confirmó la presencia de gonadoblastoma puro bilateral de ovarios. Los hallazgos permiten confirmar el diagnóstico de 46, XY CGD. La novedad del caso radica en su baja frecuencia de aparición, la edad del diagnóstico y la presentación con una talla baja

Complete gonadal dysgenesis 46 XY (46, XY CGD) is a disorder of sexual development. It is characterized by 46 XY karyotype, normal female external genitalia, presence of Müllerian structures, and undeveloped gonads. It is a rare syndrome, in which patients have normal female phenotype, with normal or increased height, diagnosed by delayed pubertal or primary amenorrhea. The majority of patients with 46, XY CGD show a normal SRY gene. In gonadal dysgenesis associated with the presence of a Y chromosome there is a marked risk of gonadal tumors, especially after puberty. Gonadoblastoma is the most frequent tumor. It has a high risk of malignancy towards dysgerminoma. We present the case of a girl who consulted at age 8 years for short stature. On physical exam, the patient presented normal female phenotype, female external genitalia, with Tanner stage 1. Weight: 21,6 kg (sds -1,43); height: 115,4 cm (sds -3,1). Laboratory tests revealed stimulation test with HCG, did not show testosterone response, antimüllerian hormone <1 pmol/L. Karyotype in peripheral blood showed 46 XY. Genetic analysis of the SRY gene was extended and no deletions were detected. Abdominal MRI showed a normal vagina, hypoplastic uterus and confirmed the absence of gonads. Exploratory laparoscopy was performed. The anatomopathological analysis confirmed the presence of pure bilateral ovarian gonadoblastoma. Thus, the diagnosis of 46, XY CGD was confirmed. The novelty of this case lies in the rarity of the pathology as well as the clinical picture. Diagnosis before puberty as well as short stature are rare in the context of 46, XY CGD

Enfermedad de Addison autoinmune en un niño con pubarquia precoz / Autoimmune Addison’s disease in child with premature pubarche

La enfermedad de Addison, o insuficiencia suprarrenal primaria, es una enfermedad rara en los niños. La baja incidencia de la enfermedad, los síntomas inespecíficos y su lenta progresión requieren un alto índice de sospecha para su diagnóstico. La terapia sustitutiva con corticoides es vital para los pacientes con insuficiencia suprarrenal, pero el diagnóstico bioquímico es básico previo al inicio del tratamiento, por lo que ante la presencia de hiponatremia y astenia crónica debe considerarse la determinación del cortisol. Además, una vez confirmada la enfermedad, debe realizarse el estudio inmunológico. Presentamos el caso de un niño de 10 años con enfermedad de Addison de etiología autoinmune, con antecedente de pubarquia precoz, dada la baja incidencia de esta patología en la edad pediátrica. Hacemos un repaso de las pruebas realizadas para llegar al diagnóstico de la enfermedad y determinar la etiología (AU)

Addison’s disease is a rare disease in children. The low incidence of the disease, unspecific symptoms, and slow progression require a high index of suspicion for its diagnosis. Replacement therapy with corticoids is vital for patients with adrenal insufficiency but the biochemical diagnosis is essential before starting treatment, so in the presence of hyponatremia and chronic fatigue the cortisol determination should be considered. In addition to this, once disease is confirmed the immune study should be performed. We report the case of a 10 years old boy with Addison’s disease of autoimmune etiology, with history of premature pubarche, for its low incidence in childhood. We do a review of the laboratory tests to diagnose the disease and determine the etiology (AU)

[Impact of diagnosis of celiac disease on metabolic control of type 1 diabetes]. / Impacto del diagnóstico de la enfermedad celíaca en el control metabólico de la diabetes tipo 1.

OBJECTIVE: To asses the prevalence of celiac disease and to evaluate the clinical effects of a gluten-free diet on metabolic control and growth in children and adolescents with type 1 diabetes mellitus (DM1). PATIENTS AND METHODS: We performed a retrospective study of 261 patients with DM1. Diagnosis of celiac disease was based on the presence of endomysium and tissue transglutaminase antibodies in serum and was confirmed by intestinal biopsy. The impact of a gluten-free diet on metabolic control (mean annual HbAlc values), growth (height and annual growth velocity) and nutritional status (body mass index) was evaluated. Patients diagnosed with DM1 and subsequently with celiac disease were compared with a control group of patients with DM1 only. RESULTS: Twenty-one (8%) of the 261 diabetic patients were diagnosed with celiac disease and 19% also had another associated autoimmune disease. No significant differences were found in growth or metabolic control after withdrawal of gluten from the diet. CONCLUSIONS: We found a high prevalence of celiac disease in our type 1 diabetes population. A gluten-free diet had no effects on metabolic control of diabetes or on height or weight. Nevertheless, given the high prevalence of celiac disease and the possible development of long-term complications, such as lymphoma and osteoporosis, we recommend systematic screening in all diabetic patients, especially in the first 5 years after diagnosis of DM1.

Impacto del diagnóstico de la enfermedad celíaca en el control metabólico de la diabetes tipo 1 / Impact of diagnosis of celiac disease on metabolic contro l of type 1diabetes

Objetivo. Determinar la prevalencia de enfermedad celíaca (EC) en pacientes pediátricos con diabetes tipo 1 (DM-1) y evaluar la repercusión de la retirada del gluten de la dieta en el crecimiento y el control metabólico. Pacientes y métodos. Estudio retrospectivo de 261 pacientes pediátricos con DM-1. El diagnóstico de EC se basó en la presencia de anticuerpos antiendomisio y transglutaminasa junto con la confirmación mediante biopsia intestinal. Valoramos el impacto de la retirada del gluten sobre el control metabólico (medias anuales de hemoglobina glucosilada [HbA1c]), el crecimiento (talla y velocidad de crecimiento anual) y el estado nutritivo (índice de masa corporal [IMC]). Comparamos los pacientes diagnosticados de DM y EC después del diagnóstico de la diabetes con un grupo control de pacientes afectados exclusivamente de DM-1. Resultados. Un total de 21 de los 261 pacientes (8 %) presentaban EC. El 19 % de ellos tenían otro tipo de autoinmunidad asociada. No evidenciamos diferencias significativas en cuanto al crecimiento y al grado de control metabólico de la diabetes tras la retirada del gluten. Conclusiones. Encontramos una alta incidencia de EC en nuestra población con DM-1. El cribado de EC no repercute en el control metabólico de la diabetes ni en el desarrollo pondero-estatural. A pesar de ello, y debido a la alta incidencia de EC en España y a la posibilidad de aparición de complicaciones a largo plazo, como la osteoporosis y los linfomas, recomendamos realizar cribado sistemático en todos los pacientes diagnosticados de DM-1, fundamentalmente, en los primeros 5 años tras el diagnóstico

Objective. To asses the prevalence of celiac disease and to evaluate the clinical effects of a gluten-free diet on metabolic control and growth in children and adolescents with type 1 diabetes mellitus (DM1). Patients and methods. We performed a retrospective study of 261 patients with DM1. Diagnosis of celiac disease was based on the presence of endomysium and tissue transglutaminase antibodies in serum and was confirmed by intestinal biopsy. The impact of a gluten-free diet on metabolic control (mean annual HbAlc values), growth (height and annual growth velocity) and nutritional status (body mass index) was evaluated. Patients diagnosed with DM1 and subsequently with celiac disease were compared with a control group of patients with DM1 only. Results. Twenty-one (8 %) of the 261 diabetic patients were diagnosed with celiac disease and 19 % also had another associated autoimmune disease. No significant differences were found in growth or metabolic control after withdrawal of gluten from the diet. Conclusions. We found a high prevalence of celiac disease in our type 1 diabetes population. A gluten-free diet had no effects on metabolic control of diabetes or on height or weight. Nevertheless, given the high prevalence of celiac disease and the possible development of long-term complications, such as lymphoma and osteoporosis, we recommend systematic screening in all diabetic patients, especially in the first 5 years after diagnosis of DM1