Hiperplasia suprarrenal congénita debida a deficiencia de 17a-hidroxilasa: a propósito de una nueva mutación en el gen CYP17A1

La enzima P450c17 cataliza 2 reacciones diferentes: 17a-hidroxilación de la progesterona y pregnenolona y segmentación de la unión del carbono 17-20 a partir de la 17,20 liasa para producir andrógenos suprarrenales. Esta enzima está codificada por el gen CYP17A1. Se presenta una paciente de 14 años con retraso en el desarrollo puberal y presión arterial elevada para su talla y edad. Cariotipo 46,XX. En el estudio hormonal destaca hipogonadismo hipergonadotropo, así como una insuficiencia suprarrenal y exceso mineralocorticoideo. El estudio genético mostró una mutación en homozigosis en el gen CYP17A1 (c.753+1G>A), no descrita previamente, la cual es responsable de la fisiopatología de la deficiencia de 17a-hidroxilasa. Esta entidad es una forma rara de hiperplasia suprarrenal congénita. Normalmente la enfermedad suele pasar desapercibida hasta la adolescencia o el inicio de la vida adulta y se debería sospechar ante individuos 46,XY con genitales ambiguos o 46,XX con retraso puberal que asocia hipertensión y/o hipopotasemia. P450c17 enzyme catalyses two different reactions: the 17a-hydroxylation of progesterone and pregnenolone, and segmenting the carbon 17-20 binding from the 17,20 lyase producing adrenal androgens. This enzyme is coded by the CYP17A1 gene. The case is presented of a 14 year old patient with delayed pubertal development and a high blood pressure for height and age. 46,XX karyotype. Hormonal studies highlighted hypergonadotropic hypogonadism, adrenal insufficiency and mineralocorticoid excess. Subsequent genetic studies showed a homozygous mutation in the CYP17A1 gene (c.753+G>A), not previously described, which is responsible for the pathophysiology of 17a-hydroxylase deficiency. This entity is a rare form of congenital adrenal hyperplasia. The disease often goes unnoticed until adolescence or early adult life, and should be suspected in 46,XY individuals with ambiguous genitalia or 46,XX with delayed puberty associated with hypertension and/or hypokalaemia

Síndrome poliglandular autoinmune tipo 1 y mutación C322fsX372

Los síndromes poliglandulares autoinmunes son raras endocrinopatías en las que coexisten alteraciones de las glándulas endocrinas, basadas en mecanismos autoinmunes con otras enfermedades no endocrinas. En el tipo 1, las manifestaciones características son la candidiasis mucocutánea crónica, el hipoparatiroidismo y la insuficiencia suprarrenal. Presentamos a una paciente que presenta la secuencia clínica típica, junto con otras alteraciones, realizando estudio genético del gen autoimmune regulator (AIRE), detectándose una mutación en homocigosis, C322fsX372. La herencia es autonómica recesiva, asociada a mutaciones en el gen AIRE, el cual codifica una proteína que interviene en procesos de autoinmunidad e inmunodeficiencia. Para el diagnóstico, se requieren al menos 2 de las 3 manifestaciones clínicas principales, aunque en el estudio de familiares de pacientes afectados solo se requiere una de ellas. Estos síndromes deben ser diagnosticados en etapas tempranas, dada su alta morbimortalidad. Es necesario tratar cada una de las alteraciones, con el objetivo de preservar la calidad de vida. Polyglandular autoimmune syndromes are rare diseases based on autoimmune mechanisms in which endocrine and non-endocrine disorders coexist. In type 1 the characteristic manifestations are chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. A case is presented of a patient with typical clinical sequence, along with other changes, and in whom a mutation in homozygosis, C322fsX372, was detected after performing a molecular analysis of autoimmunity regulator gene (AIRE). Inheritance is autosomal recessive, associated with mutations in the AIRE gene, which encodes a protein involved in autoimmunity and immunodeficiency. For diagnosis, At least two of the three major clinical manifestations are required for a diagnosis. However, only one of them is necessary in the study of relatives of affected patients. These syndromes must be diagnosed early, given their high morbidity and mortality. Every manifestation needs to be treated, in order to maintain the quality of life

Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.

Context: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. Objective: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. Design: This study was an international, multicenter, retrospective case collection/database analysis. Setting: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. Patients: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. Results: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n 13), nonsecreting adenomas (n 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P 0.00026), with higher GH levels (P 0.00068), more frequent extension (P 0.018) and prolactin cosecretion (P 0.00023), and occurred 2 decades before controls (P0.000001). Gigantism was more common in the AIPmut group (P0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P 0.00069) and had lower decreases in GH (P 0.00037) and IGF-I (P 0.028) and less tumor shrinkage with somatostatin analogs (P 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. Conclusions: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility