Osteopetrosis autosómica dominante: a propósito de 3 casos y una mutación / Autosomal dominant osteopetrosis: A presentation of 3 cases and a new gene mutation

La osteopetrosis (OP) es una rara enfermedad ósea congénita producida por una alteración funcional en los osteoclastos con incapacidad para la reabsorción ósea normal, produciéndose un aumento de la densidad mineral ósea y esclerosis ósea. Puede clasificarse en autosómica recesiva (OPTB) o autosómica dominante (OPTA1-2). Existe una gran variabilidad clínica de la enfermedad, desde asintomática a letal en los primeros meses de vida, con expresividad variable en los miembros de una familia. Su diagnóstico es principalmente clínico con confirmación genética, y el tratamiento es sintomático. Se presentan una serie de casos de OP, con el hallazgo de una nueva mutación en el gen LRP5 causante de OPTA1 en uno de ellos

Osteopetrosis (OP) is a congenital bone disease which is caused by a functional disorder in osteoclasts with inability for normal bone resorption, leading to increased bone mineral density and bone sclerosis. It can be classified into different groups according to their clinical and their genetic characteristics: autosomal recessive with several subtypes (OPTB) or autosomal dominant type 1 or 2 (OPTA1-2). There is a wide clinical variability of the disease, from asymptomatic to lethal in the first months of life, with variable expressivity in the family members. Diagnosis is mainly clinical with genetic confirmation of the OP, and treatment is symptomatic. Three cases of OP are presented, with the discovery of a new gene mutation in LRP5 which caused OPTA1 in one of them

Síndrome poliglandular autoinmune tipo 1 y mutación C322fsX372 / Type i polyglandular autoimmune syndrome associated with C322fsx372 mutation

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 protei′na 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). 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)

Hiperplasia suprarrenal congénita debida a deficiencia de 17 -hidroxilasa: a propósito de una nueva mutación en el gen CYP17A1 / Congenital adrenal hyperplasia due to lack of 17 -hydroxylase: A report of a new mutation in the gene CYP17A1

La enzima P450c17 cataliza 2 reacciones diferentes: 17alfa-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 17alfa-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 17Alpha-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 17Alpha-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

[Type 1 polyglandular autoimmune syndrome associated with C322fsx372 mutation]. / Síndrome poliglandular autoinmune tipo 1 y mutación C322fsX372.

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.

[Congenital adrenal hyperplasia due to lack of 17α-hydroxylase: a report of a new mutation in the gene CYP17A1]. / Hiperplasia suprarrenal congénita debida a deficiencia de 17α-hidroxilasa: a propósito de una nueva mutación en el gen CYP17A1.

P450c17 enzyme catalyses two different reactions: the 17α-hydroxylation of progesterone and pregnenolone, and segmenting the carbon 17-20 binding from the 17,20lyase 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 17α-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.

[Autosomal dominant osteopetrosis: a presentation of 3 cases and a new gene mutation]. / Osteopetrosis autosómica dominante: a propósito de 3 casos y una mutación.

Osteopetrosis (OP) is a congenital bone disease which is caused by a functional disorder in osteoclasts with inability for normal bone resorption, leading to increased bone mineral density and bone sclerosis. It can be classified into different groups according to their clinical and their genetic characteristics: autosomal recessive with several subtypes (OPTB) or autosomal dominant type 1 or 2 (OPTA1-2). There is a wide clinical variability of the disease, from asymptomatic to lethal in the first months of life, with variable expressivity in the family members. Diagnosis is mainly clinical with genetic confirmation of the OP, and treatment is symptomatic. Three cases of OP are presented, with the discovery of a new gene mutation in LRP5 which caused OPTA1 in one of them.

[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.