Two novel heterozygous missense variations within the GLI2 gene in two unrelated argentine patients / Two novel heterozygous missense variations within the GLI2 gene in two unrelated Argentine patients

Several heterozygous GLI2 gene mutations have been reported in patients with isolated GH deficiency (IGHD) or multiple pituitary hormone deficiency (MPHD) with or without other malformations. The primary aim of this study was to analyze the presence of GLI2 gene alterations in a cohort of patients with IGHD or MPHD and ectopic/absent posterior pituitary. The coding sequence and flanking intronic regions of GLI2 gene were amplified and directly sequenced from gDNA of 18 affected subjects and relatives. In silico tools were applied to identify the functional impact of newly found variants (Polyphen2, SIFT, Mutation Taster). We identified two novel heterozygous missense variations in two unrelated patients, p.Arg231Gln and p.Arg226Leu, located in the repressor domain of the protein. Both variations affect highly conserved amino acids of the Gli2 protein and were not found in the available databases. In silico tools suggest that these variations might be disease causing. Our study suggests that the GLI2 gene may be one of the candidate genes to analyze when an association of pituitary hormone deficiency and developmental defects in posterior pituitary gland. The highly variable phenotype found suggests the presence of additional unknown factors that could contribute to the phenotype observed in these patients.

Mutaciones heterocigotas en el gen GLI2 fueron previamente comunicadas como causa de déficit aislado de hormona de crecimiento (IGHD) o déficit múltiple de hormonas hipofisarias (MPHD), con o sin otras malformaciones. El objetivo del estudio fue analizar la presencia de alteraciones en el gen GLI2 en un grupo de pacientes con IGHD o MPHD acompañado de neurohipófisis ectópica o ausente. La secuencia codificante y las regiones intrónicas flanqueantes del gen GLI2 fueron amplificadas y secuenciadas de manera directa a partir de ADN genómico extraído de sangre periférica proveniente de 18 sujetos afectados y sus familiares. Se utilizaron herramientas informáticas para predecir el impacto funcional de las nuevas variantes encontradas (Polyphen2, SIFT, Mutation Taster). Identificamos dos nuevas variantes heterocigotas con pérdida de sentido en dos pacientes no relacionados, p.Arg231Gln y p.Arg226Leu, localizadas en el dominio represor de la proteína. Estas variantes afectan aminoácidos altamente conservados en la secuencia proteica de GLI2 y no se encuentran informadas en las bases de datos disponibles. Las herramientas informáticas utilizadas sugieren que estas variantes pueden ser la causa del desarrollo de la enfermedad. Nuestro resultados indican que el gen GLI2 es uno de los genes candidatos a estudiar cuando existe una asociación entre déficit de hormonas hipofisarias y alteraciones en el desarrollo de la neurohipófisis. Se sugiere la existencia de otros factores adicionales que podrían contribuir a la variabilidad del fenotipo observado.

A Case of Congenital Hypopituitarism with Anterior Pituitary Aplasia and Ectopic Posterior Pituitary Gland / 대한소아내분비학회지

Congenital hypopituitarism is a rare disorder with absence or reduction of hormones produced by the pituitary gland. The clinical manifestations are hypoglycemia, prolonged jaundice, hyponatremia, micropenis, underdeveloped clitoris, lethargy, convulsion, pallor, cyanosis, apnea, hypotension, temperature instability etc. in neonates and growth failure, delayed or absent puberty in older infants and children. We experienced a case of congenital hypopituitarism who was a 20-year-old male patient with short stature and delayed puberty. Combined pituitary function test revealed panhypopituitarism and magnetic resonance imaging of brain showed anterior pituitary aplasia and ectopic posterior pituitary gland.

A Case of Congenital Hypopituitarism with Anterior Pituitary Aplasia and Ectopic Posterior Pituitary Gland / 대한소아내분비학회지

Congenital hypopituitarism is a rare disorder with absence or reduction of hormones produced by the pituitary gland. The clinical manifestations are hypoglycemia, prolonged jaundice, hyponatremia, micropenis, underdeveloped clitoris, lethargy, convulsion, pallor, cyanosis, apnea, hypotension, temperature instability etc. in neonates and growth failure, delayed or absent puberty in older infants and children. We experienced a case of congenital hypopituitarism who was a 20-year-old male patient with short stature and delayed puberty. Combined pituitary function test revealed panhypopituitarism and magnetic resonance imaging of brain showed anterior pituitary aplasia and ectopic posterior pituitary gland.

A Case of Congenital Hypopituitarism with Anterior Pituitary Hypoplasia and Ectopic Posterior Pituitary Gland

The pituitary gland develops from two different parts of the brain. The anterior pituitary gland originates from the Rathke pouch and the posterior one from the infundibulum. Therefore, the pathologic findings of congenital hypopituitarism can be different in each case. Congenital hypopituitarism is a rare disorder. The characteristic clinical features of the affected newborns are prolonged jaundice, persistent or recurrent hypoglycemia without hyperinsulinism and microphallus. Their genitalia are usually underdeveloped and sexual maturation may be delayed or absent. In adulthood, patients retain childish feature, short stature with normal body proportion. We experienced a case of congenital hypopituitarism in a 12-year-old female patient with short stature and delayed sexual maturation(Tanner stageI). The endocrinological studies revealed growth hormone, FSH, LH and TSH deficiencies. Magnetic resonance imaging indicated a hypoplastic anterior pituitary and an ectopic posterior pituitary gland located within the tuber cinereum of the hypothalamus.

A Case of Congenital Hypopituitarism with Anterior Pituitary Hypoplasia and Ectopic Posterior Pituitary Gland

The pituitary gland develops from two different parts of the brain. The anterior pituitary gland originates from the Rathke pouch and the posterior one from the infundibulum. Therefore, the pathologic findings of congenital hypopituitarism can be different in each case. Congenital hypopituitarism is a rare disorder. The characteristic clinical features of the affected newborns are prolonged jaundice, persistent or recurrent hypoglycemia without hyperinsulinism and microphallus. Their genitalia are usually underdeveloped and sexual maturation may be delayed or absent. In adulthood, patients retain childish feature, short stature with normal body proportion. We experienced a case of congenital hypopituitarism in a 12-year-old female patient with short stature and delayed sexual maturation(Tanner stageI). The endocrinological studies revealed growth hormone, FSH, LH and TSH deficiencies. Magnetic resonance imaging indicated a hypoplastic anterior pituitary and an ectopic posterior pituitary gland located within the tuber cinereum of the hypothalamus.

A case of congenital hypopituitarism presenting ectopic pituitary gland and pituitary stalk transection identified by magnetic resinance imaging

No abstract available.