Day Three: Gigantism: The importance of FIPA, AIP mutations and X-LAG

2019-09-23T11:18:25+00:00September 21st, 2019|Growth disorders, News report, Paediatric endocrinology, Uncategorized|

medwireNews: Recent developments in the field of pituitary gigantism, including the discovery of a new syndrome and genes related to this syndrome, were presented in a plenary session at the 58th Annual ESPE Meeting in Vienna, Austria.

The engaging talk by Albert Beckers, from the University of Liege in Belgium, began with him reviewing the inherited causes of inherited pituitary adenomas of which he said familial isolated pituitary adenoma (FIPA) is the most important for gigantism.

He continued by discussing the role of AIP gene mutations in FIPA, presenting data from a study among 73 FIPA families, published in 2007, which showed that 15% of these families carried AIP mutations. The mutation carriers had a significantly greater tumour diameter than noncarriers and were significantly younger at diagnosis.

A subsequent study of AIP mutations in 307 patients with pituitary adenomas found that mutation carriers were diagnosed with acromegaly at an earlier age than noncarriers and had higher growth hormone (GH) levels.

Furthermore, there were nearly five times as many cases of gigantism reported in the group with versus without AIP mutations. This led Beckers to consider whether AIP is a major cause of gigantism.

And after presenting further data in support of this theory, he showed that AIP mutations are indeed the most frequent known cause of pituitary gigantism, being responsible for 29% of cases in an international study published in 2015, compared with 5% of cases due to McCune-Albright Syndrome and 1% each due to Carney Complex and MEN1.

This study also showed that 10% of gigantism cases were due to X-linked acro-gigantism (X-LAG), a novel syndrome of paediatric onset that Beckers and team discovered following a discussion about two patients with gigantism who had duplication of 11 genes on chromosome X.

Further testing of these two patients and others with FIPA and AIP mutations confirmed microduplication of Xq26.3 in four genes.

The clinical characteristics of X-LAG include female sex, early rapid growth, early diagnosis, high insulin-like growth factor-1 levels and high prolactin co-secretion.

Investigation of the four candidate genes revealed substantial overexpression of GPR101 in pituitary tissue from X-LAG children with Xq26.3 microduplications, leading Beckers and co-researchers to conclude that GPR101 “was the culprit for the explanation of X-LAG.”

Beckers explained that GPR101 is an orphan receptor that is highly expressed in the foetal anterior pituitary and in the human and mouse hypothalamus. He added that duplication of GPR101 causes pituitary adenomas and gigantism in X-LAG.

Beckers then suggested that many famous historical cases of gigantism could be due to X-LAG. In pursuit of this hypothesis, he tested samples from the skeleton of Julius Koch, the 4th tallest person in history at 2.59 m, and found that there was duplication of GPR101.

Finally, Beckers showed results from a study that has been submitted for publication, which uses an in vivo model to study the mechanisms involved in the impact of GPR101 on GH secretion and pituitary tumours. This study showed that GPR101 “increases the basal tonus of the signalling pathway”, which drives GH-releasing hormone-mediated GH hypersecretion in vivo, he explained.

By Laura Cowen

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