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  • Author: Ana-Claudia Latronico x
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Applying precision medicine to the diagnosis and management of endocrine disorders

Martin Bidlingmaier, Helena Gleeson, Ana-Claudia Latronico, and Martin O Savage

Precision medicine employs digital tools and knowledge of a patient’s genetic makeup, environment and lifestyle to improve diagnostic accuracy and to develop individualised treatment and prevention strategies. Precision medicine has improved management in a number of disease areas, most notably in oncology, and it has the potential to positively impact others, including endocrine disorders. The accuracy of diagnosis in young patients with growth disorders can be improved by using biomarkers. Insulin-like growth factor I (IGF-I) is the most widely accepted biomarker of growth hormone secretion, but its predictive value for recombinant human growth hormone treatment response is modest and various factors can affect the accuracy of IGF-I measurements. These factors need to be taken into account when considering IGF-I as a component of precision medicine in the management of growth hormone deficiency. The use of genetic analyses can assist with diagnosis by confirming the aetiology, facilitate treatment decisions, guide counselling and allow prompt intervention in children with pubertal disorders, such as central precocious puberty and testotoxicosis. Precision medicine has also proven useful during the transition of young people with endocrine disorders from paediatric to adult services when patients are at heightened risk of dropping out from medical care. An understanding of the likelihood of ongoing GH deficiency, using tools such as MRI, detailed patient history and IGF-I levels, can assist in determining the need for continued recombinant human growth hormone treatment during the process of transitional care.

Open access

FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies

Fernanda A Correa, Ericka B Trarbach, Cintia Tusset, Ana Claudia Latronico, Luciana R Montenegro, Luciani R Carvalho, Marcela M Franca, Aline P Otto, Everlayny F Costalonga, Vinicius N Brito, Ana Paula Abreu, Mirian Y Nishi, Alexander A L Jorge, Ivo J P Arnhold, Yisrael Sidis, Nelly Pitteloud, and Berenice B Mendonca

The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca2 + pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.