Sarah J Larkin, Francesco Ferraù, Niki Karavitaki, Laura C Hernández-Ramírez, Olaf Ansorge, Ashley B Grossman and Márta Korbonits
The pathogenetic mechanisms of sporadic somatotroph adenomas are not well understood, but derangements of the cAMP pathway have been implicated. Recent studies have identified L206R mutations in the alpha catalytic subunit of protein kinase A (PRKACA) in cortisol-producing adrenocortical adenomas and amplification of the beta catalytic subunit of protein kinase A PRKACB in acromegaly associated with Carney complex. Given that both adrenocortical adenomas and somatotroph adenomas are known to be reliant on the cAMP signalling pathway, we sought to determine the relevance of the L206R mutation in both PRKACA and PRKACB for the pathogenesis of sporadic somatotroph adenomas.
Somatotroph adenoma specimens, both frozen and formalin-fixed, from patients who underwent surgery for their acromegaly between 1995 and 2012, were used in the study.
The DNA sequence at codon 206 of PRKACA and PRKACB was determined by PCR amplification and sequencing. The results were compared with patient characteristics, the mutational status of the GNAS complex locus and the tumour granulation pattern.
No mutations at codon 206 of PRKACA or PRKACB were found in a total of 92 specimens, comprising both WT and mutant GNAS cases, and densely, sparsely and mixed granulation patterns.
It is unlikely that mutation at this locus is involved in the pathogenesis of sporadic somatotroph adenoma; however, gene amplification or mutations at other loci or in other components of the cAMP signalling pathway, while unlikely, cannot be ruled out.
Claudia Ramírez, Guadalupe Vargas, Baldomero González, Ashley Grossman, Julia Rábago, Ernesto Sosa, Ana Laura Espinosa-de-Los-Monteros and Moisés Mercado
Somatostatin analogs (SA) have been used for over 25 years in the treatment of acromegaly. A major disadvantage is the need to continue therapy indefinitely.
To evaluate the feasibility of discontinuing therapy in well-controlled patients with acromegaly treated chronically with SA.
Design and methods
Of the 205 subjects on octreotide LAR, we selected those who met the following criteria: two or more years of treatment, a stable dose and injection interval of 20 mg every 8 weeks or longer for the previous year, no history of radiation, no cabergoline for the previous 6 months, a GH <1.5 ng/ml, and an IGF1 <1.2×upper limit of normal (ULN). Octreotide LAR was stopped and both GH and IGF1 were measured monthly for 4 months; a glucose-suppressed GH value and magnetic resonance imaging were obtained at the 4th month, thereafter, basal GH and IGF1 were measured q. 3 months, for 12–18 months. Patients were removed from the study if GH or IGF1 rose to 1.5 ng/ml or 1.2×ULN respectively.
Twelve patients (ten women, mean age 48±13 years) were studied. Seven patients (58.3%) relapsed biochemically within 1 year of having stopped the SA; two patients relapsed by GH and IGF1 criteria, the remaining five patients kept GH levels within target. Five patients (41.7%) remain in remission after 12 months of follow-up. Non-recurring patients were on longer injection intervals but no other characteristic was associated with a successful withdrawal.
Withdrawal of SA is possible in a small but distinct subset of patients, particularly in those who are very well controlled on relatively low doses administered at long intervals.
Ana Claudia Keselman, Ayelen Martin, Paula Alejandra Scaglia, Nora María Sanguineti, Romina Armando, Mariana Gutiérrez, Débora Braslavsky, María Gabriela Ballerini, María Gabriela Ropelato, Laura Ramirez, Estefanía Landi, Sabina Domené, Julia F Castro, Hamilton Cassinelli, Bárbara Casali, Graciela del Rey, Ángel Campos Barros, Julián Nevado Blanco, Horacio Domené, Héctor Jasper, Claudia Arberas, Rodolfo A Rey, Pablo Lapunzina-Badía, Ignacio Bergadá and Patricia A Pennisi
IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation.
We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from −1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth.
The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.