In the case of a positive family history, the most common diseases are related to AIP or MEN1 mutations.
A positive family history is very suggestive of a genetic disease, but we should be aware of phenocopies-the same phenotype by chance and not due to common genetic background this has been described in several AIP- and succinate dehydrogenase ( SDHx)-positive families already. 1).Īpart from age of onset, the other major significant feature for GH excess patients is the family history. In NF1, approximately 10% of cases with optic glioma have GH excess often manifesting in childhood and causing accelerated growth the exact mechanism of the GH excess is unknown (Fig. In case of very early onset, XLAG (3 years of age but still in childhood, AIP, MEN1 and 4, CNC, MAS, 3Pa and a non-pituitary condition neurofibromatosis type 1 (NF1), should be considered. įor true acromegalic gigantism we need to consider the age of onset of rapid growth. While the usual cause of acromegalic gigantism is a GH-secreting pituitary adenoma, resulting in elevated GH- and insulin-like growth factor 1 (IGF-1) levels, we should remember other conditions with tall stature, either as a normal variant or part of a syndrome with no abnormalities in the GH axis. The most common cause of a germline genetic abnormality in a patient with a pituitary adenoma is growth hormone (GH) excess, especially childhood-onset GH excess leading to gigantism. Here we approach this issue from the practical point of view, centring the discussion on the presentation of the patient. Genetic testing might lead to the recognition of a syndromic disease and therefore beneficial effects of timely identification of other aspects of the disease, or it can diagnose disease in family members at an early stage leading to earlier diagnosis and treatment, and ultimately to better outcomes. Pituitary tumours can occur in a familial setting, either isolated, or as part of a syndromic condition, such as MEN1 or MEN4, Carney complex (CNC), McCune–Albright syndrome (MAS), phaeochromocytoma/paraganglioma with pituitary adenoma ( 3P associations, 3Pa), DICER1 syndrome and a USP8-related syndrome and some other rare conditions where the nature of association with pituitary adenomas needs further studies (Table 1). Indeed, most pituitary tumours are sporadic, but approximately 5% can be due to a hereditary disease. While in families with multiple endocrine neoplasia type 1 (MEN1) syndrome it was long recognised that members can develop pituitary adenomas with incomplete penetrance, the flurry of conditions we can now list with a genetic cause of pituitary adenoma would have been well beyond imagination 20 years ago. The identification of the causative mutation allows genetic and clinical screening of relatives at risk, resulting in earlier diagnosis, a better therapeutic response and ultimately to better long-term outcomes.Ĭonsideration of genetic abnormalities in a patient with a pituitary tumour has only recently entered the clinical thinking of the practising endocrinologist. In this practical summary, we take a practical approach: which genetic syndromes should be considered in case of different presentation, such as tumour type, family history, age of onset and additional clinical features of the patient. Genetically determined pituitary tumours usually present at younger age and show aggressive behaviour, and are often resistant to different treatment modalities.
While most pituitary tumours are sporadic, around 5% of the cases arise in a familial setting, either isolated, or in a syndromic disorder, such as multiple endocrine neoplasia type 1 or 4, Carney complex, McCune–Albright syndrome, phaeochromocytoma/paraganglioma with pituitary adenoma, DICER1 syndrome, Lynch syndrome, and USP8-related syndrome. Pituitary tumours are usually benign and relatively common intracranial tumours, with under- and overexpression of pituitary hormones and local mass effects causing considerable morbidity and increased mortality.