Growth hormone (GH)-secreting pituitary tumours represent the most genetically determined pituitary tumour type. This is true both for germline and somatic mutations. Germline mutations occur in several known genes (AIP, PRKAR1A, GPR101, GNAS, MEN1, CDKN1B, SDHx, MAX) as well as familial cases with currently unknown genes, while somatic mutations in GNAS are present in up to 40% of tumours. If the disease starts before the fusion of the epiphysis, then accelerated growth and increased final height, or gigantism, can develop, where a genetic background can be identified in half of the cases. Hereditary GH-secreting pituitary adenoma (PA) can manifest as isolated tumours, familial isolated pituitary adenoma (FIPA) including cases with AIP mutations or GPR101 duplications (X-linked acrogigantism, XLAG) or can be a part of systemic diseases like multiple endocrine neoplasia type 1 or type 4, McCune–Albright syndrome, Carney complex or phaeochromocytoma/paraganglioma-pituitary adenoma association. Family history and a search for associated syndromic manifestations can help to draw attention to genetic causes; many of these are now tested as part of gene panels. Identifying genetic mutations allows appropriate screening of associated comorbidities as well as finding affected family members before the clinical manifestation of the disease. This review focuses on germline and somatic mutations predisposing to acromegaly and gigantism.

Pituitary adenomas are rare in children and young people under the age of 19 (hereafter referred to as CYP) but they pose some different diagnostic and management challenges in this age group than in adults. These rare neoplasms can disrupt maturational, visual, intellectual and developmental processes and, in CYP, they tend to have more occult presentation, aggressive behaviour and are more likely to have a genetic basis than in adults. Through standardized AGREE II methodology, literature review and Delphi consensus, a multidisciplinary expert group developed 74 pragmatic management recommendations aimed at optimizing care for CYP in the first-ever comprehensive consensus guideline to cover the care of CYP with pituitary adenoma. Part 2 of this consensus guideline details 57 recommendations for paediatric patients with prolactinomas, Cushing disease, growth hormone excess causing gigantism and acromegaly, clinically non-functioning adenomas, and the rare TSHomas. Compared with adult patients with pituitary adenomas, we highlight that, in the CYP group, there is a greater proportion of functioning tumours, including macroprolactinomas, greater likelihood of underlying genetic disease, more corticotrophinomas in boys aged under 10 years than in girls and difficulty of peri-pubertal diagnosis of growth hormone excess. Collaboration with pituitary specialists caring for adult patients, as part of commissioned and centralized multidisciplinary teams, is key for optimizing management, transition and lifelong care and facilitates the collection of health-related quality of survival outcomes of novel medical, surgical and radiotherapeutic treatments, which are currently largely missing.

Tumours of the anterior part of the pituitary gland represent just 1% of all childhood (aged <15 years) intracranial neoplasms, yet they can confer high morbidity and little evidence and guidance is in place for their management. Between 2014 and 2022, a multidisciplinary expert group systematically developed the first comprehensive clinical practice consensus guideline for children and young people under the age 19 years (hereafter referred to as CYP) presenting with a suspected pituitary adenoma to inform specialist care and improve health outcomes. Through robust literature searches and a Delphi consensus exercise with an international Delphi consensus panel of experts, the available scientific evidence and expert opinions were consolidated into 74 recommendations. Part 1 of this consensus guideline includes 17 pragmatic management recommendations related to clinical care, neuroimaging, visual assessment, histopathology, genetics, pituitary surgery and radiotherapy. While in many aspects the care for CYP is similar to that of adults, key differences exist, particularly in aetiology and presentation. CYP with suspected pituitary adenomas require careful clinical examination, appropriate hormonal work-up, dedicated pituitary imaging and visual assessment. Consideration should be given to the potential for syndromic disease and genetic assessment. Multidisciplinary discussion at both the local and national levels can be key for management. Surgery should be performed in specialist centres. The collection of outcome data on novel modalities of medical treatment, surgical intervention and radiotherapy is essential for optimal future treatment.

DOI: 10.20452/pamw.16232, Published online: March 15, 2022, Authors: Anna Bogusławska, Aleksandra Gilis-Januszewska, Magdalena Godlewska, Andrzej Nowak, Jerzy Starzyk, Alicja Hubalewska-Dydejczyk

Familial Hyperinsulinemic Hypoglycemia (FHH) is a very rare disease with heterogeneous clinical manifestations. There are only a few reports of heterozygous activating mutations of glucokinase (GCK) attributable to FHH, with no reports describing effects in the course in pregnancy with affected mother/affected child. A large kindred with FHH and GCK:c.295T>C (p.Trp99Arg) pathogenic variant was identified in which four family members from three generations were affected. The clinical follow up in one clinical center lasted up to 30 years, with different times of diagnosis ranging from neonate period to adulthood. The severity of hypoglycemia was mild/severe and fasting was the trigger for hypoglycemia. Response to diazoxide varied from good, in the neonate, to moderate/poor, in childhood/adulthood; however, this was biased by poor compliance. Treatment with somatostatin analogues was discontinued due to side effects. Over time, patients developed clinical adaptation to very low glucose levels. During pregnancy, episodes of severe hypoglycemia in the first trimester were observed, which responded very well to steroids. The clinical course of the GCK:c.295T>C (p.Trp99Arg) mutation varied in the same family, with the development of clinical adaptation to very low glucose levels over time. Treatment with steroids might prevent hypoglycemia during pregnancy in an affected mother.

Multiple neuroendocrine neoplasia type 1 (MEN1) is a rare genetic disorder with an autosomal dominant inheritance, predisposing carriers to benign and malignant tumors. The phenotype of MEN1 syndrome varies between patients in terms of tumor localization, age of onset, and clinical aggressiveness, even between affected members within the same family. We describe a heterogenic phenotype of the MEN1 variant c.781C>T (LRG_509t1), which was previously reported only once in a family with isolated hyperparathyroidism. A heterozygous missense variant in exon 4 of the gene was identified in the sequence of the MEN1 gene, i.e., c.781C>T, leading to the amino acid change p.Leu261Phe in a three-generation family. In the screened family, 5/6 affected members had already developed hyperparathyroidism. In the index patient and two other family members, an aggressive course of pancreatic neuroendocrine tumor (insulinoma and non-functioning neuroendocrine tumors) with dissemination was diagnosed. In the index patient, late diagnosis and slow progression of the disseminated neuroendocrine tumor have been observed (24 years of follow-up). The very rare variant of MEN1, LRG_509t1 c.781C>T /p.Leu261Phe (LRG_509p1), diagnosed within a three-generation family has a heterogenic clinical presentation. Further follow-up of the family members should be carried out to confirm the spectrum and exact time of clinical presentation.