Pituitary neuroendocrine tumours (PitNETs) of the mammosomatotroph type are exceedingly rare in childhood, particularly in children under 10 years old. Existing high-quality, evidence-based data primarily derive from large adult cohorts, while paediatric evidence remains extremely limited. Case presentation A 7-year-old boy presented with headaches, transient amaurosis, and accelerated linear growth (+3.0 SDS), clinically consistent with pituitary gigantism. MRI revealed a 1.9 × 1.7 × 2.8 cm predominantly cystic sellar-suprasellar mass compressing the optic chiasm, radiologically indistinguishable from craniopharyngioma. Preoperative biochemistry showed GH > 40 ng/mL, IGF-1 = 479 ng/mL (reference range: 40-255 ng/mL), and PRL = 129 ng/mL (reference range: 2.1-17.7 ng/mL). Transcranial gross-total resection normalized GH (5.15 ng/mL), PRL (9.56 ng/mL), and IGF-1 (257 ng/mL) without adjuvant medical therapy. Histology confirmed a paediatric case of mammosomatotroph PitNETs. Targeted next-generation sequencing detected a pathogenic SMARCB1 deletion but no AIP, GNAS, or USP8 variants. The patient remains clinically and biochemically well 8 months postoperatively. This 7-year-old boy represents one of the youngest recorded cases of a mammosomatotroph pituitary neuroendocrine tumour. The atypical presentation, dominated by mass-effect symptoms and pituitary gigantism, highlights the necessity of early hormonal and genetic screening when evaluating complex paediatric sellar masses.

Pituitary gigantism is a rare condition associated with significant morbidity and early mortality if untreated. It should be considered as a differential diagnosis in tall patients with accelerated growth velocity. It is challenging to diagnose, as often the age of presentation overlaps with puberty, a time of natural increased growth velocity. This review aims to support general paediatricians in recognising and assessing these patients by summarising the aetiology, investigations, management and long-term outcomes of pituitary gigantism.

Somatotropinomas are extremely rare in children and frequently associated with genetic causes. Among pituitary gigantism, approximately 30 % are attributed to the aryl hydrocarbon receptor-interacting protein (AIP) gene mutations, whereas other genetic causes are less common. These mutations cause more aggressive tumors that are challenging to control with a single intervention and often exhibit resistance to somatostatin analogs (SSAs). Our aim is to present a pediatric patient with a somatotropinoma due to a novel AIP variant who responded positively to SSA therapy following a single surgical intervention. A 15-year and 8-month-old male patient presented with complaints of excessive height and enlargement of the hands and feet over the past 2 years. Laboratory investigations revealed a random growth hormone level of 50 μg/L (normal range [NR]: 0.077-10.8) and insulin-like growth factor-1(IGF-1) level of 1,107 ng/mL (age-adjusted NR: 224-978/>+2 standardised deviation scores). Magnetic resonance imaging demonstrated a pituitary macroadenoma extending into the suprasellar region. A craniotomy was performed, and the majority of the tumor was resected. Due to the presence of residual tumor, SSA therapy (octreotide-LAR) was initiated. After 1 year of follow-up, IGF-1 levels returned to the normal range, and tumor growth was controlled. Genetic analysis identified a heterozygous frameshift novel variant (c.25delC, p.(Arg9Glyfs*9)) in the AIP gene. Although AIP mutation-positive cases are typically resistant to SSAs, our patient carrying a novel AIP variant demonstrated a favorable response to SSA treatment.

X-linked acrogigantism (X-LAG; OMIM: 300942) is a rare X-linked dominant, fully penetrant form of infancy-onset pituitary gigantism caused by Xq26.3 tandem duplications involving the GPR101 gene. All previously reported X-LAG-associated duplications disrupt the integrity of the resident topologically associating domain (TAD). This creates a neo-TAD, permitting ectopic chromatin interactions between GPR101 and centromeric pituitary enhancers postulated to lie between RBMX and VGLL1, and culminating in pituitary GPR101 misexpression and growth hormone excess. Conversely, none of the few previously reported cases of Xq26.3 duplications in unaffected individuals include the tissue-invariant TAD border that shields GPR101 from its centromeric enhancers. Preservation of this boundary has thus been considered synonymous with non-penetrance of X-LAG. We examined a series of four family members from the same kindred with an incidentally detected GPR101-containing Xq26.3 duplication involving the invariant TAD border. Chromosome microarray demonstrated an interstitial chromosome Xq26.3 duplication: arr[GRCh37] Xq26.3(135,954,223 - 136,224,319)x2, including GPR101, the TAD invariant border and RBMX, but not VGLL1. None of the relatives with the Xq26.3 duplication exhibited evidence of growth hormone excess, making this the first unaffected family with a GPR101-containing Xq26.3 duplication involving the invariant TAD border. The predicted neo-TAD in this kindred excludes the VGLL1 region, which is present in all previously described X-LAG patients and absent in all previously described unaffected individuals with Xq26.3 duplications. Our clinical findings suggest that TAD border involvement is not sufficient for X-LAG to develop, and implicates the VGLL1 region as likely the sole pituitary enhancer responsible for GPR101 misexpression and the X-LAG phenotype. Pending corroborative studies, this new insight into X-LAG pathogenesis may guide interpretation of future Xq26.3 duplications and counselling of families in whom such duplications are found.

Multiple endocrine neoplasia type 5 (MEN5) is an emerging syndrome of endocrine and non-endocrine tumors caused by germline pathogenic variants or genomic rearrangements of the MAX gene. Although MAX variants are predominantly associated with pheochromocytoma-paraganglioma (PPGL) risk, there are a growing number of associated tumors in other organs, including pituitary adenomas. We characterized the clinical presentation of various tumors in an extensive new kindred with a novel germline pathogenic variant of MAX. Clinical, genetic, pathological, radiological and hormonal investigations to identify and characterize disease status related to germline MAX gene sequence status. We identified a novel germline pathological variant in exon 4 of the MAX gene, c.228delG, which was predicted to lead to a truncated protein (p.Asn78Thrfs*92). The propositus had developed pituitary gigantism due to a mixed growth hormone-prolactin secreting pituitary macroadenoma, which was controlled after two surgeries, medical therapy and radiotherapy. He subsequently developed bilateral and recurrent pheochromocytomas and following his death, an extra-adrenal myelolipoma was identified that was negative on MAX immunohistochemistry. An extensive history of pheochromocytomas or uncontrolled hypertension was present in the kindred and multiple affected and unaffected carriers of the c.228delG MAX pathogenic variant were characterized. We report the first case of pituitary gigantism in association with a pathogenic variant in the MAX gene, and characterize myeloplipoma as a new disease-association in MEN5. Increased awareness of MEN5 as a clinical entity and comprehensive screening of MAX pathogenic variant carriers can help to identify rare disease associations beyond PPGL.