Endocrinology

Genetic testing is clinically relevant for the following indications, including but not limited to:

• Neonates and infants with hypercalcaemia and an inappropriately high parathyroid hormone concentration
• Children with parathyroid hormone resistance, hypocalcaemia or features of Albright hereditary osteodystrophy
• Children with short stature and facial dysmorphism or skeletal abnormality
• Children with short stature and mesomelic limb shortening suggesting SHOX deficiency
• Newborns and children with suspected congenital adrenal hyperplasia, most often 21-hydroxylase deficiency
• Children with obesity of early onset, arising in the first years of life
• Patients with phaeochromocytoma or paraganglioma, given the hereditary nature of these tumours
• Patients with medullary thyroid cancer, phaeochromocytoma or primary hyperparathyroidism suggesting multiple endocrine neoplasia type 2
• Patients with acromegaly or gigantism of young onset, or a family history of pituitary adenoma

Testing is most informative when the endocrine phenotype indicates an inherited cause that biochemistry alone cannot assign. In children with short stature it improves the diagnostic process in both isolated and syndromic presentations, and the yield is higher where dysmorphic or skeletal features are present. In parathyroid hormone resistance, molecular analysis is highly specific, and combining it with clinical evaluation gives the fuller picture of the GNAS inactivation disorders.

• A pathogenic or likely pathogenic variant confirms the molecular diagnosis.
• A variant of uncertain significance (VUS) is an unclear finding: current evidence is insufficient to classify it as likely benign or likely pathogenic, and reanalysis can be offered after a few years as evidence accumulates.
• In other cases, no pathogenic variant is detected in the analysed genes. The presence of a pathogenic variant cannot, however, be entirely excluded: the causative change may lie in a gene not yet linked to the condition, or in a regulatory region that current methods cannot reliably capture.
• Each variant is classified according to criteria, and the report states the variant, its classification, and its clinical relevance for the referring clinician.

• Gorvin CM. Genetic causes of neonatal and infantile hypercalcaemia. Pediatric nephrology (Berlin, Germany). 2022;37(2):289-301. doi: 10.1007/s00467-021-05082-z. PMID: . PMCID: PMC8816529.
• Tőke J, Czirják G, Enyedi P, Tóth M. Rare diseases caused by abnormal calcium sensing and signalling. Endocrine. 2021;71(3):611-617. doi: 10.1007/s12020-021-02620-5. PMID: . PMCID: PMC8016752.
• Xu X, Shen Y, Yang W, Wei H, Chen T, Chen L, et al. Clinical evaluation and molecular analysis of genetic and epigenetic inactivation defects in GNAS in children: A multicenter experience in China. European journal of endocrinology. 2025;192(6):776-786. doi: 10.1093/ejendo/lvaf120. PMID: .
• Scalco RC, Schoones JW, Galetaki D, Santillan-Vasconez AM, Kim GJ, Cellin LP, et al. Diagnostic yield of genetic testing in children with short stature: a systematic review. European journal of endocrinology. 2026;194(2):S15-S24. doi: 10.1093/ejendo/lvag011. PMID: .
• Doğan Arı AB, Arı H, Çakar EŞ, Solmaz TM, Taşdelen E, Büyükyılmaz G, et al. Clinical and genetic spectrum of SHOX deficiency: phenotypic heterogeneity and the “Jumping SHOX” phenomenon. European journal of pediatrics. 2026;185(6). doi: 10.1007/s00431-026-07128-6. PMID: .
• Ishii T, Kashimada K, Amano N, Takasawa K, Nakamura-Utsunomiya A, Yatsuga S, et al. Clinical guidelines for the diagnosis and treatment of 21-hydroxylase deficiency (2021 revision). Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology. 2022;31(3):116-143. doi: 10.1297/cpe.2022-0009. PMID: . PMCID: PMC9297175.
• Harvengt J, Hannon M, Palmeira L, Lebrethon MC, Dideberg V, Bours V. Monogenic etiologies in a cohort of early onset obesity: a real-world experience from Belgium. Frontiers in endocrinology. 2025;16:1608398. doi: 10.3389/fendo.2025.1608398. PMID: . PMCID: PMC12353736.
• Tanabe A, Katabami T, Hashimoto S, Izawa S, Ichijo T, Otsuki M, et al. Japan Endocrine Society Clinical Practice Guideline for the Diagnosis and Management of Pheochromocytoma and Paraganglioma 2025. Endocrine journal. 2026;73(1):115-157. doi: 10.1507/endocrj.EJ25-0165. PMID: . PMCID: PMC12819074.
• Kurzawinski TR, Butler CR, Aziz TA. MEN2: surgical precision in the era of precision medicine. Endocrine-related cancer. 2025;32(6). doi: 10.1530/ERC-24-0251. PMID: . PMCID: PMC12147403.
• Bogusławska A, Korbonits M. Genetics of Acromegaly and Gigantism. Journal of clinical medicine. 2021;10(7). doi: 10.3390/jcm10071377. PMID: . PMCID: PMC8036715.