Table 1.
Hereditary Hyperparathyroidism.
| Disorder | Gene | Gene location | Mechanism | Clinical Features |
|---|---|---|---|---|
| Syndromic HPT | ||||
| Multiple Endocrine Neoplasia (MEN) | ||||
| MEN Type 1 | MEN1 | 11q13 | TS; LoF | Multigland hyperparathyroidism, functional and/or non-functional pancreatic NET and anterior pituitary adenomas. Associated features include foregut NET, cutaneous lipomas, collagenomas, facial angiofibromas; esophageal, uterine leiomyoma |
| MEN Type 2A | RET | 10q11.21 | PO; GoF | Medullary thyroid carcinoma, bilateral pheochromocytoma; hyperparathyroidism due to parathyroid adenoma |
| MEN Type 4 | CDKN1B | 12p13.1 | TS; LoF | Multigland hyperparathyroidism; pituitary adenoma; reproductive organ tumors (e.g., testicular cancer, neuroendocrine cervical carcinoma); adrenal & renal tumors |
| Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT) | CDC73 (formerly HRPT2) | 1q31.2 | TS; LoF | Single- or multigland hyperparathyroidism with an increased predisposition to parathyroid carcinoma; cemento-ossifying fibromas of the maxilla or mandible (“jaw tumors”); Wilms tumor, renal MEST; uterine pathology including adenomyosis and leiomyoma |
| Isolated HPT | ||||
| Familial Hypocalciuric hypercalcemia (FHH) | ||||
| FHH type 1 | CASR | 3q13.3 - q21.1 | ICSST; LoF | Lifelong elevation of serum calcium with inappropriately low urinary calcium excretion (FeCa < 1%) and normal or mildly elevated PTH |
| FHH type 2 | GNA11 | 19p13.3 | ICSST; LoF | |
| FHH type 3 | AP2S1 | 19q13.32 | ICSST; LoF | |
| Neonatal Severe Primary Hyperparathyroidism (NSHPT) | CASR | 3q13.3-q21.1 | ICSST; LoF | Severe hypercalcemia at birth with associated bone demineralization and failure to thrive (associated with bi-allelic LoF of CASR) |
| Familial isolated hyperparathyroidism (FIHP) | Multigland hyperparathyroidism | |||
| GCM2 | GCM2 | 6p24.2 | PO; GoF | Multigland hyperparathyroidism (enriched in Ashkanazi Jewish populations) |
HPT, primary hyperparathyroidism; TS, tumor supressor gene, LoF, loss of function; NET, neuroendocrine tumor; PO, proto-oncogene; GoF, gain of function; MEST, mixed epithelial and stromal tumor [of the kidney]; ICSST, impaired calcium sensing or signal transduction.