Table 2. [Genes of Interest in the...]. - GeneReviews®

Gene	Disorder	MOI	Clinical Characteristics
AP2S1 CASR GNA11	Familial hypocalciuric hypercalcemia (FHH) (OMIM PS145980)	AD	CASR-related FHH is a benign condition characterized by hypercalcemia, low urinary calcium excretion (assessed via a calcium-to-creatinine clearance ratio), normal to minimally ↑ PTH, & frequent hypermagnesemia. Biochemical findings in FHH can overlap w/those of primary hyperparathyroidism. However, FHH is not a pathologic process & represents a higher, yet normal, baseline serum calcium concentration. In a small proportion of persons w/FHH, germline pathogenic variants in GNA11 or AP2S1 have been identified. It is not known whether pathogenic variants in these genes account for any proportion of FIHP.
CASR	Familial isolated hyperparathyroidism (FIHP) ¹	AD	Heterozygous CASR pathogenic variants have been reported in 14%-18% of persons w/FIHP. ¹
Neonatal severe primary hyperparathyroidism (OMIM 239200)	AR (AD)	Rare condition assoc w/severe neonatal or infantile hypercalcemia & hyperparathyroidism that may lead to death if untreated. Diagnosis is typically w/in 1st mo of life but may range from birth to ~3 mos. ²
CDKN1B	Multiple endocrine neoplasia type 4 (MEN4)	AD	Phenotype overlaps w/MEN1; however, less is known about penetrance of MEN4 & assoc lifetime risk for endocrine tumors. Primary hyperparathyroidism tends to occur at a later age in MEN4 than in MEN1. The proportion of simplex or familial primary hyperparathyroidism explained by MEN4 remains unknown. Additional endocrine tumors seen in persons w/MEN4 incl pituitary adenomas & foregut neuroendocrine tumors, which also appear to exhibit a less aggressive course than those seen in MEN1.
GCM2	FIHP type 4 (OMIM 617343)	AD	Early data suggest that persons w/GCM2-related primary hyperparathyroidism are more likely to have aggressive disease, incl lower rate of biochemical cure & ↑ incidence of parathyroid carcinoma. Persons in these kindreds do not appear to be at ↑ risk for other endocrine tumors.
MAX	Multiple endocrine neoplasia type 5 (MEN5) ³	AD	Primarily hereditary pheochromocytoma & paraganglioma syndrome that may be assoc w/other endocrine neoplasms incl primary hyperparathyroidism & pituitary adenomas ³
MEN1	FIHP ⁴	AD	MEN1 germline pathogenic variants have been reported in ~20% of persons w/FIHP.
Multiple endocrine neoplasia type 1 (MEN1)	AD	Most common hereditary cause of primary hyperparathyroidism, accounting for 2%-4% of primary hyperparathyroidism MEN1-related primary hyperparathyroidism is characterized by onset in late adolescence to early adulthood (w/nearly all persons affected by age 50 yrs), multiglandular disease, & histology usually demonstrating parathyroid hyperplasia. MEN1 is also assoc w/pituitary adenomas & foregut neuroendocrine tumors, primarily gastrinomas & insulinomas.
RET	Multiple endocrine neoplasia type 2A (MEN2A)	AD	Primary hyperparathyroidism occurs in up to 20%-30% of persons w/MEN2A but is rarely the presenting feature. Additional manifestations of MEN2A incl medullary thyroid carcinoma & pheochromocytoma.

Gene

Disorder

MOI

Clinical Characteristics

AP2S1
CASR
GNA11

Familial hypocalciuric hypercalcemia (FHH) (OMIM PS145980)

CASR-related FHH is a benign condition characterized by hypercalcemia, low urinary calcium excretion (assessed via a calcium-to-creatinine clearance ratio), normal to minimally ↑ PTH, & frequent hypermagnesemia. Biochemical findings in FHH can overlap w/those of primary hyperparathyroidism. However, FHH is not a pathologic process & represents a higher, yet normal, baseline serum calcium concentration.
In a small proportion of persons w/FHH, germline pathogenic variants in GNA11 or AP2S1 have been identified. It is not known whether pathogenic variants in these genes account for any proportion of FIHP.

CASR

Familial isolated hyperparathyroidism (FIHP) ¹

Heterozygous CASR pathogenic variants have been reported in 14%-18% of persons w/FIHP. ¹

Neonatal severe primary hyperparathyroidism (OMIM 239200)

AR
(AD)

Rare condition assoc w/severe neonatal or infantile hypercalcemia & hyperparathyroidism that may lead to death if untreated. Diagnosis is typically w/in 1st mo of life but may range from birth to ~3 mos. ²

CDKN1B

Multiple endocrine neoplasia type 4 (MEN4)

Phenotype overlaps w/MEN1; however, less is known about penetrance of MEN4 & assoc lifetime risk for endocrine tumors.
Primary hyperparathyroidism tends to occur at a later age in MEN4 than in MEN1.
The proportion of simplex or familial primary hyperparathyroidism explained by MEN4 remains unknown.
Additional endocrine tumors seen in persons w/MEN4 incl pituitary adenomas & foregut neuroendocrine tumors, which also appear to exhibit a less aggressive course than those seen in MEN1.

GCM2

FIHP type 4 (OMIM 617343)

Early data suggest that persons w/GCM2-related primary hyperparathyroidism are more likely to have aggressive disease, incl lower rate of biochemical cure & ↑ incidence of parathyroid carcinoma.
Persons in these kindreds do not appear to be at ↑ risk for other endocrine tumors.

MAX

Multiple endocrine neoplasia type 5 (MEN5) ³

Primarily hereditary pheochromocytoma & paraganglioma syndrome that may be assoc w/other endocrine neoplasms incl primary hyperparathyroidism & pituitary adenomas ³

MEN1

FIHP ⁴

MEN1 germline pathogenic variants have been reported in ~20% of persons w/FIHP.

Multiple endocrine neoplasia type 1 (MEN1)

Most common hereditary cause of primary hyperparathyroidism, accounting for 2%-4% of primary hyperparathyroidism
MEN1-related primary hyperparathyroidism is characterized by onset in late adolescence to early adulthood (w/nearly all persons affected by age 50 yrs), multiglandular disease, & histology usually demonstrating parathyroid hyperplasia.
MEN1 is also assoc w/pituitary adenomas & foregut neuroendocrine tumors, primarily gastrinomas & insulinomas.

RET

Multiple endocrine neoplasia type 2A (MEN2A)

Primary hyperparathyroidism occurs in up to 20%-30% of persons w/MEN2A but is rarely the presenting feature.
Additional manifestations of MEN2A incl medullary thyroid carcinoma & pheochromocytoma.

From: CDC73-Related Disorders

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Adam MP, Feldman J, Mirzaa GM, et al., editors.

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