Abstract
Context
Familial isolated hyperparathyroidism (FIHP) is defined as familial primary hyperparathyroidism (FH) without a characteristic extraparathyroidal feature of a more complex hyperparathyroid syndrome. New concepts of FIHP have been developed within this definition. FIHP has been difficult to study due to small kindreds and mildly symptomatic cases.
Evidence Acquisition
Searches were through PubMed for FIHP, other FH syndromes, and the gene(s) mutated in each.
Evidence Synthesis
Within its definition, the current concept of FIHP has clinical and mutational components that can include incomplete expressions of multiple endocrine neoplasia type 1 (MEN1) familial hypocalciuric hypercalcemia, hyperparathyroidism-jaw tumor syndromes, or their mutations. Newest concepts of FIHP focus on kindreds without mutation of the MEN1, CASR, or CDC73 genes; 17% have germline activating mutation of the gene for the GCM2 transcription factor. The FIHP kindreds with or without GCM2 mutation contain a median of only two cases of primary hyperparathyroidism. The small kindred size in both subgroups of FIHP is probably caused by a low rate of screening among relatives. Persons with FIHP and GCM2 mutation present as adults with mild hypercalcemia and multiple parathyroid tumors.
Conclusion
The current concept of FIHP led to a focus on small kindreds without mutation of MEN1, CASR, or CDC73. These assisted in identifying germline activating GCM2 mutations in 17% of kindreds. Clinical and mutational characterization in more cases is needed to determine if there are any unique clinical features of FIHP, with or without mutation of GCM2.
The current concept of FIHP led to a focus on small kindreds without mutation of MEN1, CASR, or CDC73. These helped identify and characterize activating GCM2 mutations in 17% of the kindreds.
There are six syndromes of familial hyperparathyroidism (FH): multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A (MEN2A), familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism, hyperparathyroidism-jaw tumor (HPT-JT), and familial isolated hyperparathyroidism (FIHP) (Table 1) (1, 2). FIHP is defined as FH without a characteristic extraparathyroidal feature of a more complex hyperparathyroid syndrome.
Table 1.
Overview of Typical Clinical and Genetic Features in Six Syndromes of FH
| Syndrome | Genes Mutateda | Inheritance | Parathyroid Expression | Extraparathyroid Expression | Comment |
|---|---|---|---|---|---|
| MEN1 or MEN4 | MEN1 b , CDKN1B b | AD | Multiple adenomas | Gut neuroendocrinec; anterior pituitary, thoracic neuroendocrine mesenchymed | Increase of breast cancer |
| MEN2A | RET e | AD | Asymmetric adenomas | Thyroid C-cell adrenal chromaffin | Prophylactic ThyrX |
| FHH1 | CASR b | AD | High set point to inhibit PTH secretion | High renal tube reabsorption of calcium | Normal parathyroid histology. |
| FHH2 | GNA11 b | AD | High set point to inhibit PTH secretion | High renal tube reabsorption of calcium | |
| FHH3 | AP2S1 b | AD | High set point to inhibit PTH secretion | High renal tube reabsorption of calcium | Slightly more severe than FHH1 |
| NSHPT | CASR f | AR | Marked hyperplasia serum calcium level > 4 mM | High renal tube reabsorption of calcium | Needs urgent total PTX |
| NSHPT | CASR b | AD | Serum calcium level 3–4 mM | High renal tube reabsorption of calcium | Subtotal PTX or no PTX. Mother often has wild-type CASR |
| HPT-JT | CDC73 b | AD | Asymmetric adenoma, atypical adenoma cancer | Jaw tumors, uterus tumors | Microcystic parathyroid |
| FIHP | GCM2, e MEN1,bCASR,b or CDC73b | AD | Multiple adenomas | None | Management specific to the mutated gene. Median of two cases per kindred if no mutation in MEN1, CASR, or CDC73 |
Abbreviations: AD autosomal dominant; AR autosomal recessive; NSHPT, neonatal severe primary hyperparathyroidism; PTX parathyroidectomy; ThyrX thyroidectomy.
No mutated gene was identified in ∼2% (MEN2A), 5% (AD NSHPT), 5% (AR NSHPT), 20% (MEN1), 20% (FHH1+FHH2+FHH3), 40% (HPT-JT), or 83% (FIHP with exclusion of mutation of MEN1, CASR, or CDC-73).
Inactivation of one allele.
The degree of asymmetry of multiple parathyroid tumors is greatest in HPT-JT > MEN2A > MEN1 = FIHP > NSHPT. FHH is symmetric but not considered to usually have multiple parathyroid tumors.
Mesenchymal tumors include lipoma, angiofibroma, collagenoma, leiomyoma, and meningioma.
Activation of one allele.
Inactivation of both alleles.
Within this definition, the detailed concepts of FIHP have changed many times over 80 years (2–7). The changing concepts have presented challenges for syndrome nomenclature. Complexity in nomenclature for FIHP is exampled by the prefix “provisional” or “preliminary” being used sometimes in the past to specify several concepts of FIHP. This is not a consensus terminology. Neither of these rear-looking terms is used herein. However, use is frequent for the more current-looking conditioning phrase “without MEN1, CASR, or CDC73” to specify only some more modern concepts of FIHP since 2004. According to the earliest concept, between 1935 and 1960, FIHP presented as small kindreds with severe hypercalcemia in young adults. Later studies indicated that such a kindred might harbor incomplete expression of MEN1, FHH, or HPT-JT. Reports and concepts of FIHP between 1960 and 1980 focused on much larger kindreds assumed unlikely to harbor incomplete expressions of MEN1, FHH, or HPT-JT. (Although sometimes there is some overlap of adjacent intervals, the beginning and ending years of the intervals for a concept of FIHP are approximated and serve to emphasize their sequential natures.) Clinical follow-up between 1970 and 1990 usually showed more complex FH syndromes. Thus, reports and concepts of FIHP between 1990 and 1997 reverted to mainly small kindreds with mild PHPT in adults. With later identification of three genes for FH (MEN1, CASR, or CDC73), some large or small kindreds with FIHP were shown between 1998 and 2015 to have incomplete clinical expression of mutation in one of these. Most recently, between 2016 and 2019, the newest concepts of FIHP without MEN1, CASR, or CDC73 have focused on presence or absence of GCM2 mutation. FIHP has long proved difficult to study, and it has probably been underrepresented in the literature.
Methods
Searches were through PubMed for FIHP, other FH syndromes, and the gene(s) mutated in each.
Results and Discussion
Earliest concept of FIHP (1935 to 1960): small kindreds with severe PHPT in adolescents and young adults
The first report and concept of FIHP was a kindred that included two young adults with severe PHPT (8). Similar families were soon reported between 1935 and 1960 (Table 2). These were reported before introduction of the PTH RIA and before widespread screening of serum calcium levels (2, 17). In retrospect, there was a bias to report kindreds with severe PHPT, because mild PHPT was then less likely to come to attention.
Table 2.
Cases in Early Reports of FIHP
| First Author | Year | Case Identification | Familial Relationship | Age at Diagnosis (y) | Serum Calcium Level (mM) | Parathyroid Tumor Sizea | |||
|---|---|---|---|---|---|---|---|---|---|
| First operation | Second operation | ||||||||
| g | cm | g | cm | ||||||
| Goldman (8) | 1936 | 1 | Siblings | 17 | 4.8 | 12 | 3 | ||
| 2 | 23 | 4.6 | 7 | ||||||
| Schneider (9) | 1947 | 9 | Second cousins once removed | 20 | 4.6 | 9 | 2.2 | ||
| NA | NA | NA | NA | ||||||
| Shallow (10) | 1948 | 1 | Parent and child | 35 | 4.0 | 4 | 3 | ||
| 2 | 14 | 3.9 | 3 | ||||||
| Frohner (11) | 1954 | 1 | Siblings | 25 | 3.9 | 3 | |||
| 2 | 25 | 4.9 | 12 | 1.2 | |||||
| 3 | 29 | 3.4 | 1.5 | ||||||
| 4 | 30 | 4.5 | 6. and 2.5 | ||||||
| 5 | 26 | 4.0 | 1.9 and 0.8 | ||||||
| Snapper (12) | 1958 | JL | Identical twins | 37 | 3.9 | 1 | |||
| HL | 33 | 3.9 | 2.2 | 3 | |||||
| Hanes (13); Laubinger (14) | 1939; 1959 | 1 | Parent and child | 49 | 5.5 | Noneb | |||
| 2 | 42 | 3.5 | NA | ||||||
| Average | 29 | 4.2 | 4.3 | 2.7 | |||||
Normal values: Serum calcium normal range was not provided in any of these studies; it was estimated by the author at approximately 2.05–2.52 mM. Normal parathyroid gland weight < 160 mg (15); parathyroid gland maximal diameter < 0.7 cm (16).
Abbreviation: NA, not available.
Measured as weight and/or largest diameter.
No parathyroid operation. Autopsy showed a cystic, partially necrotic parathyroid (size not described) (13).
A reversal in the concept of FIHP between 1960 and 1980: focus on large kindreds expressing mild PHPT
Subsequent studies showed that the penetrance for PHPT is high at all ages in FHH (18, 19) and high in adults in MEN1 (20) and in HPT-JT (21, 22). Furthermore, the penetrance of PHPT in each of these three syndromes is higher and occurs at younger ages than that of its extraparathyroidal traits. Thus, one of the newly recognized syndromes of either MEN1, FHH, or HPT-JT could present in incomplete form as FIHP (23). These considerations led to the belief that most of the archival and small FIHP kindreds had been likely to harbor a more complex FH syndrome in incomplete form (23). Therefore, the concept of FIHP was revised to minimize its overpopulation by incomplete expressions of the more complex syndrome. The unusual and larger kindreds came to dominate the reports of FIHP between 1960 and 1980 (Table 3).
Table 3.
Large Kindreds With Initial Diagnosis of FIHP and a Later Clinical Diagnosis of a More Complex FH Syndrome
| Initial Report as FIHPa | Follow-Up Report as More Complex FH Syndrome | |||||
|---|---|---|---|---|---|---|
| First Author | Year | No. of Hyperparathyroid Cases | First Author | Year | Complex Diagnosis | Syndromal Trait |
| No author (24) | 1962 | 7 | No author (24) | 1969 | MEN1 | Islet, pituitary, and adrenocortical microadenomas |
| Goldsmith (25) | 1976 | 16 | Marx (26) | 1982 | MEN1 | Prolactinoma, insulinoma |
| Jackson (27) (abstract) | 1966 | 19 | Jackson (28) (abstract) | 1981 | FHH | Relative hypercalciuria failed parathyroidectomies |
| Spiegel (29) | 1977 | 12 | Marx (30) | 1982 | FHH | Relative hypocalciuria, failed parathyroidectomies |
| Marsden (31) | 1971 | 6 | Wassif (32) | 1999 | HPT-JT | Parathyroid cancer, jaw tumors |
The few kindreds with initial report of two cases of neonatal severe primary hyperparathyroidism (and follow-up report of FHH in relatives) are excluded from this table because this is not FIHP and does not constitute a large kindred in its initial report.
Another reversal in the concept of FIHP between 1990 and 1997: de-emphasizing large kindreds and revisiting small kindreds
Clinical follow-up of many of these large families between 1970 and 1990 revealed that they usually had harbored incomplete expressions of either MEN1, FHH, or HPT-JT (Table 3). Thus, kindreds with FIHP between 1990 and 1997 were reported independently of kindred size (33, 34). PHPT in these kindreds was generally mild and was detected during adulthood. The median number of cases of PHPT was two or three per kindred.
New concept of FIHP between 1998 and 2015: mutation of one gene among MEN1, CASR, or CDC73 in some large or small kindreds
Furthermore, later mutational data contradicted the earlier assumption about focusing on large kindred size in FIHP. Mutation analysis among candidate genes and gene cloning led to identification of MEN1, CASR, and CDC73 as the principal genes for MEN1, FHH, and HPT-JT, respectively (2, 35–37). Mutation findings with MEN1, CASR, and CDC73 between 1998 and 2015 also proved that most of the larger FIHP kindreds had incomplete expression for MEN1, FHH, or HPT-JT (Tables 1 and 4). Presumably, with longer follow-up, most of these FIHP kindreds would express one or more of FH’s syndromal extraparathyroidal features. The concept of many large FIHP kindreds having only isolated PHPT was set aside as a major requirement for inclusion in the group with FIHP. Furthermore, approximately one-fourth of probands in small kindreds with FIHP had a mutation in one of the MEN1, CASR, or CDC73 genes (Table 5). Thus, FIHP with mutation in one of the MEN1, CASR, or CDC73 genes was sometimes still termed FIHP (Table 1).
Table 4.
Large Families With FIHP Leading to Diagnosis of an Incomplete PHPT Syndrome
| First Author | Year | No. of Cases With Initial Diagnosis of Isolated PHPT in Kindred | No. of Unaffected Carriers of Mutation | Affected Gene or Linked Locus |
|---|---|---|---|---|
| Teh (38) | 1998 | 7 | 0a | MEN1 |
| Kassem (39) | 2000 | 14 | 3 | MEN1 |
| Villablanca (40) | 2002 | 8 | 1 | MEN1 |
| Carrasco (41) | 2004 | 11 | 3 | MEN1 |
| Isakov (42) | 2013 | 8 | 0 | MEN1 |
| Carling (43) | 2000 | 20 | 0 | CASRb |
| Simonds (3) | 2002 | 11 | 0 | CASR |
| Teh (44) | 1998 | 6 | 2 | CDC73 |
| Silveira (45) | 2008 | 9c | 3 | CDC73 |
Large families were defined as having six or more members with PHPT. Diagnosis of an incomplete but complex syndrome of PHPT was based either on genetic linkage to locus of the causative gene or on mutation of CASR, MEN1, or CDC73.
Screening for asymptomatic carriers was not performed in studies with a designation of zero unaffected carriers, and it was incomplete in most others.
This family had mild hypercalcemia, hypercalciuria, and curable parathyroid tumors. Thus, they did not have FHH. This was autosomal dominant mild hypercalcemia.
Renal cysts and uterine leiomyomas.
Table 5.
Large Series of Kindreds and Probands With FIHP and With Mutation Testing of Probands in Each Member of a Three-Gene Panel
| First Author | Year | No. of Kindreds or Probands | Median No. of PHPT Cases per Kindred | Average Age (y) | Average Serum Calcium Level (mM)a | No. of Mutated Genes in a Proband | |||
|---|---|---|---|---|---|---|---|---|---|
| CASR | MEN1 | CDC73 | None | ||||||
| Warner (4) | 2004 | 22 | 2 | 47 | 2.8 | 4 | 5 | 0 | 13 |
| Cetani (46); Pardi (47) | 2006; 2017 | 15 | 2 | 44 (46) | NA | 0 | 3 | 1 | 11 |
| Simonds (3); Simonds (48) | 2002; 2004 | 40 | 2 | 39 (3) | 3.1 (3) | 5 | 0 | 1 | 34 |
| Total probands in three studies, no. (%) | 77 (100) | 9 (12) | 8 (10) | 2 (3) | 56 (75) | ||||
Abbreviation: NA, not available.
Normal serum calcium range, 2.05–2.52 mM.
New concept of FIHP between 2004 and 2015: no mutation among each of three genes (MEN1, CASR, or CDC73) in few large and many small kindreds expressing FIHP
Almost simultaneously, between 2004 and 2015, FIHP without mutation in any of the MEN1, CASR, or CDC73 genes became a new concept of FIHP (46–48). FIHP nomenclature became problematic and remained so. For example, a family with long adherence to the definition of FIHP could more recently, and simultaneously, meet a genetic definition of MEN1 (49). For want of a nomenclature consensus, and depending on nomenclature preference, large or small FIHP kindreds with mutation in one of the MEN1, CASR, or CDC73 genes may be termed as FIHP (with syndromal mutation) or alternately termed as renamed to only the more complex FH syndrome.
Another new concept of FIHP between 2016 and 2019: a role for GCM2 mutation
As for MEN1 or HPT-JT, one or more large, well-characterized kindreds were required whenever using genetic linkage to promote positional cloning of a gene (35, 37). Therefore, small kindred size in FIHP precluded linkage analysis and delayed identification of GCM2 mutation in FIHP by 14 years, after identification of CDC73 in HPT-JT in 2002 (37, 50).
However, gene identification with whole-exome sequencing could be accomplished with very small kindreds (51). In 2016, germline mutation of the GCM2 (or GCMB) transcription factor was identified by whole-exome sequencing in FIHP (50). GCM2 germline mutations were found in seven of 40 probands (17%). The pathologic GCM2 mutations disrupted transcriptional inhibition in a 17 amino acid, conserved C-terminal inhibitory domain of GCM2 and were thus activating mutations. The role of GCM2 was supported in an independent series that found GCM2 activating mutation in four of 24 probands with FIHP (51). The largest kindred with GCM2 mutation showed an autosomal dominant transmission pattern of PHPT in five of six mutation carriers (50). In “sporadic” parathyroid adenoma, GCM2 (germline but apparently not somatic) activating mutation has a limited role (1% to 5% of tumors) (50, 52, 53). Pathologic activating GCM2 mutation was found for Y394 (in one of 107) parathyroid adenomas (50). Independently, pathologic activating GCM2 mutations were found for V382M (one of 396 mutations) and Y394 (five of 396 mutations) (54). A polymorphism of Y282D was also found (in 20 of 396 mutations), but its role in tumorigenesis is not proved (50, 54). Parathyroid tumors with GCM2 mutation were multiple, whereas without GCM2 mutation, they were single (P < 0.005) (52). Among six pathologic GCM2 mutations in adenomas, five were heterozygous and in the germline. One was homozygous in tumor; however, homozygous mutation was not tested for in the germline. In another series, one case of FIHP had homozygous germline mutation of GCM2 with a typical heterozygote phenotype (50). In sum, no instance of a second hit was documented (54). Inactivating germline mutations of GCM2 in a similar transcriptional assay had long been proved as one cause of hereditary hypoparathyroidism in man and mouse (55). GCM2, therefore, was analogous to some other genes (i.e., CASR or GNA11), which could also cause either familial hyperparathyroidism or familial hypoparathyroidism, by dissimilar mutations (19).
Some details in the newest concepts of FIHP: small kindreds with or without GCM2 mutation (each kindred without mutation of MEN1, CASR, or CDC73)
Surprisingly each of three recent and large series of FIHP (each kindred with or without mutation of MEN1, CASR, or CDC73) reported a median of only two cases of PHPT per kindred (Table 5). Furthermore, the median number of PHPT cases was two per family with GCM2 mutation and also two per family without GCM2 mutation (50). The small kindreds with FIHP contrasted with large kindreds among the other forms of FH, including several with >50 affected cases (56–58). A large FIHP kindred without mutation of MEN1, CASR, or CDC73 was rare; only two such kindreds, each with eight affected members, have been reported (3, 48, 59). One kindred with GCM2 mutation showed expression of PHPT in five of six mutation carriers (50).
Small kindred size might arise from a mutational effect before, during, or after conception. An example of a mutation causing relatively small kindred size from an effect before conception is CDC73 mutation. Women expressing HPT-JT often have menorrhagia from uterine tumors. Many undergo total hysterectomy during reproductive ages, with obvious compromise of fertility (60). Another example of size effect before conception is selected RET mutation. In MEN2B, patients have poor fertility due to early and aggressive medullary thyroidal cancer (61). However, an effect before conception from the PHPT of GCM2 mutation on kindred size is very unlikely because PHPT in FIHP is clinically much like that in other more complex PHPT syndromes with large kindreds and high penetrance.
Embryonic or zygotic lethal effect around conception has been found in model organisms but rarely in man. Maternal homozygous TLE6 mutation causes a preimplantation zygotic defect from failure of early cleavage of the zygote, recognized during in vitro fertilization (62). This is a striking and rare phenotype, and a similar mechanism seems unlikely in FIHP.
One possible size effect after conception is low penetrance of PHPT. A trait with low penetrance may be diagnosed by chance in two or three members of a small family and without expression in distant branches of the same kindred (63, 64). In theory, this might explain few cases of PHPT in a kindred with FIHP with mutation of GCM2; however, it is less likely to explain size of the other, similarly small, FIHP families without GCM2 mutation (and without MEN1, CASR, or CDC73 mutation).
A different mechanism after conception could be low or absent outreach in screening for PHPT selectively in small families with FIHP. This seems the most likely mechanism. The clinical features of the complex FH syndromes (e.g., severe peptic ulcer in MEN1, failed parathyroidectomies in FHH, or parathyroid cancer in HPT-JT) in the distant branches of a family could be evident on brief questioning; thus, they could selectively encourage screening outreach in that family. Importantly, this low outreach mechanism could also account for the similarly small kindred size in FIHP without GCM2 mutation. This mechanism could alternately be termed as one form of low penetrance. Penetrance or outreach for PHPT has not been reported in detail in FIHP.
FIHP without identified mutation between 2016 and 2019: no mutation found in the tested genes
Recent studies have raised the question of the disease mechanisms in 83% of kindreds with FIHP but no mutation of GCM2 (or of the MEN1, CASR, or CDC73 genes) (50). Large deletion in the MEN1, CASR, CDC73, or GCM2 gene, seemingly uncommon, were rarely screened for systematically in FIHP (47, 50, 65). Furthermore, some other FH genes also were generally not included in the screening panels, because of the likely rarity of their mutation in these families: RET, GNA11, AP2S1, CDKN1A, CDKN1B, CDKN2B, or CDKN2C (17, 66).
There are zero unidentified genes for FIHP
There could be mutation of zero, one, or more than one unidentified mutated genes in this group of FIHP. Some kindreds with two affected cases might represent an accidental occurrence from one or two cases of PHPT unrelated to GCM2 mutation (58). Considering that single adenoma is more common than multiple and about half of “small” FIHP kindreds have more than two affected members, and considering that such accidents have rarely been reported, this is unlikely to be the explanation for this half or for even more (58).
Alternately, all or most FIHP kindreds without identified mutation might have unrecognized mutation in one of the known genes, including GCM2. For example, this could result from an unrecognized promoter mutation or deep intronic mutation; these are common somatic mutations in some cancers but rare in the germline, making this an unlikely cause of FIHP (67, 68). Or mutation might be only pathologic in parts of the open reading frame of GCM2, only recognizable with thus far unexplored bioassays of GCM2 protein function (50).
There are several other genes for FIHP
This is highly plausible. This would recapitulate the high number of mutated genes in some syndromes with neoplasia confined to one tissue (69, 70). Considering that a mutated gene was not identified in 83% of FIHP probands (without mutation of MEN, CASR, or CDC73), and considering the clinical and technical resources available, then one or more additional genes for FIHP are likely to be identified shortly.
There is only one other major gene for FIHP
This too is plausible but less so than for several other genes. There are occasional syndromes for which mutation in two different genes can cause all or most cases (usually termed digenic inheritance or sometimes epistasis) (71). Often the encoded proteins interact in contact with each other in a shared pathway (15, 71).
Clinical features and management consequences of FIHP: with or without GCM2 mutation (and without mutation of MEN1, CASR, or CDC73)
Presentation and management in FIHP with or without GCM2 mutation (and without mutation of MEN1, CASR, or CDC73) are based on limited data in small kindreds (50, 52). Interventions should be individualized in FIHP. Nephrolithiasis or osteopenia each occurred in 20% of cases. Hypercalcemia in seven probands with GCM2 mutation was mild, averaging 2.9 mM (normal range, 2.05 to 2.52 mM). In both groups with or without GCM2 mutation, there were similar levels of serum calcium, serum PTH, and urine calcium, although the diameter of the largest parathyroid gland at surgery was 1.5-fold larger with GCM2 mutation (P < 0.05) versus without. One of 18 operated cases with GCM2 mutation showed possible parathyroid cancer or possible parathyromatosis (50). Most operated patients with GCM2 mutation had multiple parathyroid tumors, with approximately 20% postoperative persistence or recurrence among cases not diagnosed preoperatively (72). Several cases presented as “sporadic” parathyroid adenoma. In the current concept, the PHPT in FIHP with GCM2 mutation probably has a phenotype similar to PHPT in MEN1 (1, 49, 50, 52). Thus, based on limited experience, the medical and surgical management of PHPT with GCM2 mutation should be similar to that in MEN1 (49).
Assuming a proband frequency in FH of approximately 10% among all PHPT, then the population percentages of probands for PHPT syndromes is roughly estimated for MEN1, FHH, FIHP with GCM2 mutation, and HPT-JT. The prevalence of FIHP without mutation of GCM2, MEN1, CASR, CDC73 was 4%, 4%, 0.4%, 0.2%, and 1.4%, respectively (1, 73, 74). The pattern of hypercalcemia in FIHP was consistent with autosomal dominant transmission in each family. One case had homozygous mutation of GCM2 with a typical heterozygote phenotype (50). The frequency of GCM2 mutation among probands with FIHP (17%) was similar to the pooled frequencies of MEN1, CASR, and CDC73 mutation therein (25%) (Table 5). Mutation of each of these genes must bring its unique syndromal consequences for management of the proband and relatives (Table 1) (49). Either low penetrance or low screening as the cause of small kindred size in FIHP would have similar consequence for management and research. Specifically, it is important to conduct counseling and screening in more relatives in the kindred. This a major topic for additional research in FIHP.
Conclusions
The concepts of FIHP have undergone striking changes and even reversals over 80 years. The most recent concepts incorporate information about GCM2 mutation. Among FIHP probands (without mutation of MEN1, CASR, or CDC73), the frequency of germline mutation of GCM2 is 17%. Mutations of additional genes for FIHP will probably be identified shortly. FIHP families (without mutation of MEN1, CASR, or CDC73) with or without GCM2 mutation have a median of two affected members per kindred; the small size of these families probably reflects low outreach of screening among any relatives. This paucity of large kindreds for genetic linkage analysis delayed recognition of the role for GCM2 in FIHP by over a decade. The features of FIHP (without mutation of MEN1, CASR, or CDC73) are similar with or without GCM2 mutation; these include adult age at diagnosis, modest degree of hypercalcemia, and multiple parathyroid tumors. There is a need for clinical and mutational characterization in more cases to determine if there are any unique clinical features of FIHP, with or without mutation of GCM2.
Acknowledgments
The author is grateful to Bin Guan for his studies of the clinical and genetic expressions of GCM2 mutation. William Simonds, Sunita Agarwal, and others also contributed importantly to both efforts. The author also is grateful to members and staff of the National Institutes of Health Interinstitute Endocrine Training Program, and to the many patients and outside physicians who participated.
Financial Support: Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Disclosure Summary: The author has nothing to disclose.
Glossary
Abbreviations:
- FH
familial hyperparathyroidism
- FHH
familial hypocalciuric hypercalcemia
- FIHP
familial isolated hyperparathyroidism
- HPT-JT
hyperparathyroidism-jaw tumor
- MEN1
multiple endocrine neoplasia type 1
- MEN2A
multiple endocrine neoplasia type 2A
- PHPT
primary hyperparathyroidism
References
- 1. Arnold A, Agarwal SK, Thakker RV. Familial states of primary hyperparathyroidism. In: Bilezekain JP, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 9th ed Hoboken NJ, John Wiley & Sons Inc., 2019:629–638. [Google Scholar]
- 2. Marx SJ, Goltzman D. Evolution of our understanding of the hyperparathyroid syndromes: a historical perspective. J Bone Miner Res. 2019;34(1):22–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Simonds WF, James-Newton LA, Agarwal SK, Yang B, Skarulis MC, Hendy GN, Marx SJ. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore). 2002;81(1):1–26. [DOI] [PubMed] [Google Scholar]
- 4. Warner J, Epstein M, Sweet A, Singh D, Burgess J, Stranks S, Hill P, Perry-Keene D, Learoyd D, Robinson B, Birdsey P, Mackenzie E, Teh BT, Prins JB, Cardinal J. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J Med Genet. 2004;41(3):155–160. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Mizusawa N, Uchino S, Iwata T, Tsuyuguchi M, Suzuki Y, Mizukoshi T, Yamashita Y, Sakurai A, Suzuki S, Beniko M, Tahara H, Fujisawa M, Kamata N, Fujisawa K, Yashiro T, Nagao D, Golam HM, Sano T, Noguchi S, Yoshimoto K. Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumour syndrome. Clin Endocrinol (Oxf). 2006;65(1):9–16. [DOI] [PubMed] [Google Scholar]
- 6. Calabria AC, Levine MA. Hyperparathyroidism-jaw tumor syndrome. In: Licata AA, and Lerma EV, eds. Diseases of the Parathyroid Glands. New York, NY: Springer-Verlag; 2012:353–272. [Google Scholar]
- 7. Cardoso L, Stevenson M, Thakker RV. Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma. Hum Mutat. 2017;38(12):1621–1648. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Goldman L, Smyth FS. Hyperparathyroidism in siblings. Ann Surg. 1936;104(6):971–981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Schneider RW, Kyger ER Jr, McCullagh EP. Primary hyperparathyroidism report of 10 cases. Cleve Clin Q. 1947;14(4):246–257. [DOI] [PubMed] [Google Scholar]
- 10. Shallow TA, Fry KE. Parathyroid adenoma; occurrence in father and daughter. Surgery. 1948;24(6):1020–1025. [PubMed] [Google Scholar]
- 11. Frohner RN, Wolgamot JC. Primary hyperparathyroidism; five cases in one family. Ann Intern Med. 1954;40(4):765–773. [DOI] [PubMed] [Google Scholar]
- 12. Snapper I, Yarvis JJ, Freund HR, Goldberg AF. Hyperparathyroidism in identical twins, one of whom suffered concomitantly of Boeck’s sarcoidosis. Metabolism. 1958;7(6):671–680. [PubMed] [Google Scholar]
- 13. Hanes FH. Hyperparathyroidism due to parathyroid adenoma. With death from parathormone intoxication. Am J Med Sci. 1939;197(1):85–90. [Google Scholar]
- 14. Laubinger G, Mellinger RC. The familial occurrence of hyperparathyroidism. Henry Ford Hosp Med Bull. 1959;7:245–248. [PubMed] [Google Scholar]
- 15. Yao K, Singer FR, Roth SI, Sassoon A, Ye C, Giuliano AE. Weight of normal parathyroid glands in patients with parathyroid adenomas. J Clin Endocrinol Metab. 2004;89(7):3208–3213. [DOI] [PubMed] [Google Scholar]
- 16. Baloch ZW, LiVolsi VA. Pathology of the parathyroid glands in hyperparathyroidism. Semin Diagn Pathol. 2013;30(3):165–177. [DOI] [PubMed] [Google Scholar]
- 17. Boonstra CE, Jackson CE. The clinical value of routine serum calcium analysis. Ann Intern Med. 1962;57(6):963–969. [DOI] [PubMed] [Google Scholar]
- 18. Marx SJ, Attie MF, Levine MA, Spiegel AM, Downs RW Jr, Lasker RD. The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine (Baltimore). 1981;60(6):397–412. [DOI] [PubMed] [Google Scholar]
- 19. Hannan FM, Babinsky VN, Thakker RV. Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis. J Mol Endocrinol. 2016;57(3):R127–R142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Trump D, Farren B, Wooding C, Pang JT, Besser GM, Buchanan KD, Edwards CR, Heath DA, Jackson CE, Jansen S, Lips K, Monson JP, O’Halloran D, Sampson J, Shalet SM, Wheeler MH, Zink A, Thakker RV. Clinical studies of multiple endocrine neoplasia type 1 (MEN1). QJM. 1996;89(9):653–669. [DOI] [PubMed] [Google Scholar]
- 21. Cavaco BM, Guerra L, Bradley KJ, Carvalho D, Harding B, Oliveira A, Santos MA, Sobrinho LG, Thakker RV, Leite V. Hyperparathyroidism-jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene. J Clin Endocrinol Metab. 2004;89(4):1747–1752. [DOI] [PubMed] [Google Scholar]
- 22. van der Tuin K, Tops CMJ, Adank MA, Cobben JM, Hamdy NAT, Jongmans MC, Menko FH, van Nesselrooij BPM, Netea-Maier RT, Oosterwijk JC, Valk GD, Wolffenbuttel BHR, Hes FJ, Morreau H. CDC73-related disorders: clinical manifestations and case detection in primary hyperparathyroidism. J Clin Endocrinol Metab. 2017;102(12):4534–4540. [DOI] [PubMed] [Google Scholar]
- 23. Jackson CE, Boonstra CE. The relationship of hereditary hyperparathyroidism to endocrine adenomatosis. Am J Med. 1967;43(5):727–734. [DOI] [PubMed] [Google Scholar]
- 24. Multiple endocrine adenomatosis. Am J Med. 1969;47(4):608–618. [PubMed] [Google Scholar]
- 25. Goldsmith RE, Sizemore GW, Chen IW, Zalme E, Altemeier WA. Familial hyperparathyroidism. Description of a large kindred with physiologic observations and a review of the literature. Ann Intern Med. 1976;84(1):36–43. [DOI] [PubMed] [Google Scholar]
- 26. Marx SJ, Spiegel AM, Levine MA, Rizzoli RE, Lasker RD, Santora AC II, Downs RW Jr, Aurbach GD. Familial hypocalciuric hypercalcemia: the relation to primary parathyroid hyperplasia. N Engl J Med. 1982;307(7):416–426. [DOI] [PubMed] [Google Scholar]
- 27. Jackson CE, Boonstra CE. Hereditary hypercalcemia and parathyroid hyperplasia without definite hyperparathyroidism. J Lab Clin Med. 1966;68:883–890. [Google Scholar]
- 28. Jackson CE, Kleerekoper M. Hereditary hypocalciuric hypercalcemia is benign in 15 year followup. Clin Res. 1981;29:409.(Abstract). [Google Scholar]
- 29. Spiegel AM, Harrison HE, Marx SJ, Brown EM, Aurbach GD. Neonatal primary hyperparathyroidism with autosomal dominant inheritance. J Pediatr. 1977;90(2):269–272. [DOI] [PubMed] [Google Scholar]
- 30. Marx SJ, Attie MF, Spiegel AM, Levine MA, Lasker RD, Fox M. An association between neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia in three kindreds. N Engl J Med. 1982;306(5):257–264. [DOI] [PubMed] [Google Scholar]
- 31. Marsden P, Anderson J, Doyle D, Morris BA, Burns DA. Familial hyperparathyroidism. BMJ. 1971;3(5766):87–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Wassif WS, Farnebo F, Teh BT, Moniz CF, Li FY, Harrison JD, Peters TJ, Larsson C, Harris P. Genetic studies of a family with hereditary hyperparathyroidism-jaw tumour syndrome. Clin Endocrinol (Oxf). 1999;50(2):191–196. [DOI] [PubMed] [Google Scholar]
- 33. Huang SM, Duh QY, Shaver J, Siperstein AE, Kraimps JL, Clark OH. Familial hyperparathyroidism without multiple endocrine neoplasia. World J Surg. 1997;21(1):22–28, discussion 29. [DOI] [PubMed] [Google Scholar]
- 34. Barry MK, van Heerden JA, Grant CS, Thompson GB, Khosla S. Is familial hyperparathyroidism a unique disease? Surgery. 1997;122(6):1028–1033. [DOI] [PubMed] [Google Scholar]
- 35. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi S-E, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276(5311):404–407. [DOI] [PubMed] [Google Scholar]
- 36. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature. 1993;366(6455):575–580. [DOI] [PubMed] [Google Scholar]
- 37. Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, Agarwal SK, Sood R, Jones MP, Moses TY, Haven C, Petillo D, Leotlela PD, Harding B, Cameron D, Pannett AA, Höög A, Heath H III, James-Newton LA, Robinson B, Zarbo RJ, Cavaco BM, Wassif W, Perrier ND, Rosen IB, Kristoffersson U, Turnpenny PD, Farnebo L-O, Besser GM, Jackson CE, Morreau H, Trent JM, Thakker RV, Marx SJ, Teh BT, Larsson C, Hobbs MR. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet. 2002;32(4):676–680. [DOI] [PubMed] [Google Scholar]
- 38. Teh BT, Esapa CT, Houlston R, Grandell U, Farnebo F, Nordenskjöld M, Pearce CJ, Carmichael D, Larsson C, Harris PE. A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors. Am J Hum Genet. 1998a;63(5):1544–1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Kassem M, Kruse TA, Wong FK, Larsson C, Teh BT. Familial isolated hyperparathyroidism as a variant of multiple endocrine neoplasia type 1 in a large Danish pedigree. J Clin Endocrinol Metab. 2000;85(1):165–167. [DOI] [PubMed] [Google Scholar]
- 40. Villablanca A, Wassif WS, Smith T, Höög A, Vierimaa O, Kassem M, Dwight T, Forsberg L, Du Q, Learoyd D, Jones K, Stranks S, Juhlin C, Teh BT, Carling T, Robinson B, Larsson C. Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism. Eur J Endocrinol. 2002;147(3):313–322. [DOI] [PubMed] [Google Scholar]
- 41. Carrasco CA, González AA, Carvajal CA, Campusano C, Oestreicher E, Arteaga E, Wohllk N, Fardella CE. Novel intronic mutation of MEN1 gene causing familial isolated primary hyperparathyroidism. J Clin Endocrinol Metab. 2004;89(8):4124–4129. [DOI] [PubMed] [Google Scholar]
- 42. Isakov O, Rinella ES, Olchovsky D, Shimon I, Ostrer H, Shomron N, Friedman E. Missense mutation in the MEN1 gene discovered through whole exome sequencing co-segregates with familial hyperparathyroidism. Genet Res. 2013;95(4):114–120. [DOI] [PubMed] [Google Scholar]
- 43. Carling T, Szabo E, Bai M, Ridefelt P, Westin G, Gustavsson P, Trivedi S, Hellman P, Brown EM, Dahl N, Rastad J. Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab. 2000;85(5):2042–2047. [DOI] [PubMed] [Google Scholar]
- 44. Teh BT, Farnebo F, Twigg S, Höög A, Kytölä S, Korpi-Hyövälti E, Wong FK, Nordenström J, Grimelius L, Sandelin K, Robinson B, Farnebo LO, Larsson C. Familial isolated hyperparathyroidism maps to the hyperparathyroidism-jaw tumor locus in 1q21-q32 in a subset of families. J Clin Endocrinol Metab. 1998b;83(6):2114–2120. [DOI] [PubMed] [Google Scholar]
- 45. Silveira LG, Dias EP, Marinho BC, Gomez RS, De Marco L, Sarquis MS. HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach? Arq Bras Endocrinol Metabol. 2008;52(8):1211–1220. [DOI] [PubMed] [Google Scholar]
- 46. Cetani F, Pardi E, Ambrogini E, Lemmi M, Borsari S, Cianferotti L, Vignali E, Viacava P, Berti P, Mariotti S, Pinchera A, Marcocci C. Genetic analyses in familial isolated hyperparathyroidism: implication for clinical assessment and surgical management. Clin Endocrinol (Oxf). 2006;64(2):146–152. [DOI] [PubMed] [Google Scholar]
- 47. Pardi E, Borsari S, Saponaro F, Bogazzi F, Urbani C, Mariotti S, Pigliaru F, Satta C, Pani F, Materazzi G, Miccoli P, Grantaliano L, Marcocci C, Cetani F. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS One. 2017;12(10):e0186485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48. Simonds WF, Robbins CM, Agarwal SK, Hendy GN, Carpten JD, Marx SJ. Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab. 2004;89(1):96–102. [DOI] [PubMed] [Google Scholar]
- 49. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990–3011. [DOI] [PubMed] [Google Scholar]
- 50. Guan B, Welch JM, Sapp JC, Ling H, Li Y, Johnston JJ, Kebebew E, Biesecker LG, Simonds WF, Marx SJ, Agarwal SK. GCM2-activating mutations in familial isolated hyperparathyroidism. Am J Hum Genet. 2016;99(5):1034–1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Koboldt DC, Steinberg KM, Larson DE, Wilson RK, Mardis ER. The next-generation sequencing revolution and its impact on genomics. Cell. 2013;155(1):27–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52. Guan B, Welch JM, Vemulapalli M, Li Y, Ling H, Kebebew E, Simonds WF, Marx SJ, Agarwal SK. Ethnicity of patients with germline GCM2-activating variants and primary hyperparathyroidism. J Endocr Soc. 2017;1(5):488–499. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53. Riccardi A, Aspir T, Shen L, Kuo C-L, Brown TC, Korah R, Murtha TD, Bellizzi J, Parham K, Carling T, Costa-Guda J, Arnold A. Analysis of activating GCM2 sequence variants in sporadic parathyroid adenomas [published online ahead of print 8 January 2019] J Clin Endocrinol Metab. 10.1210/jc.2018-02517. [DOI] [PubMed] [Google Scholar]
- 54. Greben R, Canaff L, Wong BYL, Cole DEC, Guarnieri V, Scillitano A, Hendy GN. Parathyroid cell transcription factor glial cells missing-2: Novel inactivating and activating mutations associated with hypoparathyroidism and hyperparathyroidism respectively [abstract PO19]. J Musculoskel Neuronal Interact. 2017:17:357. [Google Scholar]
- 55. Maret A, Ding C, Kornfield SL, Levine MA. Analysis of the GCM2 gene in isolated hypoparathyroidism: a molecular and biochemical study. J Clin Endocrinol Metab. 2008;93(4):1426–1432. [DOI] [PubMed] [Google Scholar]
- 56. Marx SJ, Vinik A, Santen RJ, Floyd JC Jr, Mills JL, Green J III. Multiple endocrine neoplasia type 1: assessment of laboratory tests to screen for the gene in a large kindred. Medicine (Baltimore). 1986;65:226–241. [PubMed] [Google Scholar]
- 57. Olufemi SE, Green JS, Manickam P, Guru SC, Agarwal SK, Kester MB, Dong Q, Burns AL, Spiegel AM, Marx SJ, Collins FS, Chandrasekharappa SC. Common ancestral mutation in the MEN1 gene is likely responsible for the prolactinoma variant of MEN1 (MEN1Burin) in four kindreds from Newfoundland. Hum Mutat. 1998;11(4):264–269. [DOI] [PubMed] [Google Scholar]
- 58. Burgess JR, Nord B, David R, Greenaway TM, Parameswaran V, Larsson C, Shepherd JJ, Teh BT. Phenotype and phenocopy: the relationship between genotype and clinical phenotype in a single large family with multiple endocrine neoplasia type 1 (MEN 1). Clin Endocrinol (Oxf). 2000;53(2):205–211. [DOI] [PubMed] [Google Scholar]
- 59. Pontikides N, Karras S, Kaprara A, Anagnostis P, Mintziori G, Goulis DG, Memi E, Krassas G. Genetic basis of familial isolated hyperparathyroidism: a case series and a narrative review of the literature. J Bone Miner Metab. 2014;32(4):351–366. [DOI] [PubMed] [Google Scholar]
- 60. Bradley KJ, Hobbs MR, Buley ID, Carpten JD, Cavaco BM, Fares JE, Laidler P, Manek S, Robbins CM, Salti IS, Thompson NW, Jackson CE, Thakker RV. Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. J Intern Med. 2005;257(1):18–26. [DOI] [PubMed] [Google Scholar]
- 61. Castinetti F, Moley J, Mulligan L, Waguespack SG. A comprehensive review on MEN2B. Endocr Relat Cancer. 2018;25(2):T29–T39. [DOI] [PubMed] [Google Scholar]
- 62. Alazami AM, Awad SM, Coskun S, Al-Hassan S, Hijazi H, Abdulwahab FM, Poizat C, Alkuraya FS. TLE6 mutation causes the earliest known human embryonic lethality. Genome Biol. 2015;16(1):240. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63. Eloy P, Dehainault C, Sefta M, Aerts I, Doz F, Cassoux N, Lumbroso le Rouic L, Stoppa-Lyonnet D, Radvanyi F, Millot GA, Gauthier-Villars M, Houdayer C. A parent-of-origin effect impacts the phenotype in low penetrance retinoblastoma families segregating the c.1981C>T/p.Arg661Trp mutation of RB1. PLoS Genet. 2016;12(2):e1005888. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64. Hes FJ, Weiss MM, Woortman SA, de Miranda NF, van Bunderen PA, Bonsing BA, Stokkel MP, Morreau H, Romijn JA, Jansen JC, Vriends AH, Bayley JP, Corssmit EP. Low penetrance of a SDHB mutation in a large Dutch paraganglioma family. BMC Med Genet. 2010;11(1):92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65. Bricaire L, Odou MF, Cardot-Bauters C, Delemer B, North MO, Salenave S, Vezzosi D, Kuhn JM, Murat A, Caron P, Sadoul JL, Silve C, Chanson P, Barlier A, Clauser E, Porchet N, Groussin L; GTE Group. Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2013;98(2):E403–E408. [DOI] [PubMed] [Google Scholar]
- 66. Agarwal SK, Mateo C, Marx SJ. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab. 2009;94(5):1826–1834. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67. Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, Kadel S, Moll I, Nagore E, Hemminki K, Schadendorf D, Kumar R. TERT promoter mutations in familial and sporadic melanoma. Science. 2013;339(6122):959–961. [DOI] [PubMed] [Google Scholar]
- 68. Vaz-Drago R, Custódio N, Carmo-Fonseca M. Deep intronic mutations and human disease. Hum Genet. 2017;136(9):1093–1111. [DOI] [PubMed] [Google Scholar]
- 69. Drougat L, Omeiri H, Lefèvre L, Ragazzon B. Novel insights into the genetics and pathophysiology of adrenocortical tumors. Front Endocrinol (Lausanne). 2015;6:96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70. Dias Pereira B, Nunes da Silva T, Bernardo AT, César R, Vara Luiz H, Pacak K, Mota-Vieira L. A clinical roadmap to investigate the genetic basis of pediatric pheochromocytoma: which genes should physicians think about? Int J Endocrinol. 2018;2018:8470642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71. Deltas C. Digenic inheritance and genetic modifiers. Clin Genet. 2018;93(3):429–438. [DOI] [PubMed] [Google Scholar]
- 72. El Lakis M, Nockel P, Guan B, Agarwal S, Welch J, Simonds WF, Marx S, Li Y, Nilubol N, Patel D, Yang L, Merkel R, Kebebew E. Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is more aggressive and has a lesser rate of biochemical cure. Surgery. 2018;163(1):31–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73. Eastell R, Brandi ML, Costa AG, D’Amour P, Shoback DM, Thakker RV. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3570–3579. [DOI] [PubMed] [Google Scholar]
- 74. Gill AJ, Lim G, Cheung VKY, Andrici J, Perry-Keene JL, Paik J, Sioson L, Clarkson A, Sheen A, Luxford C, Elston MS, Meyer-Rochow GY, Nano MT, Kruijff S, Engelsman AF, Sywak M, Sidhu SB, Delbridge LW, Robinson BG, Marsh DJ, Toon CW, Chou A, Clifton-Bligh RJ. Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) parathyroid tumors demonstrate distinctive morphologic features. Am J Surg Pathol. 2019;43(1):35–46. [DOI] [PMC free article] [PubMed] [Google Scholar]