No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Surgical Management of Familial Hyperparathyroidism
... Data have revealed an interplay between mutational status and clinical manifestations of the disease. MEN 1 and CaSR mutations are more likely in younger patients with multiglandular disease, whereas HRPT2 mutations should be considered in those families with parathyroid carcinomas or cystic parathyroid tumors [48][49][50]. ...
... Parathyroid surgery is the treatment of choice for FIPH, particularly when complications of the disease have been observed; nevertheless, the optimal type of surgical procedure in FIPH is yet to be defined [48][49][50][51]. Surgical procedure differs from that followed in sporadic forms of PHT and even among the familial forms per se. ...
... On the other hand, given the high rate of recurrence or persistence, the morbidity of a second operation and the risk of parathyroid carcinoma, some authors suggest ipsilateral hemithyroidectomy and total parathyroidectomy [51][52][53]. Good results have been reported with the use of intraoperative PTH assay during minimally invasive parathyroidectomy [49]. ...
Primary hyperparathyroidism is a heterogeneous clinical entity. In the clinical setting, the diagnosis and management of familial isolated hyperparathyroidism (FIHP) and other familial hyperparathyroidism (FHPT) forms continue to rely on clinical, laboratory, and histological findings, with careful examination of the family. In this article, we report a case series of FIHP in a four-generation Greek family, with no identifiable gene mutations. Clinical approach and long-term follow-up are discussed and a narrative review of the genetic basis of this entity has been performed.
... In the course of familial pHPT, severe hypercalcemia (above 3.75 mmol/l) is more commonly seen, the percentage of multiglandular disease approaches 45%, and the risk of parathyroid carcinoma is increased (evidence level IV). Hence, in these cases, BNE is recommended, and oftentimes subtotal parathyroidectomy is indicated as well (16). ...
... The remnant left in situ should originate from a superior parathyroid, since in these patients, reoperations are often necessitated by nodal relapses of medullary carcinoma of the thyroid, what would put the remnant originating from an inferior parathyroid at risk of being inadvertently resected during supplementary lymphadenectomy of the central compartment lymph nodes within the scarified tissues, thus exposing the patient to danger of fixed hypoparathyroidism. Simultaneous parathyroid tissue autotransplantation in the course of primary operations minimizes the risk of the patient developing the complication in the future (15,16). ...
... Unfortunately, intraoperative iPTH assay, so useful in prognosing early postoperative normocalcemia, cannot be of use in prognosing late therapeutic results. Patients with MEN 1 syndrome are at risk of hypercal-cemia recurrence at considerably diversified intervals after parathyroidectomy, hence the necessity of life-long monitoring of calcemia and iPTH in this group (15,16). CONCLUSIONS 1. ...
At present, the majority of patients with sporadic primary hyperparathyroidism (pHPT) qualify to minimally invasive parathyroidectomy (MIP). Nevertheless, in some patients, especially those with multiglandular parathyroid disease, achieving normocalcemia necessitates bilateral neck exploration (BNE).The aim of the study was evaluation of current indications for BNE and results obtained employing this method in an endocrine surgery referral center.Material and methods. A prospective analysis included 385 patients with pHPT qualified to parathyroidectomy (300 to MIP and 85 to BNE procedures) in the period between 12/2002 and 05/2008. Prior to the procedure, all the patients underwent preoperative imaging diagnostic studies (scintiscans of the parathyroids and ultrasound of the neck). Intraoperative parathormone assay was carried out in the course of all the operations. Indications for BNE and therapeutic results were evaluated.Results. The most common indication for BNE was lack of preoperative location of a parathyroid adenoma in imaging studies aiming either at lateralization or regionalization (49.4%), followed by concomitant thyroid pathology that required surgical treatment (23.5%), MEN 1 syndrome (12.9%), long-term lithium therapy (5.9%), refusal of the patient to grant informed consent to a minimally invasive parathyroidectomy (5.9%) and MEN 2A syndrome (2.4%). In the discussed group, 31 subtotal parathyroidectomies were performed, along with ten resections of two parathyroid adenomas and 44 resections of single parathyroid adenomas. Intraoperative iPTH assay affected the extent of parathyroid tissues resection in eight (9.4%) cases. One case of persistent and one case of recurrent hyperparathyroidism were noted in the follow-up of mean 37.4 ± 19.4 months postoperatively.Conclusions. In an endocrine surgery referral center, BNE is a procedure of choice in patients suspected of multiglandular parathyroid disease (MEN 1 and 2A, familial pHPT, long-term lithium therapy), in cases when a pathological parathyroid has not been located preoperatively and in patients which refuse their consent to MIP. Supplementing BNE with intraoperative iPTH assay allows for maintaining the highest quality of surgical treatment.
... Finally, IOPTH can also assist in determining whether autografting should be performed in patients undergoing subtotal parathyroidectomy. If the IOPTH value is not measurable (<10 pg/mL) after subtotal parathyroidectomy has been performed, autografting to prevent permanent hypoparathyroidism is recommended (20). The most normal-appearing portion (40-80 mg) of 1 gland should be autografted (1,6). ...
... For patients who have undergone an initial subtotal parathyroidectomy, we recommend completion parathyroidectomy with forearm autografting (13,20) rather than debulking remnant hyperfunctioning tissue. For patients who have undergone subtotal or total parathyroidectomy with autografting, recurrence due to autonomous function of parathyroid autografts ranges from 3% to 67%; the higher rates are seen in familial HPT cases or when autotransplant of hyperplastic or adenomatous tissue occurs in sporadic cases. ...
To discuss the etiology of multiple gland disease in the context of primary hyperparathyroidism, as well as indications for surgery, operative management and technical considerations of subtotal parathyroidectomy, and postoperative/long-term management.
We conducted a systematic review of the literature using evidence-based criteria.
Approximately 15% of patients with primary hyperparathyroidism have multiple gland disease, and a small subset of these cases is due to a familial syndrome. Subtotal parathyroidectomy is one operative approach to the management of multiple gland disease. Subtotal parathyroidectomy for multiple gland disease results in normocalcemia in at least 95% of cases. Intraoperative parathyroid hormone monitoring can help guide the extent of the operation and determine the need to perform a concurrent autograft. After subtotal parathyroidectomy, most patients develop postoperative hypocalcemia and require calcium and possibly calcitriol supplementation; approximately 10% to 15% develop permanent hypoparathyroidism. All patients after parathyroidectomy, especially those with familial primary hyperparathyroidism, should undergo long-term follow-up for surveillance of recurrent primary hyperparathyroidism. If persistent or recurrent primary hyperparathyroidism occurs after subtotal parathyroidectomy, completion total parathyroidectomy and parathyroid autotransplant should be performed.
Subtotal parathyroidectomy is an excellent surgical approach for patients with primary hyperparathyroidism due to multiple gland disease from either sporadic or familial causes.
... On the other hand, surgical procedure in familial cases is still controversial in the literature, especially concerning HRPT2-related FIHP (29)(30)(31)(32). To allow a proper management of the parathyroid tumors, it is essential that we better comprehend the natural history of familial syndromes associated with hyperparathyroidism. ...
... Most of the already reported good results using minimally invasive parathyroidectomy (MIP) in FIHP, required intraoperative parathyroid hormone (IOPTH) assay combined with accurate and expensive preoperative and intraoperative identifi cation of the parathyroid glands, including those that may exist in ectopic locations (30). However, citations available in PubMed when HRPT2 AND hyperparathyroidism AND surgery are searched, show that the time of follow-up, the scarcity of molecular data and the small number of patients reported in several series are not suffi cient to lead to a defi nive conclusion (Table 2) (25,29,31,(36)(37)(38)(39)(40)(41)(42). ...
It is still debatable which is the best management to familial forms of hyperparathyroidism. Conservative, minimally invasive or aggressive surgical approaches have been proposed from different groups around the world. Our objective was to study the gene mutation, expression of HRPT2 and the clinical outcome after 32 years of follow-up in one Brazilian kindred with familial isolated hyperparathyroidism (FIHP). Clinical and biochemical data, direct sequencing of the HRPT2 gene, analysis of parafibromin expression using RT-PCR, and immunohistochemistry were done. A nonsense mutation was found in exon 1 (c.96G>A)(p.Trp32X) in all affected members studied. Using RT-PCR, mRNA transcription was altered with complete absence of both transcripts in tumor tissue. Immunohistochemical analysis of tumors showed loss of parafibromin immunoreactivity. In this kindred there was a high prevalence of recurrence (75%), or persistence after less than subtotal parathyroidectomy that led us to consider a more aggressive surgical approach should be discussed among the affected family members, once surgical criteria was met. We concluded that it is necessary to individualize the surgical approach for HRPT2-related hyperparathyroidism until we can gather a better phenotype-genotype correlation in larger series, to best define their treatment.
... In 3% to 5% of pa-tients, pHPT occurs as a component of an inherited syndrome (eAppendix in the Supplement). [7][8][9] • Recommendation 1-3: In patients with suspected pHPT, a personal and family history should be taken (strong recommendation; moderate-quality evidence). Patients with otherwise asymptomatic pHPT may have nephrocalcinosis or silent nephrolithiasis; both are indications for parathyroidectomy. ...
Importance
Primary hyperparathyroidism (pHPT) is a common clinical problem for which the only definitive management is surgery. Surgical management has evolved considerably during the last several decades.
Objective
To develop evidence-based guidelines to enhance the appropriate, safe, and effective practice of parathyroidectomy.
Evidence Review
A multidisciplinary panel used PubMed to review the medical literature from January 1, 1985, to July 1, 2015. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus.
Findings
Initial evaluation should include 25-hydroxyvitamin D measurement, 24-hour urine calcium measurement, dual-energy x-ray absorptiometry, and supplementation for vitamin D deficiency. Parathyroidectomy is indicated for all symptomatic patients, should be considered for most asymptomatic patients, and is more cost-effective than observation or pharmacologic therapy. Cervical ultrasonography or other high-resolution imaging is recommended for operative planning. Patients with nonlocalizing imaging remain surgical candidates. Preoperative parathyroid biopsy should be avoided. Surgeons who perform a high volume of operations have better outcomes. The possibility of multigland disease should be routinely considered. Both focused, image-guided surgery (minimally invasive parathyroidectomy) and bilateral exploration are appropriate operations that achieve high cure rates. For minimally invasive parathyroidectomy, intraoperative parathyroid hormone monitoring via a reliable protocol is recommended. Minimally invasive parathyroidectomy is not routinely recommended for known or suspected multigland disease. Ex vivo aspiration of resected parathyroid tissue may be used to confirm parathyroid tissue intraoperatively. Clinically relevant thyroid disease should be assessed preoperatively and managed during parathyroidectomy. Devascularized normal parathyroid tissue should be autotransplanted. Patients should be observed postoperatively for hematoma, evaluated for hypocalcemia and symptoms of hypocalcemia, and followed up to assess for cure defined as eucalcemia at more than 6 months. Calcium supplementation may be indicated postoperatively. Familial pHPT, reoperative parathyroidectomy, and parathyroid carcinoma are challenging entities that require special consideration and expertise.
Conclusions and Relevance
Evidence-based recommendations were created to assist clinicians in the optimal treatment of patients with pHPT.
... To our knowledge, only 157 patients with FHPT have been previously reported in literature; [4][5][6][7] to which we add another 28 patients ( Table 1). All patients in this series have at least one first degree relative with hyperparathyroidism, with six patients in a single family all receiving surgery at EUH. ...
Isolated familial hyperparathyroidism (FHPT) not associated with multiple endocrine neoplasia is a rare and aggressive form of primary hyperparathyroidism. The traditional management of FHPT is a bilateral neck exploration with an increased rate of multigland hyperplasia, supernumerary glands, and recurrence. A prospective database was queried, which included 1383 consecutive parathyroidectomies between 1992 and 2008, and 28 patients with FHPT were identified. Patient demographics, pathology, intraoperative parathyroid hormone (IOPTH) kinetics, recurrence patterns, and accuracy of localization studies were analyzed. Twenty-one patients underwent bilateral neck explorations as an initial surgery, and seven patients had nine unilateral neck explorations for recurrent hyperparathyroidism. Overall cure rate was 89.2 per cent with a mean follow-up of 2.9 years (range: 6 months to 9.2 years); 64.3 per cent of patients had multigland disease. IOPTH helped identify supernumerary glands in three (12.5%) patients and accurately lateralized recurrent disease in eight of nine surgeries (88.8%). Tc-99m-Sestamibi failed to identify multigland disease in 11 patients (52.3%). FHPT has a greater prevalence of multigland disease, decreased utility of sestamibi scanning, and a higher recurrence rate than sporadic primary hyperparathyroidism. In FHPT, IOPTH is a useful adjunct in identifying additional tumors and in select cases may play a role in tumor localization.
Introduction:
Patients with primary hyperparathyroidism (1HPT) undergoing reoperative or subtotal parathyroidectomy (PTX) may undergo autotransplantation (ATX) when the viability of remaining tissue is unknown. This study aims to identify whether intraoperative parathyroid hormone levels (IOPTH) can determine ATX candidacy.
Methods:
Patients with 1HPT who underwent PTX with ATX at our institution were identified. IOPTH and PTH values within 24 h, 2-4 weeks, and >1 month postoperative were analyzed. Patients were classified as either a candidate for ATX (low PTH after 2-4 weeks) or not a candidate based on postoperative PTH (normal PTH after 2-4 weeks). Associations of ATX candidate status with demographic and clinical attributes were studied.
Results:
268 had a reoperative (49%) or subtotal PTX with ATX. 151 had data for PTH analysis, and 21 (14%) were identified as candidates for ATX. The mean % decline in IOPTH from baseline to 20 min post-excision was 51% in noncandidates vs 73% in candidates (P = .002). The mean change in IOPTH from baseline to final was 52% in noncandidates and 83% in candidates (P = .009). A decrease in IOPTH from baseline to 20 min post-excision of 23.4% or greater or a final PTH of 52 pg/mL or less would be an indication for ATX. Of the 21 who needed an ATX, it failed in 10.
Conclusion:
Parathyroid ATX is frequently unnecessary, and the viability is less than expected. While candidates for ATX have a greater IOPTH % decline at all points during surgery and a lower final IOPTH, the clinical practicality of using IOPTH to determine ATX candidacy is limited.
Primary hyperparathyroidism (PHPT) resulting from multiple endocrine neoplasia (MEN) type 1 or MEN 2A is a relatively uncommon cause of PHPT. However, it is important that the physicians treating patients with inherited PHPT be well versed in the management of this condition. The diagnosis of MEN 1 should be considered in patients with two or more MEN 1–related tumors or a clinical history otherwise suggestive of MEN 1. PHPT is often the first clinical manifestation of disease in the proband of an MEN 1 family or in at-risk members of a known MEN 1 kindred. The diagnosis of MEN 2A is typically made before the onset of PHPT because of the near 100% penetrance of medullary thyroid cancer (MTC). Genetic testing (before surgery on the neck) is particularly important in patients with MEN 2A because of the strong genotype-phenotype correlation of the specific rearranged during transfection (RET) mutation identified. We prefer to know the RET status of the patient before thyroid/parathyroid surgery because it will indicate the location of a parathyroid autograft if one is performed. Indications for surgery in MEN–associated PHPT are no different than for those with sporadic PHPT. The goals of initial parathyroidectomy in patients with MEN–associated PHPT are to achieve eucalcemia and minimize the risk of immediate hypoparathyroidism. Forearm autografting of remnant parathyroid tissue should be considered for all patients with MEN 2A–associated PHPT and invasive MTC as well as all patients with inherited PHPT who undergo reoperative neck surgery.
Background:
Multi-institutional data describing remedial parathyroidectomy compared with index parathyroidectomy are scarce.
Methods:
Using data in the Collaborative Endocrine Surgery Quality Improvement Program (2014-2017), baseline characteristics and outcomes of patients undergoing remedial parathyroidectomy versus index parathyroidectomy were examined using bivariate and multivariate methods. Rates of hypercalcemia and hypocalcemia at ≥ 180 days were assessed.
Results:
Among 6,795 patients, 367 (5.4%) underwent remedial parathyroidectomy. A single localization study was done in 24.8% versus 26.9% of remedial parathyroidectomy versus index parathyroidectomy (P = .37). Patients undergoing remedial parathyroidectomy had higher rates of preoperative laryngoscopy (45.5% versus 6.2%, P < .001), intraoperative nerve monitoring (57.5% versus 34.5%, P < .001), and < 50% drop in hyperparathyroidism than those undergoing index parathyroidectomy (9.6% versus 3.3%, P < .001). Among patients with ≥ 180 days follow-up, none of the remedial parathyroidectomy versus three index parathyroidectomy patients (0.3%) had vocal cord dysfunction. Hypercalcemia rates for remedial parathyroidectomy and index parathyroidectomy were 10.5% versus 5.0 (P = .07), and hypocalcemia rates were 10.5% versus 2.4% (P < .001). After multivariate adjustment, failure to cure was 4.0 times more likely in remedial parathyroidectomy than index parathyroidectomy (P < .001).
Conclusion:
This is the first multi-institutional examination of remedial parathyroidectomy outcomes in the Collaborative Endocrine Surgery Quality Improvement Program. Nerve injury rates are low; high rates of hypercalcemia and hypocalcemia suggest potential opportunities to refine the preoperative and intraoperative management of patients undergoing remedial parathyroidectomy.
Multiple endocrine neoplasia (MEN) describes a group of syndromes characterized by neoplasms in two or more endocrine organs. Neoplasms can be benign, malignant, and in some cases nonsecretory. To date there are seven MEN syndromes, which includes MEN 1, MEN 2, MEN 4, Carney Complex, McCune–Albright syndrome, Von Hippel–Lindau disease, and neurofibromatosis type 1. This chapter focuses on those syndromes in which primary hyperparathyroidism (PHPT) has been described: MEN 1, MEN 2, and MEN 4 [1]. MEN 1 and MEN 2 are neoplastic syndromes which demonstrate an autosomal dominant inheritance pattern. Due to the unique expression, evaluation, and management of PHPT and the associated endocrine neoplasms in these hereditary syndromes, special discussion on these disorders is deserved.
To discuss the implications of a young age at diagnosis in a family member with hyperparathyroidism-jaw tumor syndrome, the youngest published case to date, due to a mutation of the CDC73 gene (formerly known as HRPT2); to review this family with regard to modifications of guidelines for surveillance of hyperparathyroidism and other associated features in affected and at-risk relatives; and to discuss surgical recommendations in this syndrome.
A review of English-language publications in PubMed and a review of GeneReviews were conducted pertaining to the subject of familial hyperparathyroidism. A case is described, and the family pedigree is discussed.
Review of the literature revealed that CDC73-related disorder has not previously been reported in patients younger than 10 years. This finding has been the basis for the recommendation for initiation of surveillance for disease manifestations at that age. Review of the family history of our current patient revealed a 7-year-old nephew with hypercalcemia attributable to primary hyperparathyroidism.
Surveillance of hyperparathyroidism in affected persons and genetic testing of relatives at risk are currently recommended to start at 10 years of age. We recommend that these be conducted at a younger age, preferably 5 to 10 years before the earliest diagnosis of hyperparathyroidism within the family, and potentially at birth in families with a known mutation of the CDC73 gene, in light of the malignant potential of the disease.
We report the clinical and genetic findings in a 23-year-old woman with hyperparathyroidism-jaw tumor syndrome (HPT-JT). The patient had a family history of primary hyperparathyroidism (PHPT) and uterine fibroma in her mother. The patient presented muscle weakness. The diagnosis of PHPT was confirmed by an elevated parathyroid hormone level above 1450 pg/ml with hypercalcemia and hypercalciuria. X-ray radiographies showed a radiolucent lesion in the right body of the mandible. Bilateral neck exploration was performed. An inferior right parathyroidectomy, a left thyroid lobectomy with isthmectomy and thymectomy were carried out. Histopathological examination of the specimen showed a diffuse hyperplasia of the parathyroid principal cells. The association of PHPT with a right jaw tumor and uterine fibroma suggested the diagnosis of HPT-JT syndrome. Mutation screening of HRPT2 gene was carried out and identified a germline mutation, consisting in a base deletion in exon 1, 85delG, inducing a frameshift. The diagnosis of HPT-JT syndrome is clinically important because of its hereditary component and its high risk of parathyroid malignancy, making a genetic inquiry necessary.
Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal disease caused by inactivating germ-line mutations of HRPT2 gene, with subsequent loss of Parafibromin expression. It is characterized by familial HPT, ossifying jaw tumors, and other associated neoplasms.
Clinical, histopathological, and genetic features of three large Italian unrelated HPT-JT kindred were assessed.
Three different germ-line HRPT2 inactivating mutations were identified. Seventeen affected members and six healthy mutation carriers were found. HPT was diagnosed in virtually all affected patients, at a median age of 36.3 years (range 11-71). In all cases, a single parathyroid involvement was found at surgery, although a metachronous multiglandular involvement causing recurrence after selective parathyroidectomy occurred in 17.6% of cases, after a mean disease-free interval of 13.7 years (range 5-27). Parathyroid carcinoma, atypical parathyroid adenoma, and jaw tumor occurred in one case; uterine involvement in 61.5% of women; other associated neoplasms were thyroid carcinoma (two cases) and renal and colon carcinoma (one case). Immunohistochemistry confirmed the loss of Parafibromin as the distinctive feature of the disease both in parathyroid and uterine tumors.
HPT-JT has a frequent single-gland parathyroid involvement and a relatively increased risk of parathyroid carcinoma. The penetrance of the disease is high but incomplete. Regardless of the denomination of the syndrome, jaw tumors occur rarely, while uterine involvement is frequently present. Selective parathyroidectomy may be an effective strategy, but a prolonged follow-up is required because of the risk of recurrences and malignancies. A systematic investigation is also required because of associated malignancies.
Familial isolated hyperparathyroidism (FIHPT) is a rare syndrome linked to HRPT2 mutations, with a variable extent of parathyroid involvement. Extensive parathyroidectomy is usually indicated, but single-gland involvement is often reported. Recently, loss of parafibromin expression (caused by HRPT2 inactivating mutations) has been suggested as a distinguishing feature of FIHPT. This study aimed to evaluate the extent of parathyroid involvement and parafibromin expression in FIHPT.
Twelve patients from 3 FIHPT families underwent bilateral neck exploration, selective excision of macroscopically enlarged parathyroids, and biopsy of the remaining glands. Parafibromin expression was evaluated and compared with that in normal parathyroids and in adenomas arising in sporadic hyperparathyroidism.
Pathology confirmed single-gland involvement in all cases (11 adenomas and 1 carcinoma). Limited parathyroidectomy achieved a cure in 91.6% (1 persistent case of parathyroid carcinoma). After a mean follow-up of 9.4 years, all remaining patients are disease free, although 3 underwent successful reoperation for single-gland long-term recurrence. Parafibromin expression was absent in all macroscopically affected glands from FIHPT patients, but present in normal parathyroids and in adenomas arising in sporadic hyperparathyroidism.
Loss of parafibromin expression is a distinguishing marker of parathyroid involvement in FIHPT. Single-gland involvement often occurs; limited parathyroidectomy is effective and achieves long disease-free periods.
Case:
A 40-year-old female presented with primary amenorrhoea at 17 years of age. She was tall at 98th centile for height with eunuchoidal body habitus. Her breast development was Tanner stage 3, pubic and axillary hair Tanner stage 4 with normal external genitalia. Her bone age was 13.4 years at a chronological age of 17.8 years. Gonadotrophins were elevated indicating primary ovarian failure. A diagnostic laparotomy revealed hypoplastic, infantile uterus with bilateral streak gonads. Chromosomal analysis showed a balanced reciprocal translocation 46X, t(X; 2) (q22 p13). She became pregnant by in vitro fertilization with egg donation at the age of 36 years. At 13 weeks of gestation, she presented with intractable vomiting. She had raised corrected serum calcium and parathyroid hormone concentrations consistent with the diagnosis of primary hyperparathyroidism (PHPT). She underwent parathyroidectomy at 24 weeks of gestation with removal of a large left inferior parathyroid adenoma which normalized her serum calcium. Multipoint linkage from a genome-wide screen has identified a region of suggestive linkage on chromosome 2p13.3-14 in some cases of familial isolated hyperparathyroidism (FIHP).
Conclusion:
To our knowledge, this is the first case of primary amenorrhoea due to reciprocal translocation involving chromosome 2 and the X chromosome associated with PHPT. PHPT in this case is most likely to be as a result of chromosome 2 involvement where a locus for FIHP has been identified. Identification of the gene involved on chromosome 2p13.3-14 will be of considerable interest.
Multiple endocrine neoplasia type 2 (MEN 2) is caused by RET proto-oncogene mutations and has a strong penetrance for medullary thyroid carcinoma (MTC). Subtypes are defined by the presence or absence of pheochromocytomas, hyperparathyroidism, and characteristic clinical stigmas. We hypothesize that specific RET mutations correlate with the MEN 2 phenotype and aggressiveness of MTC.
Review of endocrine surgery database from 1951 through 2002.
Tertiary referral center.
Eighty-six patients from 47 kindreds were identified with MEN 2A, MEN 2B, or familial MTC. Patients were classified into 3 RET mutation risk groups: level 1, low risk for MTC (codons 609, 768, 790, 791, 804, and 891); level 2, intermediate risk (codons 611, 618, 620, and 634); and level 3, highest risk (codons 883 and 918).
Stage of MTC at diagnosis and at last follow-up and frequency of pheochromocytomas and hyperparathyroidism.
RET analysis was complete for 71 patients from 39 kindreds. Multivariate analysis identified an increased likelihood of stage III or IV MTC at diagnosis with increasing age (odds ratio, 1.12 per year of age at thyroidectomy; 95% confidence interval, 1.07-1.17; P<.001) and increasing risk group (odds ratio, 14.23 per incremental increase in MTC risk group from 1 to 3; 95% confidence interval, 3.05-66.55; P<.001). Pheochromocytomas were found in 21 patients from 12 kindreds; 20 of 21 patients had codon 634 or 918 mutations. Hyperparathyroidism was found in 10 patients from 7 kindreds; 7 of 10 patients had codon 634 mutations.
Specific RET mutations predict the phenotypic expression of disease and the MTC aggressiveness in patients with MEN 2, guiding the timing of thyroidectomy and screening for pheochromocytoma.
Three-gland parathyroidectomy with trans-cervical thymectomy and cryopreservation is the preferred initial surgical approach for hyperparathyroidism (HPT) in patients with multiple endocrine neoplasia type 1.
Retrospective cohort study.
Tertiary referral center.
Thirty-seven patients with multiple endocrine neoplasia type 1 who underwent 1 or more surgical procedures for HPT from January 1, 1973 to April 30, 2004.
At initial parathyroid surgery, 16 (43%) of 37 patients had fewer than 3 parathyroid glands resected (group 1); 16 (43%) had at least 3 but fewer than 4 glands (group 2), and 5 (14%), 4 or more glands (group 3). Follow-up of at least 6 months after initial surgery was complete for 31 (84%) of 37 patients.
Recurrent HPT in patients with multiple endocrine neoplasia type 1 is frequent if fewer than 3 glands are removed at initial parathyroidectomy. Optimal surgical intervention must balance the risk of recurrent hypercalcemia with the morbidity of permanent hypoparathyroidism. Three-gland parathyroidectomy, transcervical thymectomy, and parathyroid cryopreservation constitute our preferred initial surgical procedure.
Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Associations between specific RET mutations (genotype) and the aggressiveness of MTC and presence or absence of other endocrine neoplasms (phenotype) are well documented. Mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains cause one of three distinctive clinical subtypes: familial MTC, multiple endocrine neoplasia (MEN) type 2A (including variants with Hirschsprung's disease and cutaneous lichen amyloidosis), and MEN 2B. Hallmarks of MEN 2A include MTC, pheochromocytoma, and hyperparathyroidism. MEN 2B is associated with an earlier onset of MTC and pheochromocytoma, the absence of hyperparathyroidism, and the presence of striking physical stigmata (e.g., coarse facies, ganglioneuromatosis, and marfanoid habitus). Familial MTC is not associated with other endocrine neoplasms; however, the accurate distinction between familial MTC and MEN 2A may be difficult in kindreds with small size, incomplete histories, or a predominance of young individuals who may not have yet fully manifested the syndrome. Genetic testing detects greater than 95% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and the extent of surgery are based upon a model that utilizes genotype- phenotype correlations to stratify mutations into three risk levels.
Familial isolated hyperparathyroidism (FIHP) is an autosomal dominantly inherited form of primary hyperparathyroidism. Although comprising only about 1% of cases of primary hyperparathyroidism, identification and functional analysis of a causative gene for FIHP is likely to advance our understanding of parathyroid physiology and pathophysiology.
A genome-wide screen of DNA from seven pedigrees with FIHP was undertaken in order to identify a region of genetic linkage with the disorder.
Multipoint linkage analysis identified a region of suggestive linkage (LOD score 2.68) on chromosome 2. Fine mapping with the addition of three other families revealed significant linkage adjacent to D2S2368 (maximum multipoint LOD score 3.43). Recombination events defined a 1.7 Mb region of linkage between D2S2368 and D2S358 in nine pedigrees. Sequencing of the two most likely candidate genes in this region, however, did not identify a gene for FIHP.
We conclude that a causative gene for FIHP lies within this interval on chromosome 2. This is a major step towards eventual precise identification of a gene for FIHP, likely to be a key component in the genetic regulation of calcium homeostasis.
We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.
Six multiple endocrine neoplasia (MEN) syndromes have received a level of attention that might seem disproportionate to their low prevalence. The attention has been given because their hormonal excesses cause striking metabolic expressions and because they might clarify pathways disrupted in more common tumours. The recent discovery of the main gene in each MEN syndrome has furthered our understanding of not only hereditary but also sporadic tumours and has fostered new avenues of research.
In 2003 we identified a family with familial hypocalciuric hypercalcemia (FHH) (heterozygous CASR gene mutation L173P) and a mutation in the pancreatic secretory trypsin inhibitor gene (SPINK1) (N34S). While family members with an isolated calcium-sensing receptor gene (CASR) mutation remained healthy, a combination of the CASR and SPINK1 gene mutation caused chronic pancreatitis (CP). We thus speculate that the combination of two genetic defects affecting calcium homeostasis and pancreatic enzyme activation might represent a novel approach in chronic inherited pancreatic disease. We therefore sought to explore whether CASR gene mutations were prevalent in a cohort of patients with CP and confirmed SPINK1 mutations.
A cohort of 19 families (n=170) with a history of idiopathic CP (ICP) was screened for mutations within the CASR gene; 104 members of that cohort had a mutation (N34S) within the SPINK1 gene and 66 of those were suffering from CP. The entire CASR gene was screened for single strand conformation polymorphism under varying polyacrylamide gel conditions and subjected to direct dideoxy nucleotide sequencing of amplified cDNA.
Single-strand conformation polymorphisms were observed in 59 samples, clustering of exons 3, 4 and 7. DNA sequence analysis revealed a yet unreported missense mutation in exon 7 (R896H) and two conservative mutations in exon 4 (F391F) and exon 7 (E790E). Furthermore, an intronic polymorphism in nucleotide position 493-19 G>A was detected in 19 out of 170 members of that cohort.
We identified three novel calcium-sensing receptor gene mutations (1 missense mutation, 2 silent mutations and 1 intronic polymorphism) in a cohort of 19 families with ICP. In particular, the kindred with the R896H mutation presenting with a similar pedigree to the family described above may indicate a role for CASR gene mutations in SPINK1-related CP. Again, only the patient with the combination of both CASR and N34S SPINK1 gene mutation developed pancreatitis, whereas in the healthy parents and children only an isolated CASR or N34S SPINK1 gene mutation could be detected. We suggest that the CASR gene is a novel yet undetected co-factor in a multifactorial genetic setting of SPINK1-related pancreatitis that alters the susceptibility for pancreatitis in these patients.
In patients with sporadic hyperparathyroidism (HPT), radioguided parathyroidectomy (RGP) has been shown to facilitate intraoperative localization of parathyroid glands, reduced operative time, and improve patient outcomes. No studies have focused on the role of RGP in patients with familial HPT.
Between 3/01 and 6/05, 419 patients underwent RGP. Nineteen had familial HPT, including 12 with Multiple Endocrine Neoplasia (MEN), and 94 had sporadic HPT with parathyroid hyperplasia. All patients were injected with sestamibi pre-operatively and a gamma probe was used intraoperatively. Radiotracer counts were recorded prospectively.
In patients with familial HPT, the gamma probe detected all abnormal parathyroid glands with a mean in vivo radiotracer count of 157 +/- 9% above background. Importantly, 5 patients (25%) had ectopic parathyroid glands localized by the probe in the thymus, thyroid and retroesophageal region. All resected hyperplastic parathyroid glands had ex vivo counts > 20%. All patients were cured after surgery with mean calcium and parathyroid hormone levels of 9.4 +/- 0.1 mg/dl and 31 +/- 7 pg/ml, respectively, and a mean hospital stay of 0.7 +/- 0.1 days. In comparing the 2 groups, while patients with familial HPT had lower pre-operative parathyroid hormone levels, the ex vivo radiotracer counts were significantly higher.
RGP in patients with familial HPT is technically feasible and perhaps more sensitive than in patients with sporadic hyperplastic disease. The gamma probe efficiently localized all parathyroid glands including those in ectopic locations, and resulted in high cure rates and short hospital stays. RGP is a viable and useful technique in patients with familial HPT.
E-mail: devans@mdanderson.org Published by Springer Science+Business Media, Inc. Ó 2007 The Society of Surgical Oncology
- M D Evans
Evans, M.D.; E-mail: devans@mdanderson.org Published by Springer Science+Business Media, Inc. Ó 2007 The Society of Surgical Oncology, Inc. Annals of Surgical Oncology 14(5):1525)1527 DOI: 10.1245/s10434-006-9282-7 REFERENCES
Medullary thyroid cancer: the importance of RET testing
- Db Evans
- Se Shapiro
- Gj Cote