Langenbeck's Archives of Surgery

, Volume 394, Issue 5, pp 817–825 | Cite as

Hyperparathyroidism–jaw tumor syndrome: a report of three large kindred

  • Maurizio Iacobone
  • Giulia Masi
  • Luisa Barzon
  • Andrea Porzionato
  • Veronica Macchi
  • Francesco Antonio Ciarleglio
  • Giorgio Palù
  • Raffaele De Caro
  • Giovanni Viel
  • Gennaro Favia
Current concepts in Endocrine Surgery

Abstract

Background

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.

Methods

Clinical, histopathological, and genetic features of three large Italian unrelated HPT–JT kindred were assessed.

Results

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.

Conclusions

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.

Keywords

HPT–JT Jaw tumor HRPT2 Parafibromin Parathyroid carcinoma 

Introduction

Primary hyperparathyroidism (HPT) is a common endocrine disorders, which arises sporadically in most cases; it may occur in a familial setting in a minority of cases (<10%) [1,2], mostly associated with other endocrine neoplasms, including multiple endocrine neoplasia (MEN) type 1 or 2. Less frequently, familial HPT may be found without MEN, as HPT–jaw tumor syndrome (HPT–JT) [3, 4, 5].

HPT–JT (OMIM #145001) is an autosomal dominant syndrome with incomplete penetrance and variable expression, characterized by multiple parathyroid tumors occurring at an earlier age, with a relatively high prevalence of carcinomas and atypical adenomas, ossifying fibromas of mandible and/or maxilla, and less frequently, a variety of renal lesions (hamartomas, polycystic disease, Wilms tumors, and adenocarcinomas) and uterine tumors [3,5]. HPT–JT has been recently linked to germ-line inactivating mutations in the tumor suppressor gene HRPT2 [3,6], which encodes for the Parafibromin, a ubiquitously expressed protein with antiproliferative properties [7]. Several reports have demonstrated a loss of Parafibromin expression in HPT–JT related adenomas and in sporadic parathyroid carcinoma carrying somatic HRPT2 mutations [8, 9, 10].

Because of its rarity, few studies have specifically evaluated HPT–JT; in most cases, it has been described (and sometimes confused) together with other familial variants of HPT.

This paper was aimed to describe the clinical, genetic, and histopathological features of three large unrelated Italian kindred with HPT–JT, at a long-term follow-up.

Materials and methods

The study population consisted of three large HPT–JT families, including 96 subjects from three to five generations (Fig. 1), which were evaluated at the Endocrine Surgery Department of the University of Padua and previously published in part [11,12]. Informed consent for collection of personal, genetic, and clinical data was obtained from all patients.
Fig. 1

AC Pedigrees of the families with HPT–JT. Square symbols indicate males, and round symbols indicate females. A diagonal slash mark through the symbol means deceased. The generations are labeled in Roman numerals, and the individuals within each generation are designated with Arabic numerals. Filled quadrants indicate a diagnosis or history of the trait indicated in the legend. The sign on the upper right of the symbol marks the subjects that have been tested for germ-line HRPT2 mutations: the plus signs indicate the presence of a HRPT2 mutation; the minus signs indicate the absence of the mutation

HPT–JT was diagnosed according to clinical and genetic criteria in case of presence of primary HPT (hypercalcemia, inappropriate intact parathormone (iPTH) levels, normal or increased urinary calcium with normal renal function) in at least two subjects in the same kindred; evidence of abnormal parathyroid glands at histology in at least one case; absence of MEN 1 or MEN 2 determined by negative personal clinical and family history, genetic analysis, and laboratory tests, including evaluation of pancreas, pituitary, adrenals, and thyroid C cells component; and presence of germ-line HRPT2 mutations [2].

Germ-line HRPT2 mutation analysis was performed as described elsewhere [6,12]. In- and out-patient medical records were reviewed for details of operative and pathology reports and the postoperative course; complete follow-up data were obtained by clinical and laboratory re-evaluation or personal telephone interview designed to elicit all information regarding the patient’s current state of health, the most recent laboratory findings, and the presence of other eventually affected relatives. Screening for tumors used orthopantomographic X-rays and/or computed tomography (CT) of the mandible and maxilla. Evaluation of the kidneys used standard ultrasound, abdominal magnetic resonance imaging, or CT scan. Uterine abnormalities were assessed by standard ultrasound and/or hysteroscopic examination and eventually confirmed at biopsy.

Complete bilateral neck exploration with selective excision of grossly abnormal parathyroids and eventual biopsies of the normal appearing glands was performed in all patients. Cure was defined as postoperative normalization of serum calcium and iPTH levels for at least 6 months; persistent disease was defined as HPT occurring within 6 months after parathyroidectomy; recurrent disease was defined as HPT occurring after surgery followed by cure for at least 6 months.

The histological diagnosis was confirmed according to the WHO guidelines [13]. The diagnosis of adenoma was based on the finding of a typical encapsulated lesion consisting of small uniform cells arranged with a delicate capillary network, with a rim of normal or atrophic parathyroid tissue evident outside the capsule. Parathyroid cancer was defined by a trabecular arrangement of tumor cells, divided by fibrous bands, mitoses, and capsular blood vessels and/or surrounding soft tissue invasion. Atypical adenoma was defined by the presence of features of malignancy without vascular and adjacent soft tissue invasion.

Parafibromin expression was evaluated and compared by immunohistochemical staining on formalin-fixed and paraffin-embedded specimens from nine abnormal parathyroids (one carcinoma and eight adenomas), three biopsies of normal parathyroids surgically removed from HPT–JT patients, and on endometrial hyperplastic polyps from a HPT–JT patient, as previously described [7,12]. Anti-parafibromin immunohistochemistry was also performed on a control group composed of 10 histologically confirmed normal parathyroids (accidentally removed at the time of thyroid surgery for benign diseases from patients without clinical and biochemical evidence of HPT), 24 parathyroid adenomas from patients with sporadic HPT (according to a negative personal and familial history), and five sporadic endometrial hyperplastic polyps from age-matched patients, in all cases without germ-line HRPT2 mutations. Slide sections were examined by scanning the entire tissue specimen under low-power magnification (×5); the findings were later confirmed at higher-power magnification. Immunohistochemical evaluation focused on the number of cells positive for nuclear staining.

Statistical analysis was performed using Fisher’s exact test, Mann–Whitney U test, Wilcoxon signed rank test, and Spearman’s correlation test, as appropriate. Differences were considered statistically significant at p < 0.05.

Results

Forty-four subjects underwent a clinical examination and/or genetic assessment (Fig. 1). Three different germ-line mutation of the HRPT2 gene were identified. A frameshift mutation in exon 6 (c.433_442delinsAGA) was found in eight out of the 14 genetically investigated subjects in the kindred A, a missense c.188T>C transition in exon 2 (resulting in the substitution Leu63Pro) was found in seven out of the 19 subjects in the kindred B, and a five-nucleotides deletion in exon 2 (c.136_144 del5) was found in two out of the four subjects in kindred C.

Clinical and/or genetic features of the disease were detected in 23 patients (six men and 17 women; median age 45.1 years, range 11–78; Table 1). To date, six subjects (median age 17, range 13–62) have no clinical manifestations of the disease and are considered healthy mutation carriers; all the remaining patients suffered from HPT, excluding a patient (C/II-2) who died at 67 years because of metastatic renal carcinoma, because of lack of data concerning parathyroid involvement. A significant correlation between age and the presence of clinically evident disease was found (r = −0.43, p = 0.039). HPT was diagnosed at a mean age of 36.3 (range 11–71). No significant differences were found between affected subjects and unaffected carriers of HRPT2 mutations concerning sex (p = NS), although age tended to be younger in healthy subjects (p = 0.058) and HPT occurred in 87.5% of cases among patients older than 20 years. In affected patients, median total serum calcium and PTH levels were 3.02 mmol/L (range 2.64–4.48) and 120 pg/mL (range 57–1,128), respectively, and were strongly correlated (r = 0.81; p = 0.002).
Table 1

Demographics, clinical and laboratory features of patients from HPT–jaw tumor families

Family/patient

Sex/age (years)

HPT, age at diagnosis (years)

Calcemiaa (mmol/L)

PTHb (pg/mL)

Parathyroid tumors (number and pathology)

Gland size (mm)

Surgical outcome and current status (length of follow-up)

Associated diseases

A/I-1

M/59c

56

4.12

313

1 carcinoma

40

Persistent HPT

Papillary thyroid carcinoma

Deceased (2.5 years)

A/II-1

M/51

30

2.74

73

1 atypical adenoma

40

Cured (21 years)

Multinodular goiter

A/II-2

F/50

18

2.80

NA

1 adenoma

20

Cured

Jaw tumor; uterine polyposis

46d

2.65d

57d

1 adenomad

10d

Recurrence after 27 years

Papillary thyroid carcinoma;

After reoperation: cured (4 years)

Colon adenocarcinoma

A/II-3

F/47

42

2.64

78

1 adenoma

15

Cured (5 years)

Uterine polyposis

A/II-5

F/42

21

3.30

116

1 adenoma

35

Cured

Uterine polyposis

30d

2.90d

120d

1 adenomad

15d

Recurrence after 9 years

After reoperation: cured (12 years)

A/III-2

F/19

11

4.48

1,128

1 adenoma

30

Cured (8 years)

A/III-4

M/22

Healthy mutation carrier

A/III-6

M/16

Healthy mutation carrier

A/III-9

F/17

Healthy mutation carrier

B/III-7

F/64

44

3.00

151

1 adenoma

20

Cured (20 years)

B/III-11

F/52

32

3.43

255

1 adenoma

30

Cured (20 years)

B/IV-3

F/45

38

2.90

155

1 adenoma

12

Cured (7 years)

Uterine polyposis

B/IV-4

F/44

25

3.15

211

1 adenoma

20

Cured

Uterine polyposis

29d

4.01d

280d

1 adenomad

10d

Recurrence after 5 years

Thyroid adenoma

After reoperation: cured (14 years)

B/II-3e

F/77

52

NA

NA

1 adenoma

NA

Cured (25 years)

Uterine polyposis

B/IV-2e

M/47

43

NA

NA

1 adenoma

NA

Cured (4 years)

B/V-2

F/17

Healthy mutation carrier

B/III-8

F/62

Healthy mutation carrier

B/IV-22

F/13

Healthy mutation carrier

C/III-1

F/45

38

2.89

103

1 adenoma

30

Cured (6 years)

Uterine polyposis

C/IV-1

F/28

23

3.24

81

1 adenoma

20

Cured (6 years)

C/III-5e

F/47

37

NA

NA

1 adenoma

NA

Cured (9 years)

Uterine polyposis

C/II-4

F/78

71

3.05

94

Not operated

NA

Persistent HPT

Chronic lymphatic leukemia

C/II-1e

M/67c

NA

NA

NA

NA

Deceased

Renal adenocarcinoma

F female, M male, NA not available, HPT hyperparathyroidism

aTotal serum calcium at diagnosis, normal values 2.10–2.60 mmol/L

bPTH at diagnosis, normal values 15–65 pg/mL

cDeceased

dAt HPT recurrence

eOperated elsewhere

In all operated patients, a single parathyroid involvement requiring selective excision was found at neck exploration. Cure was achieved by limited parathyroidectomy in 16 patients (93.3%); HPT persisted only in a patient with suspected parathyroid carcinoma (A/I-1), despite of “en bloc” parathyroidectomy and thyroid lobectomy (Fig. 2). The remaining patients remained disease free during a mean period of 12.3 years (range 4–27). A recurrent HPT occurred in three patients at 5, 9, and 27 years after successful initial surgery; a metachronous single-gland involvement was found at reoperation. Cure was achieved again by selective excision of the abnormal parathyroid; to date, all these patients are disease free at a follow-up of 14, 12, and 4 years, respectively.
Fig. 2

Parathyroid carcinoma: en bloc parathyroidectomy and thyroid lobectomy

Pathology confirmed the diagnosis of parathyroid carcinoma in the patient A/I-1 (who died 2.5 years later because of metabolic complications of the metastatic disease, as previously described) [14,15] and atypical adenoma in the patient A/II-1; in all the remaining patients, including recurrent cases, typical adenomas were diagnosed; the latter were significantly smaller than carcinoma and atypical adenomas (mean size 19.5 mm versus 40 mm; p < 0.0001). No significant differences concerning the location of the affected glands (superior versus inferior) were found (p = NS); an ectopic location was detected in three cases (two intrathymic and one supernumerary parathyroid in the carotid sheath.)

An ossifying fibroma of the jaw was diagnosed and excised in a patient at the age of 26 years (A/II-2; Fig. 3). Renal involvement (adenocarcinoma) was detected only in a patient (C/II-1). Uterine involvement (multiple recurrent endometrial polyps requiring surgery) was detected in eight women (61.5% of affected females). Other associated disease were two cases of multifocal papillary thyroid carcinoma (pT1N0M0; surgery performed at 56 and 46 years, respectively), two cases of benign thyroid disease (surgery performed at 30 and 29 years, respectively), one case of left colon carcinoma (pT2N1M0; surgery performed at 42 years), and chronic lymphatic leukemia (diagnosed at the age of 70 years).
Fig. 3

Orthopantomographic X-ray: ossifying fibroma of the left mandibular ramus

Anti-parafibromin nuclear immunostaining was virtually absent in almost all tumor cells from parathyroid carcinoma and parathyroid adenomas from HPT–JT patients; at variance, intense nuclear immunostaining (>90% of parathyroid cells) was present in all biopsies from normal parathyroids obtained at surgery from HPT–JT patients (Fig. 4). Parafibromin nuclear staining was also strongly positive in all parathyroids from control group (both normal glands and sporadic adenomas).
Fig. 4

Immunohistochemical analysis of Parafibromin expression in HPT–JT parathyroids. a Normal parathyroid showing strong and diffuse nuclear immunostaining. b Parathyroid adenoma showing loss of positivity in the same HPT–JT patient. Scale bars 37.5 μm

In the HPT–JT-related uterine polyp, stromal and epithelial cells had negative nuclear immunostaining, whereas strong and diffuse positive nuclear anti-parafibromin immunostaining was evident in both epithelial and stromal cells in the five sporadic uterine polyps from the control group (Fig. 5).
Fig. 5

Immunohistochemical analysis of Parafibromin expression in uterine polyps. a Sporadic uterine polyp showing nuclear immunostaining in stromal and epithelial cells. b HPT–JT-related uterine polyp showing loss of nuclear immunoreactivity. Scale bars 75 μm

Discussion

HPT–JT is considered a rare variant of familial HPT; it was first described in 1990 [5], but the genetic marker has been identified only in 2002 [3]; for these reasons, its real incidence is still unknown and might be possibly underestimated. Our study focused on three large kindreds and, to the best of our knowledge, is one of the largest series from a single center. We confirmed the role of germ-line HRPT2 mutations in HPT–JT; all the reported mutations predicted to result in truncated or inactive Parafibromin, in agreement with its tumor suppressor activity. The frameshift mutation c.433_442delinsAGA in the kindred A (which predicts an alteration of the reading frame with a premature truncation at codon 201) and the five-nucleotides deletion of the kindred C (c.(136_144)del5, which determines a frameshifting that leads to formation of a stop codon at residue 62), result in truncated forms of Parafibromin. The Leu63Pro missense mutation of the kindred B changes a conserved hydrophobic leucine at codon 63 with helix breaker proline, possibly causing a significant alteration in the structure of Parafibromin and impairing its activity.

These data were further confirmed by immunostochemical analysis of the Parafibromin expression since we demonstrated a significant loss of expression in all pathological tissues from HPT–JT patients, suggesting that the absence of Parafibromin expression may be considered a distinguishing feature of HPT–JT-related tumors [8,11].

Parafibromin immunostaining, a rather simple and inexpensive diagnostic test, may represent a cost-effective strategy for first-line evaluation of parathyroid tumors in case of suspected familial non-MEN HPT, but also in unusual case of atypical parathyroid tumors and in very young patients, even with apparently sporadic HPT. It may be a guide for selecting patients and relatives for HRPT2 screening, which is expensive and not ubiquitously available [8,16].

The typical feature of the syndrome (the ossifying jaw tumors) occurred only in one case in the present series. We performed a review of the most recent literature (papers published since the identification of the putative gene in 2002 to date, and focusing on HRPT2-related HPT) [2, 3, 4,6,9,10,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]; at least 245 cases from 63 families have been reported; mandibular or maxillary involvement has been reported only in 27.5% of cases (Table 2). Since the jaw tumor is evident only in a minority of cases, this disease might be named “HRPT2-related HPT”, according to genetic criteria instead of clinical ones [35]. In fact, in absence of a personal or family history of jaw tumor, the disease might be misdiagnosed.
Table 2

Revision of the literature focusing on HRPT2-related HPT (period 2002–2009)

Reference

Family (n)

Affected patients (n)

Healthy mutation carriers (n)

Single-gland involvement (n)

Synchronous multiglandular involvement (n)

Recurrencesa (n)

JT (n)

PC (n)

R (n)

U (n)

Carpten [3]

8

41

4

NA

NA

NA

12

7

12

NA

Shattuk [6]

3

3

NA

NA

NA

NA

NA

3

NA

NA

Howell [17]

3

7

NA

NA

NA

0

0

3

0

NA

Simonds [18]

1

4

0

4

0

0

0

1

0

NA

Cetani [2]

2

4

NA

3

1

NA

0

0

0

NA

Villablanca [19]

2

9

5

4

2

3

0

0

0

NA

Cavaco [20]

6

11

19

5

1

0

2

0

2

3

Howell [21]

1

2

NA

2

0

NA

1

0

NA

NA

Gimm [22]

1

3

NA

1

1

1

NA

1

NA

NA

Bradley [4]

10

46

12

NA

NA

NA

20

9

6

17

Moon [23]

1

2

0

2

0

NA

1

2

NA

NA

Mizusawa [24]

3

7

0

6

0

1

1

1

0

0

Aldred [25]

1

3

NA

3

0

0

2

0

NA

NA

Bradley [10]

5

5

NA

4

1

NA

2

0

0

1

Juhlin [9]

1

1

NA

11

NA

NA

NA

0

NA

NA

Guarnieri [26]

1

4

7

4

NA

1

NA

1

0

2

Kelly [27]

1

3

5

0

1

2

NA

2

NA

NA

Yamashita [28]

1

1

0

1

0

0

1

0

NA

NA

Cetani [29]

1

1

0

1

0

1

0

0

0

NA

Cetani [30]

2

3

NA

NA

NA

NA

NA

3

NA

NA

Raue [31]

1

2

1

1

1

NA

1

1

NA

NA

Cetani [32]

1

1

1

1

0

NA

0

1

NA

NA

Sarquis [16]

3

11

3

5

6

6

1

1

2

5

Guarnieri [33]

3

3

10

3

0

0

0

2

3

3

Howell [34]

1

1

NA

1

0

0

NA

NA

NA

NA

Totalb

63

178

67

89%

13.2%

22.3%

27.5%

24.3%

16.3%

60%

Present seriesb

3

17

6

82.4%

0%

17.6%

5.9%

11.8%c

5.9%

61.5%

NA not available, JT jaw tumor, PC parathyroid carcinoma, R renal involvement, U uterine involvement

aCases with parathyroid carcinoma have been excluded

bResults are expressed as number or percentage

cIncluding an atypical parathyroid adenoma

HPT is the most frequent clinical feature of HPT–JT, with high but incomplete expression; in our series, it occurred in 70% of HRPT2 mutated subjects; to date, six subjects are still considered unaffected mutation carriers. However, the presence of a clinically evident disease was significantly related with age, and subsequently, the expression of HPT is likely to increase during a long-term follow-up. However, HPT may occur at an earlier age; in our experience, it was diagnosed at a mean age of 36 years, although the youngest patient underwent surgery at 11 years.

HPT–JT has been classically described as a more aggressive disease with frequent multiglandular involvement (45–75%), increased risk of persistence and recurrences (20–50%), and parathyroid carcinoma (10–40%) compared with sporadic HPT [4,22,36,37], suggesting extensive parathyroidectomy, but these data derive from mixed populations of patients possibly, including misdiagnosed cases of MEN, as the majority of these studies were conducted before the identification of the HRPT2 gene. Following the identification of HRPT2 mutations, an increasing number of cases of single-gland involvement, a lower recurrence rate, a lower risk of parathyroid carcinoma, and long-term cure after limited parathyroidectomy have been reported [38,39]; however, the optimal treatment remains controversial.

The most recent literature [2, 3, 4,6,9,10,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34] reports a single-gland involvement in 89%, with a synchronous multiglandular involvement confirmed only in 13.2% and recurrences in 22.3% of cases (Table 2), although data are scarce, often incomplete, and derive from small sized series and case report. In our series, we found a single-gland involvement in all operated patients at each surgical procedure; recurrent HPT occurred in 17.6%, after a long disease-free period (mean 13.7 years); in all cases, recurrences involved a single gland, and cure was achieved again at reoperation by selective parathyroidectomy. Furthermore, limited parathyroidectomy achieved a long-term cure (mean of 12.3 years after initial surgery and 10 years after reoperation, ranging between 4 and 27 years).

Single-gland involvement was further confirmed by immunohistochemical analysis of Parafibromin expression that was uniformly lost in all investigated parathyroid tumors from HPT–JT patients, but not in normal parathyroids from the same subjects, supporting the hypothesis that HRPT2 is an oncosuppressor gene and that biallelic inactivation is required for tumor development, according to Knudson’s “two hit” theory. The rather low prevalence of multiglandular parathyroid involvement, either synchronous or metachronous, suggests that HRPT2 germ-line mutations might achieve a predisposition to the neoplastic progression; a second hit or other genetic or epigenetic events should be necessary to the development of parathyroid tumors [3,6,17].

For these reasons, limited parathyroidectomy might be an adequate procedure in HRPT2-related hyperparathyroidism, different from other familial variant of HPT, especially when preoperative imaging techniques localize concordantly a single affected gland [1,11]. In fact, a focused and minimally invasive parathyroidectomy might be proposed in these cases in the same setting of sporadic HPT, with the potential advantage of causing lower risk of hypoparathyroidism and minimal tissue trauma, facilitating reoperations in case of recurrent hyperparathyroidism. At variance, other authors have suggested extensive parathyroidectomy in order to prevent the risk of recurrences and parathyroid carcinoma [16,36,37]. Parathyroid malignancies may occur more frequently in HPT–JT; a rate of 24.3% has been reported by recent literature (Table 2) [2, 3, 4,6,9,10,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34], although it may be overestimated since most papers focused prevalently on parathyroid carcinoma. In our experience, parathyroid carcinoma and/or atypical adenoma occurred only in two patients; in these cases, affected glands were significantly larger than typical adenomas, confirming that size might be useful to suspect malignancy preoperatively also in these setting.

Other non-endocrine tumors may be present in HPT–JT patients. In the present series, uterine involvement was the second most common clinical feature (60% according to the literature) [2, 3, 4,6,9,10,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34] (Table 2). Some of these reported tumors (such as leyomiomas, endometrial hyperplasia, adenomyosis) are very common also in the general population; others (adenosarcomas, adenofibromas, multiple adenomyomatous polyps) are less frequent and possibly related to the syndrome [5]. Interestingly, most of these tumors appear to have a common embryological origin from the mesodermal Mullerian duct system. Furthermore, the absence of Parafibromin expression also in uterine polyps (in contrast with sporadic ones, as evident in our study) seems to support the pathogenetic role for HRPT2 mutations in HPT–JT-related uterine involvement.

Renal involvement may be found in 16.3% of HPT–JT patients [2, 3, 4,6,9,10,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34] (Table 2); at variance, we found only one case of kidney cancer; we also found two cases of multifocal papillary thyroid carcinoma, as also previously reported [3,4,20], although the exclusive finding of microscopic foci at a preclinical stage might be also considered an occasional finding during targeted neck investigation. Finally, we found a locally advanced colon carcinoma in a relatively young patient; this association has been previously reported only in one case [40]. Because of the risk of other tumors, a systematic, multidisciplinary, and prolonged follow-up is required.

In conclusion, HPT–JT is a rare disease related with inactivating mutations of HRPT2. Penetrance of mutations is high, but disease expression may be incomplete. Loss of parafibromin expression is a distinctive feature of the disease and may be used to select patients and relatives for further genetic analysis. The most common clinical presentation is primary HPT that may occur very early, with a frequent single-gland involvement and a relatively increased risk of parathyroid malignancy. Other non-endocrine tumors are also frequently diagnosed, such as uterine and renal neoplasms. Regardless of the denomination of the syndrome, jaw tumors may occur rarely. 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.

Notes

Acknowledgments

We thank the families that graciously agreed to participate in the study. The study was supported by a grant from University of Padua (no. 60A07-5808/09) to Maurizio Iacobone and by a grant from Istituto Superiore di Sanità (no. 526D/40).

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Maurizio Iacobone
    • 1
  • Giulia Masi
    • 2
  • Luisa Barzon
    • 2
  • Andrea Porzionato
    • 3
  • Veronica Macchi
    • 3
  • Francesco Antonio Ciarleglio
    • 1
  • Giorgio Palù
    • 2
  • Raffaele De Caro
    • 3
  • Giovanni Viel
    • 1
  • Gennaro Favia
    • 1
  1. 1.Endocrine Surgery Unit, Department of Surgical and Gastroenterological SciencesUniversity of PaduaPaduaItaly
  2. 2.Department of Histology, Microbiology and Medical BiotechnologiesUniversity of PaduaPaduaItaly
  3. 3.Department of Human Anatomy and PhysiologyUniversity of PaduaPaduaItaly

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