Endocrine DOI 10.1007/s12020-017-1318-1
ORIGINAL ARTICLE
Clinical profile of juvenile primary hyperparathyroidism: a prospective study Federica Saponaro 1 Claudio Marcocci1,2 Federica Cacciatore1 Mario Miccoli1 Elena Pardi1 Simona Borsari1 Gabriele Materazzi3 Paolo Miccoli3 Filomena Cetani2 ●
●
●
●
●
●
●
●
Received: 6 February 2017 / Accepted: 1 May 2017 © Springer Science+Business Media New York 2017
Abstract Introduction Juvenile primary hyperparathyroidism is uncommon and more symptomatic than the adult counterpart. The aim of this prospective monocentric study, conducted in a tertiary referral center, was to evaluate the clinical, biochemical, and densitometric data, and the outcome of a series of patients with juvenile primary hyperparathyroidism. Material and Methods The study group included 154 patients with sporadic and familial juvenile primary hyperparathyroidism, aged ≤40 years. Relative frequency of sporadic and familial forms, comparison of the clinical and biochemical characteristics, rate of cure after parathyroidectomy and the outcome of patients not undergoing surgery were evaluated. Results Familial cases (n = 42) were younger, less frequently females, and had milder disease compared to sporadic cases (n = 112). No difference was observed in biochemical and densitometric parameters. Among patients undergoing parathyroidectomy (n = 116), familial cases had a higher rate of multigland disease and a higher persistence/ relapse rate compared to sporadic cases (73 vs. 3.6% and 48.1 vs. 5.7%, respectively). Patients who did not undergo parathyroidectomy had stable clinical, biochemical, and densitometric parameters during follow-up
* Filomena Cetani
[email protected] 1
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
2
University Hospital of Pisa, Endocrine Unit 2, Pisa, Italy
3
Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
(median 27 months). Using the cut-off age of 25 years, there was no difference in clinical, biochemical and densitometric parameters between younger and older patients, with the exception of parathyroid hormone and phosphate, which were significantly lower and higher, respectively, in patients <25 years. Conclusions In conclusion, this prospective study shows that juvenile primary hyperparathyroidism is frequently a sporadic disease, with no difference in the biochemical phenotype between sporadic and familial forms. Patients with familial juvenile primary hyperparathyroidism have a milder clinical phenotype and higher rate of persistence/ recurrence after PTx than those with sporadic juvenile primary hyperparathyroidism. Keywords Young hyperparathyroidism Familial hyperparathyroidism MEN1 FIHP Nephrolithiasis ●
●
●
●
Introduction Primary hyperparathyroidism (PHPT) is commonly diagnosed in adults at an asymptomatic, uncomplicated stage [1]. It mostly occurs in the 6th decade, with a female/male ratio of approximately 3:1 [2], and an annual incidence in Europe between 87/100,000 person-year in Scotland in 2006 [3] and 16/100,000 person-years in Denmark in 2010 [4]. Conversely, PHPT is rare in infants, and uncommon in children and adolescents, with an estimated incidence of 2–5/100,000 person-year, without a gender predilection [5]. The first case of juvenile PHPT (J-PHPT) was reported in 1930 in a 12-year-old patient. Small retrospective series and case reports have since been described using different cutoff age to define J-PHPT [6–18]. In a recent meta-analysis a cut off of 25 years was chosen [19].
Endocrine
Most patients with J-PHPT typically present with moderate symptomatic hypercalcemia, nephrolithiasis, and bone disease [5]. It is unclear whether this symptomatic presentation reflects a true biologic difference between J-PHPT and adult PHPT or whether it might be due, at least in part, to the fact that, at variance with the adult counterpart, routine biochemical testing including serum calcium is rather infrequent in children and young subjects. No information is available on the prevalence of sporadic and familial forms of J-PHPT. A single parathyroid adenoma accounts for up to 80% of J-PHPT, the remaining being due to multigland hyperplasia and double adenomas. Approximately 50% of the cases with multigland disease are due to multiple endocrine neoplasia (MEN) type 1 (MEN1), 2 A and 4, hyperparathyroidism-jaw tumor syndrome and familial isolated hyperparathyroidism (FIHP) [20]. When a young patient presents with mild hypercalcemia the differential diagnosis should be made between J-PHPT and familial hypocalciuric hypercalcemic (FHH), a benign condition due to inactivating mutations of the calcium sensing receptor [21, 22]. In the present study, we prospectively evaluated a series of consecutive patients with J-PHPT to investigate the frequency of sporadic and familial forms, and compare among them the clinical and biochemical presentations, the rate of cure of parathyroidectomy (PTx) and the course of the disease in patients not undergoing surgery.
assumption that there might be latency between the onset of the disease and its diagnosis (being most cases either asymptomatic or overlooked because of the rarity of the disease). The diagnosis of PHPT was based on the finding of elevated ionized (>1.32 mmol/L) or albumin-corrected serum calcium [>10.2 mg/dL (2.55 mmol/L)], associated with increased [>65 pg/mL (65 ng/L)] or inappropriately normal parathyroid hormone (PTH). Between January 2006 and December 2014, 1100 consecutive patients with PHPT were referred to the Endocrine Unit 2 of the University Hospital of Pisa (Fig. 1). The Institutional Review Board approved the study; patients signed an informed consent.
Patients
In the present study, a cut-off age of ≤40 at diagnosis was chosen to define J-PHPT. This choice was based upon the
A case report form was used to record: gender, age at diagnosis, major PHPT features (hypercalcemic and neuropsychiatric symptoms, history of nephrolithiasis and/or previous fragility fractures), use of drugs affecting bone metabolism, familial history of PHPT and/or neuroendocrine tumors, and previous PTx. Sporadic J-PHPT (SJ-PHPT) was defined as follows: (i) no familial history of PHPT and neuroendocrine tumors; (ii) normal values of serum calcitonin, pituitary hormones and neuroendocrine markers and (iii) normal albumin-adjusted serum calcium (s-AlbCa) in the first-degree relatives. These data were available in all patients. The diagnosis of MEN1 was based on standard criteria [23]. The diagnosis of FIHP was based upon: (i) PHPT in the proband and at least one first-degree relative; (ii) abnormal parathyroid gland at histology in one family member; and (iii) absence of clinical manifestations other than related to PHPT.
Fig. 1 Flowchart of patient’s enrollment. *Diagnostic criteria for sporadic primary hyperparathyroidism (PHPT): (i) familial clinical history negative for PHPT, (ii) absence of familial PHPT features at physical examination; (iii) serum calcium in first-degree relatives in
the normal range. **Diagnostic criteria for familial isolated PHPT: PHPT and exclusion of other multiple endocrine neoplasia type 1associated features (neuroendocrine markers, calcitonin, pituitary hormones in the normal range at diagnosis and last follow-up visit)
Materials and methods Study design
Endocrine
Fasting blood samples were collected for measurement of total and ionized calcium, PTH, 25-hydroxyvitamin D, bone-specific alkaline phosphatase (BSAP), prolactin, growth hormone, insuline-like growth factor 1, Thyroidstimulating hormone, adreno cortico tropic hormone, cortisol, follicle-stimulating hormone, luteinizing hormone, insulin, gastrin, vasoactive intestinal peptide, glucagon, and serotonin. In addition, 24-h urinary calcium excretion was measured. Bone mineral density (BMD) at lumbar spine, femur and one-third distal radius were measured by dual-energy x-ray absorptiometry (DXA) at baseline and at last follow-up visit. Laboratory methods Serum calcium, albumin and 24-h urinary calcium were measured using standard methods. Ionized calcium, plasma PTH, serum BSAP, serum osteocalcin were measured as previously described [24, 25]. 25(OH)D was measured by RIA (DiaSorin) until September 2013 and CLIA (IDS ISYS) up to the end of the study. Intraoperative PTH (iPTH) was measured in patients with SJ-PHPT using a quick PTH assay performed as previously described [26]. A decline of PTH > 50% compared to the higher pre-excision value was considered as a proof that all hyperfunctioning parathyroid tissue was removed.
used to compare continuous and non-parametric variables, respectively. Chi-square and Fisher tests were used for comparison of categorical variables, as appropriate. A P value ≤0.05 was considered statistically significant. Statistical analysis was carried out using “SPSS Statistics 17.0.1(Chicago, Illinois, USA) and R 3.0.2 (Auckland, New Zealand).
Results One hundred and sixty (14.5%) of the 1100 patients with PHPT met the diagnostic criteria of J-PHPT. Six patients were excluded from the study because of the diagnosis of FHH (n = 3) or refusal to participate (n = 3) (Fig. 1). The study group included 154 patients, 114 (74.0%) females and 40 (26.0%) males (female to male ratio of 2.8:1), with a mean age of 32 ± 7 years (range 12–40 years). One hundred twelve (72.7%) patients were classified as SJPHPT and 42 (27.3%) as FJ-PHPT (Fig. 1). The clinical, biochemical and densitometric characteristics of the whole study group are summarized in Tables 1 and 2. Serum calcium, osteocalcin, BALP, and 24-h urinary calcium were slightly, but significantly higher and one-third distal radius z-score significantly lower in males than in females (Table 2).
BMD
Sporadic J-PHPT (n = 112)
BMD was measured by DXA (QDR-4500; Hologic Inc., Waltham, MA) at the lumbar spine (L1–L4, antero-posterior), proximal femur, and nondominant forearm. The coefficients of variations were 1.1% at lumbar spine, 1.2% at femoral neck, 1.4% at one-third distal radius. Results are expressed as mean ± SD and z-score. In patients aged ≤23 years z-score was calculated with BMDCS z-score calculator (https://bmdcs.nichd.nih.gov/zscore.htm) for young patients. Low BMD was defined by z-score lower than −2.
This group included 88 (78.6%) females and 24 (21.4%) males (F:M = 3.6:1), with a mean age of 33.3 ± 6.7 years (range 12–40 years). PHPT was diagnosed in 64 (57.1%) patients because of the presence of classical manifestations of the disease (nephrolithiasis, either symptomatic or incidentally detected at ultrasound, n = 62, or previous clinical fragility fractures n = 4) and incidentally discovered in 48 (42.9%) by routine biochemical testing. The clinical, biochemical, and densitometric data at baseline are summarized in Table 1. Low BMD (z-score < −2) was found at lumbar spine in 21 patients (18.7%), femoral neck in 17 (15.2%) and one-third distal radius in 17 (15.2%). No difference in any other parameter was found between males and females (data not shown). Patients with nephrolithiasis (n = 62) had significantly higher total and ionized calcium concentrations (11.15 ± 0.94 vs. 10.84 ± 0.9 mg/dL P < 0.01 and ionized calcium 1.53 ± 0.12 vs. 1.46 ± 0.12 mmol/L P < 0.001, respectively), and PTH levels [138 (85,184) vs. 101 (69,169) pg/ mL, P = 0.047] compared with those without nephrolithiasis (n = 50). No statistically significant difference was found between the two groups in 24-h urinary calcium (382 ± 153 mg in patients with nephrolithiasis vs. 359 ± 156 mg
Statistical analysis Sample size was calculated to reveal significant differences between sporadic and familial forms of J-PHPT (primary end-point) in the biochemical parameters. The sample size was estimated in 90 patients, with an unequal allocation ratio of 9/1, according to the literature ratio Sporadic/ Familial forms (N1 = 81 N2 = 9) [27] with 80% power (b = 0.20) and type I error of 5% (a = 0.05). The Shapiro–Wilk test was performed to check normality of distributions. Results are expressed as means ± SD for continuous variables and median (interquartile range) for serum PTH. The student and the Mann–Whitney tests were
Endocrine Table 1 Clinical, biochemical and densitometric data of patients with juvenile PHPT and comparison between sporadic and familial cases Whole group (n = 154)
Normal range
Sporadic (n = 112)
Familial (n = 42)
P
Sex (F:M)
2.8:1
–
3.6:1
1.6:1
P = 0.036
Age at diagnosis (years)
32 ± 7
–
33.3 ± 7
29 ± 8
0.001
Serum calcium (mg/dL)
10.9 ± 1
8.6–10.2
11 ± 0.9
10.9 ± 1.1
0.3
Serum albumin adjusted calcium (mg/dL)
10.6 ± 1
8.6–10.2
10.6 ± 1.1
10.6 ± 1.2
0.7
Ionized serum calcium (mmol/L)
1.50 ± 0.1
1.13–1.32
1.49 ± 0.13
1.50 ± 0.16
0.8
Serum phosphate (mg/dL)
2.4 ± 0.56
2.7–4.5
2.4 ± 0.54
2.5 ± 0.61
0.3
Plasma intact PTH (pg/mL)
111 (78–171)
15–75
118 (80–174)
97 (71–161)
0.05
Serum 25OHD (ng/mL)
19.6 ± 10
30–100
17.7 ± 9.8
21.7 ± 12.4
0.2
Serum osteocalcin (ng/mL)
32.5 ± 25.2
6.8–34
33.2 ± 27.5
30.9 ± 19.1
0.9
Serum BSAP (µg/L)
23.2 ± 15.8
2–20
23.8 ± 16.2
21.9 ± 14.9
0.2
24-h Urinary calcium (mg/24 h)
376.7 ± 154
<300
372.2 ± 156.4
401.3 ± 230
0.2
–
Lumbar spine BMD (g/cm²)
0.93 ± 0.18
0.93 ± 0.18
0.94 ± .17
0.4
z-score
−1.08 ± 1.16
−1.06 ± 1.16a
−0.85 ± 1.26a
0.4
–
Femoral neck BMD (g/cm²)
0.74 ± 0.12
0.73 ± 0.17
0.78 ± 0.13
0.5
z-score
−0.98 ± 0.95
−1.02 ± 0.96
−0.87 ± 0.93
0.4
–
One-third distal radius BMD (g/cm²)
0.66 ± 0.19
0.67 ± 0.14
0.62 ± 0.23
0.6
z- score
−0.84 ± 1.31
−0.71 ± 1.34
−1.18 ± 1.27
0.07
Nephrolithiasis n (%)
77 (50%)
–
62 (55%)
15 (35.7%)
0.005
Clinical fractures n (%)
7 (4.5%)
–
4 (3.5%)
3 (2.6%)
0.5
Neuropsychiatric symptoms n (%)
49 (31.8%)
–
41 (36.6%)
8 (19%)
0.04
Low BMD (%)
27 (17.5%)
–
21 (18.7%)
6 (14.2%)
0.5
All value are mean ± standard deviation, with the exception of PTH (median and interquartile range) a
In patients aged ≤23 years z-score was calculated with BMDCS z-score calculator (https://bmdcs.nichd.nih.gov/zscore.htm) for young patients
in those without nephrolithiasis, P = 0.4) and densitometric parameters (data not shown). Parathyroid surgery was advised to all patients, but only 89 (79.5%) underwent PTx. In all but four patients, iPTH assay had a drop of 50%. compared to the highest preexcision value. The histological examination showed a single adenoma in 85 patients (95.6%), hyperplasia in 1 (1.1%), carcinoma in 2 (2.2%), and a lymphonode in one (1.1%). Four patients had persistent PHPT (1 hyperplasia, 2 adenomas, 1 “white cervicotomy” i.e., no parathyroid tissue was found during surgery and at histology). A >50% decline in iPTH occurred in two of the four cases with persistent PHPT, who were subsequently shown to have a double parathyroid adenoma. Patients, either those who underwent PTx or those who did not, were regularly followed at our Institution, with a median follow-up of 27 months (2–96) in the former group and 20 months in the latter (range 2–96). All but five patients underwent PTx, were cured after surgery and remained normocalcemic for the entire follow-up. Four patients had persistent PHPT (1 hyperplasia, 2 adenomas, 1 “white cervicotomy” i.e., no parathyroid tissue was
found during surgery and at histology). The remaining patient had a relapse of PHPT 4 years after PTx and is currently followed without surgery because of the mild disease. Seventeen of 23 patients who refused PTx showed no significant changes in serum calcium, PTH, and BMD at any site during follow-up (Table 3). The remaining six patients refused further evaluations. Familial J-PHPT (n = 42) This subgroup included 26 (61.9%) females and 16 (38.1%) males, (F:M = 1.6:1), with a mean age of 29 ± 8 years (range 12–40 years). PHPT was diagnosed in the index cases (n = 19) for the presence of symptomatic nephrolithiasis in 14 (73%) or incidentally discovered hypercalcemia in 5 (27%) and in the remaining 23 cases during the familial screening. Eight patients (19.0%) complained of neuropsychiatric symptoms upon questioning (fatigue, depression, agitation, apathy, lack of concentration). The whole cohort of patients with J-PHPT included 31 patients with MEN 1 (13 kindreds) and 11 with FIHP (9 kindreds). Patients with MEN1 had other syndromic manifestations:
Endocrine Table 2 Clinical, biochemical and densitometric data (mean ±SD) of males and females patients with juvenile PHPT
Normal range Males (n = 40)
Females (n = 114) P
Age at diagnosis (years)
–
30.5 ± 7
32.7 ± 7
0.1
Serum calcium (mg/dL)
8.6–10.2
11.2 ± 0.6
10.9 ± 1.0
0.04
Serum albumin adjusted calcium (mg/ 8.6–10.2 dL)
10.9 ± 1.25
10.5 ± 0.99
0.03
Ionized serum calcium (mmol/L)
1.13–1.32
1.52 ± 0.04
1.48 ± 0.13
0.03 0.7
Serum phosphate (mg/dL)
2.7–4.5
2.3 ± 0.6
2.4 ± 0.5
Plasma intact PTH (pg/mL)
15–75
115.2 (75–173)
107.8 (85–149)
0.1
Serum 25OHD (ng/mL)
30–100
19.1 ± 12.1
19.7 ± 9.3
0.7
Serum osteocalcin (ng/mL)
6.8–34
37.8 ± 16.7
31.9 ± 29.4
0.04
Serum BSAP (µg/L)
2–20
27.8 ± 12.9
23.4 ± 17.7
0.02
24-h Urinary calcium (mg/24 h)
<300
418 ± 145.9
348.2 ± 141.5
0.03
Lumbar spine
–
BMD (g/cm²)
0.89 ± 0.18
0.95 ± 0.17
0.9
z-score
−1.27 ± 1.4
−1.04 ± 1.07
0.2a
Femoral neck
–
BMD (g/cm²)
0.76 ± 0.12
0.78 ± 0.12
0.3
z-score
−0.94 ± 0.94
−0.99 ± 0.95
0.7a
One-third distal radius
–
BMD (g/cm²)
0.64 ± 0.21
0.71 ± 0.07
0.05
z-score
−1.34 ± 1.62
−0.53 ± 1.31
0.002a
Nephrolithiasis n (%)
–
21 (52%)
58 (50.8%)
0.5
Clinical fractures
–
3 (7.5%)
4 (3.5%)
0.2
a In patients aged ≤23 years z-score was calculated with BMDCS z-score calculator (https://bmdcs.nichd.nih. gov/zscore.htm) for young patients
pituitary adenomas (n = 6), neuroendocrine gastro-enteropancreatic tumors (n = 24), lung well-differentiated neuroendocrine tumors (n = 2), multiple cutaneous or visceral lipomas (n = 8), and angioma (n = 1). Patients diagnosed at familial screening were younger and had a significantly lower serum calcium concentration, compared to index cases (data not shown). The clinical, biochemical and densitometric data are summarized in Tables 1 and 2. Low BMD was found at lumbar spine in six patients (14.2%), femoral neck in 1 (2.4%) and one-third distal radius in 1 (2.4%). There was no statistically significant gender difference in all parameters (data not shown). Nineteen of 31 (61.3%) patients with MEN1 underwent PTx. The surgical strategy consisted in bilateral neck exploration with: (i) subtotal PTx was performed when 4 or more identified parathyroid glands were abnormal, and (ii) excision of enlarged gland/s when other parathyroid glands were judged as normal or not found. Thyroid surgery was also performed in two patients with a concomitant thyroid nodule with suspicious fine needle aspiration cytology. Parathyroid histology showed a single adenoma in four patients (21.1%) and hyperplasia in 15 (78.9%). Eight of 11 (72.7%) patients with FIHP underwent cervical exploration, using the same strategy described for
patients with MEN 1. The histological examination showed a single adenoma in 3 patients (37.5%) hyperplasia in 4 (50%), and a thyroid nodule in one (12.5%). All MEN1 and FIHP patients who underwent PTx were followed at our Institution, with a median follow-up of 27 months (2–97) in the former and 22 months (1–94) in the latter. All but 10 (69.2%) MEN1 patients were cured after surgery. Four had a relapse of PHPT between 3 and 5 years after PTx and six patients had persistent PHPT. Two relapsing patients were given cinacalcet and two monitored without therapy. Among patients with persistent PHPT: one underwent successful PTx, one was given cinacalcet, and four were followed without therapy. All but 2 (66.7%) FIHP patients were cured after surgery. Two patients had a relapse of PHPT 12–18 months after PTx. No patient developed other MEN1-related endocrine tumors during the follow-up. Fifteen patients (12 MEN1 and 3 FIHP) refused PTx. All patients had asymptomatic PHPT with mild bone involvement at baseline evaluation. No significant changes were found in serum calcium, creatinine, and markers of bone turnover, PTH, 24-h urinary calcium and BMD at any site during follow up (median 20 months, range 2–96) (Table 3).
Endocrine Table 3 Biochemical and densitometric data (mean ± SD) at baseline and latest follow-up of patients with sporadic and familial juvenile PHPT (J-PHPT) followed without surgery Sporadic patients (n = 17)
Familial patients (n = 15) a
Normal range Baseline evaluation Last follow-up P
Baseline evaluation Last follow-up Pa
Serum calcium (mg/dL)
8.6–10.2
10.3 ± 0.3
10.3 ± 0.3
0.8
10.3 ± 0.8
10.6 ± 0.4
0.09
Serum albumin adjusted calcium (mg/ dL)
8.6–10.2
10.2 ± 0.3
10.2 ± 0.4
0.9
10.2 ± 0.6
10.4 ± 0.5
0.05 0.2
Ionized serum calcium (mmol/L)
1.13–1.32
1.40 ± 0.08
1.42 ± 0.08
0.2
1.40 ± 0.08
1.423 ± 0.09
Serum phosphate (mg/dL)
2.7–4.5
2.7 ± 0.4
2.7 ± 0.4
0.9
2.7 ± 0.4
2.7 ± 0.3
0.9
Plasma intact PTH (pg/mL)
15–75
74 (59–90)
68 (57–91)
0.7
62 (43–89)
71 (59–76)
0.9
Serum 25OHD (ng/mL)
30–100
21.2 ± 8
22.4 ± 9
0.8
22.1 ± 8
23.4 ± 8
0.8
Serum osteocalcin (ng/mL)
6.8–34
27.6 ± 14
25.8 ± 8
0.7
26.6 ± 12
25.7 ± 6
0.7
Serum BSAP (µg/L)
2–20
15.8 ± 5
19.6 ± 7
0.1
14.9 ± 5
20 ± 7
0.1
Serum creatinine (mg/dL)
0.4–1.2
0.7 ± 0.12
0.7 ± 0.13
0.9
0.7 ± 0.6
0.7 ± 0.7
0.9
24-h urinary calcium (mg/24 h)
<300
370.2 ± 156.4
410.3 ± 199
0.2
378.5 ± 170
371 ± 140
0.9
Lumbar spine
–
BMD (g/cm²)
0.94 ± 0.05
0.93 ± 0.04
0.4
0.87 ± 0.14
0.88 ± 0.08
0.8
z-score
−0.96 ± 0.44
−0.98 ± 0.48
0.5
−1.4 ± 0.6
−1.2 ± 0.6
0.3b
Femoral neck
–
BMD (g/cm²)
0.77 ± 0.07
0.71 ± 0.09
0.05 0.82 ± 0.07
0.78 ± 0.09
0.3
z-score
−0.53 ± 0.9
−0.63 ± 0.6
0.8
−0.84 ± 0.8
−0.96 ± 0.9
0.8b
BMD (g/cm²)
0.68 ± 0.03
0.66 ± 0.06
0.2
0.67 ± 0.04
0.65 ± 0.05
0.7
z-score
−0.5 ± 0.6
−0.4 ± 0.6
0.2
−2.3 ± 0.5
−2.4 ± 0.3
0.4b
One-third distal radius
a
–
P-value are referred to the comparisons between baseline and follow up data
In patients aged ≤20 years (n = 1 in the group of sporadic and n = 2 in the group of familial) z-score was calculated with BMDCS z-score calculator for young patients (https://bmdcs.nichd.nih.gov/zscore.htm) b
Comparison between SJ-PHPT and FJ-PHPT The F:M ratio was significantly higher in SJ-PHPT than in those with FJ-PHPT. Patients with FJ-PHPT were significantly younger than those with SJ-PHPT, less frequently complained of neuropsychiatric symptoms upon questioning, and showed a significantly lower rate of nephrolithiasis than SJ-PHPT (Table 1). No significant difference was observed in all other parameters. Among patients undergoing PTx the rate of multigland disease was significantly (P < 0.001) higher in patients with FJ-PHPT (19/26, 73.0%) than in those with SJ-PHPT (3/84, 3.6%). As expected the rate of persistence/relapse of PHPT after PTx was significantly (P < 0.001) higher in patients with FJ-PHPT (13/ 27; 48.1%) than in those with SJ-PHPT (5/87; 5.7%).
subgroups included 31 (20%) and 123 patients (80%), respectively. At baseline, there was no statistically significant difference in any biochemical parameter, with the exception of PTH, that was significantly lower, and serum phosphate, that was significantly higher, in the younger group. Younger patients had more often familial form of PHPT, as expected (Table 4). The rate of nephrolithiasis and fragility fracture and densitometric parameters did not differ between the two groups. One hundred eighteen patients (21 aged ≤25 years and 97 aged >25 years) underwent PTx. No difference in the rate of cure of PHPT was found between the two groups (P = 0.53).
Discussion Comparison of J-PHPT according to age of patients (≤25 vs. 26–40 years) To establish whether the choice of ≤40 years as a cut-off to define J-PHPT could impact in our analyses patients were grouped according to age: ≤25 years (as in a recent metaanalysis) or between 26 and 40 years (Table 4). The two
The aim of our study was to extend the knowledge on the phenotype and clinical course of J- PHPT and highlight differences between sporadic and familial forms. There is no agreement on the cut-off age to define JPHPT, even though an age of less than 25 years has been used in several studies [14, 16, 19]. In the present
Endocrine Table 4 Clinical, biochemical and densitometric data of patients with juvenile PHPT: comparison between patients according to age ≤25 and >25 years
Normal range
≤25 years (n = 31)
>25 years (n = 123)
P
Age at diagnosis (years)
–
19.9 ± 3.7
35.3 ± 4
0.00
Serum calcium (mg/dL)
8.6–10.2
10.8 ± 1.2
10.5 ± 1.0
0.09
Albumin adjusted calcium (mg/dL)
8.6–10.2
10.8 ± 1.1
10.4 ± 1.0
0.09
Ionized calcium (mmol/L)
1.13–1.32
1.51 ± 0.1
1.48 ± 0.1
0.3
Phosphate (mg/dL)
2.7–4.5
2.6 ± 0.5
2.3 ± 0.5
0.02
Plasma intact PTH (pg/mL)
15–75
89 (70–139)
119 (81–181)
0.03
Serum 25OHD (ng/mL)
30–100
21 ± 11.6
19.2 ± 9.6
0.3
Osteocalcin (ng/mL)
6.8–34
38.9 ± 32
30.8 ± 22.8
0.1
BSAP (µg/L)
2–20
14 ± 3
16 ± 5
0.8
24 h urinary calcium (mg/24 h)
<300
357 ± 134
365 ± 148
0.7
Lumbar spine
–
BMD (g/cm²)
0.91 ± 0.1
0.94 ± 0.2
0.4
z-score
−0.85 ± 1.2a
−1.0 ± 1.1
0.5
BMD (g/cm²)
0.8 ± 0.1
0.7 ± 0.1
0.1
z-score
−1.03 ± 0.9
−0.97 ± 0.95
0.7
Femoral neck
One-third distal radius
– a
–
BMD (g/cm²)
0.58 ± 0.3
0.67 ± 0.1
0.03
z-score
−1.37 ± 1.4a
−0.71 ± 13
0.03 0.01
Sporadic
17 (54.8%)
95 (77.2%)
Familial
14 (45.2%)
28 (22.8%)
0.01
Nephrolithiasis n (%)
–
13 (41.9%)
64 (52%)
0.4
Clinical fractures
–
5 (4.1%)
5 (4.1%)
0.6
a In patients aged ≤20 years z-score was calculated with BMDCS z-score calculator (https://bmdcs.nichd.nih. gov/zscore.htm) for young patients
All value are mean ± standard deviation, with the exception of PTH (median and interquartile range)
prospective study, performed in a single tertiary referral Center, we choose a cut-off age of ≤40 years on the assumption that very likely there is a delay between the onset of the disease and its recognition. A total of 321 cases aged less than 40 years have been reported to date in the literature. These studies are retrospective, performed on mixed population (either familial or sporadic) and include in the majority of cases small cohorts of patients. It is commonly stated that J-PHPT manifests at diagnosis with more severe biochemical and clinical features as compared with adult PHPT [5, 11–13]. The more severe presentation of J-PHPT could be likely due to the fact that, at variance with adult counterpart, the diagnosis is made on the basis of suspicious symptoms rather than following routine biochemical testing. Thus, the possibility that a cohort of patients with “asymptomatic J-PHPT” could exist cannot be ruled out. Indeed, in our cohort, when cases identified at the screening of first-degree relatives of MEN1/ FIHP probands were excluded, the diagnosis of PHPT was occasionally made in a substantial proportion (38%) of cases at routine blood tests. On the other hand, Roizen and Levine have reported that only 14% of patients with JPHPT were asymptomatic [20].
In the current study, females were most frequently affected by PHPT than males (F:M 2.5), but this ratio decreased to 1.6:1 when only familial cases were considered, and 1.4 in patients aged < 25 years. The latter ratio is more close to that reported by Roizen and Levine (1:1) using the same cut-off age [5]. Males showed a higher serum calcium concentration and a greater bone involvement at one-third distal radius, compared with females, suggesting that estrogens might have a protective role in young females. This hypothesis is not supported by the study of Shah et al. performed in India, where PHPT is often a very symptomatic disease. These authors did not find any difference in serum calcium between males and females, but bone involvement was more common in the latter; conversely males showed a higher rate of nephrolithiasis and pancreatitis [14]. We do not have an explanation for the discrepant results, but a lower level of 25OHD as compared with that of our population, could account for the difference in the bone involvement. A novelty of our study is the comparison of clinical and biochemical parameters between patients with FJ-PHPT and SJ-PHPT. The former patients are younger, less frequently women, have a lower rate of nephrolithiasis, but higher
Endocrine
rates of multigland disease and persistence/relapse of PHPT after PTx. The large proportion (54.8%) of subjects identified at the familial screening could account for the younger age and the lower rate of nephrolithiasis in patients with FJPHPT as compared with those with SJ-PHPT. The lower female prevalence and the higher multigland disease and persistence/relapse rate after surgery are commonly reported in hereditary forms of PHPT, independently of age at diagnosis. [28]. No differences in biochemical and BMD parameters were observed between the two groups. To our knowledge no other study has compared the clinical phenotypes between patients with FJ-PHPT and SJ-PHPT. In the current study, in the whole cohort of patients undergoing surgery, a single parathyroid gland involvement was found in most cases (82.5%), whereas in patients with FJ-PHPT, particularly in MEN1, multigland hyperplasia was typically detected. Likewise, a single parathyroid adenoma was the most common cause of PHPT in most studies included in the meta-analysis of Roizen and Levine, with a similar prevalence among patients with adult and J-PHPT [19]. The high prevalence of uniglandular disease may account for the high cure rate of surgery in patients with JPHPT, similar to that observed in the adult counterpart. Therefore, a mini-invasive PTx, combined with iPTH monitoring, instead of bilateral neck exploration, could be a reasonable surgical approach in patients with SJ-PHPT. This surgical approach could decrease the higher rate of complications associated with bilateral neck exploration, even though false positive results of iPTH may rarely occur, as in two of the four patients with SJ-PHPT who had persistent PHPT [29]. No evidence of progression of PHPT was observed in patients who did not undergo PTx, either familial or sporadic form. The latter finding could suggest that patients with mild J-PHPT could be safely followed without surgery, at least for a limited number of years. Several studies used a cut-off of ≤25 years to diagnosed J-PHPT [19]. Therefore, we also performed an additional analysis after grouping patients according to age ≤25 years and between 26 and 40 years. We found that, with the exception of serum phosphate and PTH levels, that were significantly higher and lower, respectively, in patients aged ≤25 years, there were no statistically significant differences in any other parameter. Thus, the choice of 25 or 40 years as the cut-off to define J-PHPT in our cohort has a limited impact in evaluating the phenotype of J-PHPT. Notably, in the meta-analysis of Roizen and Levine, which included patients aged less 25 years, mean serum calcium and PTH levels were higher than those found in the subgroup of our patients of the same age [19]. This difference could be due to inclusion in the Roizen and Levine’ meta-analysis of patients mostly derived from surgical series. The strengths of our study are: (i) its prospective nature; (ii) the large series of patients with J-PHPT, comprising
both females and males followed at a single Institution; (iii) the inclusion of sporadic and familial PHPT; (iv) the extensive clinical, biochemical, and densitometric evaluation at baseline and last follow up; (v) the histology of patients who underwent surgery; and (vi) the comparison of patients with FJ-PHPT and SJ-PHPT. Our study has also some limitations: (1) the cut-off of age (40 years) to define J-PHPT was arbitrarily established, (2) the limited cohort size (n = 31) of patients with J-PHPT aged less than 25 years limited the power of the study to detect significant differences in clinical parameters (nephrolithiasis and fracture risk) compared to the older group. In conclusion, our prospective study shows that J-PHPT is frequently a sporadic disease, with no difference in the biochemical phenotype between sporadic and familial forms. Patients with familial J-PHPT have a milder clinical phenotype and higher rate of persistence/recurrence after PTx than those with SJ-PHPT. Acknowledgements We thank Dr. Giuseppe Viccica for his work collecting some clinical data used in this study. Compliance with ethical standards Conflict of interest interests.
The authors declare that they have no competing
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.
References 1. J.P. Bilezikian, M.L. Brandi, R. Eastell, S.J. Silverberg, R. Udelsman, C. Marcocci, J.T. Potts, Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the fourth international workshop. J. Clin. Endocrinol. Metab. 99, 3561–3569 (2014) 2. C. Marcocci, F. Cetani, Clinical practice. Primary hyperparathyroidism. N. Engl. J. Med. 365, 2389–2397 (2011) 3. N. Yu, P.T. Donnan, M.J. Murphy, G.P. Leese, Epidemiology of primary hyperparathyroidism in Tayside, Scotland, UK. Clin. Endocrinol. 71, 485–493 (2009) 4. A. Abood, P. Vestergaard, Increasing incidence of primary hyperparathyroidism in Denmark. Dan. Med. J. 60, A4567 (2013) 5. J. Roizen, M.A. Levine, Primary hyperparathyroidism in children and adolescents. J. Chin. Med. Assoc. 75, 425–434 (2012) 6. M. Allo, N.W. Thompson, J.K. Harness, R.H. Nishiyama, Primary hyperparathyroidism in children, adolescents, and young adults. World J. Surg. 6, 771–776 (1982) 7. C.S. Cronin, T.S. Reeve, B. Robinson, P. Clifton-Bligh, A. Guinea, L. Delbridge, Primary hyperparathyroidism in childhood and adolescence. J. Paediatr. Child Health 32, 397–399 (1996)
Endocrine 8. E. Kandil, D.S. Majid, K.A. Carson, R.P. Tufano, A comparison of outcomes for younger and older adult patients undergoing surgery for primary hyperparathyroidism. Ann. Surg. Oncol. 19, 1897–1901 (2012) 9. M.L. Lawson, S.F. Miller, G. Ellis, R.M. Filler, S.W. Kooh, Primary hyperparathyroidism in a paediatric hospital. QJM 89, 921–32 (1996) 10. K.C. Loh, Q.Y. Duh, D. Shoback, L. Gee, A. Siperstein, O.H. Clark, Clinical profile of primary hyperparathyroidism in adolescents and young adults. Clin. Endocrinol. 48, 435–443 (1998) 11. S.C. Hsu, M.A. Levine, Primary hyperparathyroidism in children and adolescents: the Johns Hopkins Children’s Center experience 1984–2001. J Bone Miner. Res. 17(Suppl 2), N44–50 (2002) 12. J. Kollars, A.E. Zarroug, J. van Heerden, A. Lteif, P. Stavlo, L. Suarez, C. Moir, M. Ishitani, D. Rodeberg, Primary hyperparathyroidism in pediatric patients. Pediatrics 115, 974–980 (2005) 13. E. Mallet, B. Amrein, C. Bost, D. David, F. Despert, G. Garabedian, L. Guillot, L. Lienhardt, L. Loirat, P. Nicolino, S. Simonin, T. Thieuleux, Y. Wagner, Primary hyperparathyroidism in neonates and childhood: The French experience (1984–2004). Horm. Res. 69, 180–188 (2008) 14. V.N. Shah, S.K. Bhadada, A. Bhansali, A. Behera, B.R. Mittal, V. Bhavin, Influence of age and gender on presentation of symptomatic primary hyperparathyroidism. J. Postgrad. Med. 58, 107–111 (2012) 15. J. George, S.V. Acharya, T.R. Bandgar, P.S. Menon, N.S. Shah, Primary hyperparathyroidism in children and adolescents. Indian J. Pediatr. 77, 175–178 (2010) 16. E.T. Durkin, P.F. Nichol, D.P. Lund, H. Chen, R.S. Sippel, What is the optimal treatment for children with primary hyperparathyroidism? J. Pediatr. Surg. 45, 1142–1146 (2010) 17. J.F. Burke, K. Jacobson, A. Gosain, R.S. Sippel, H. Chen, Radioguided parathyroidectomy effective in pediatric patients. J. Surg. Res. 184, 312–317 (2013) 18. I. Paunovic, V. Zivaljevic, R. Stojanic, N. Kalezic, M. Kazic, A. Diklic, Primary hyperparathyroidism in children and young adults: a single institution experience. Acta Chir. Belg. 113, 35–39 (2013) 19. J. Roizen, M.A. Levine, A meta-analysis comparing the biochemistry of primary hyperparathyroidism in youths to the biochemistry of primary hyperparathyroidism in adults. J. Clin. Endocrinol. Metab. 99, 4555–4564 (2014) 20. J.P. Bilezikian, C.S. Kovacs, The parathyroids Section II, Chapter 23, AP Editor (2015)
21. Y.H. Chou, E.M. Brown, T. Levi, G. Crowe, A.B. Atkinson, H.J. Arnqvist, G. Toss, G.E. Fuleihan, J.G. Seidman, C.E. Seidman, The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families. Nat. Genet. 1, 295–300 (1992) 22. A. Szalat, S. Shpitzen, A. Tsur, I. Zalmon Koren, S. Shilo, L. Tripto-Shkolnik, R. Durst, E. Leitersdorf, V. Meiner, Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia. Endocrine 55(3), 741–747 (2017) 23. R.V. Thakker, P.J. Newey, G.V. Walls, J. Bilezikian, H. Dralle, P. R. Ebeling, S. Melmed, A. Sakurai, F. Tonelli, M.L. Brandi, Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J. Clin. Endocrinol. Metab. 97, 2990–3011 (2012) 24. F. Cetani, E. Pardi, S. Borsari, M. Tonacchera, E. Morabito, A. Pinchera, C. Marcocci, Two Italian kindreds with familial hypocalciuric hypercalcaemia caused by loss-of-function mutations in the calcium-sensing receptor (CaR) gene: functional characterization of a novel CaR missense mutation. Clin. Endocrinol. 58, 199–206 (2003) 25. G. Viccica, F. Cetani, E. Vignali, M. Miccoli, C. Marcocci, Impact of vitamin D deficiency on the clinical and biochemical phenotype in women with sporadic primary hyperparathyroidism. Endocrine 25, (2016). doi:10.1007/s12020-016-0931-8 26. E. Vignali, A. Picone, G. Materazzi, S. Steffe, P. Berti, L. Cianferotti, F. Cetani, E. Ambrogini, P. Miccoli, A. Pinchera, C. Marcocci, A quick intraoperative parathyroid hormone assay in the surgical management of patients with primary hyperparathyroidism: a study of 206 consecutive cases. Eur. J. Endocrinol. 146, 783–788 (2002) 27. E. Pardi, C. Marcocci, S. Borsari, F. Saponaro, L. Torregrossa, M. Tancredi, B. Raspini, F. Basolo, F. Cetani, Aryl hydrocarbon receptor interacting protein (AIP) mutations occur rarely in sporadic parathyroid adenomas. J. Clin. Endocrinol. Metab. 98, 2800–2810 (2013) 28. R.V. Thakker, Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol. Cell. Endocrinol. 386, 2–15 (2014) 29. R. Udelsman, G. Akerström, C. Biagini, Q.-Y. Duh, P. Miccoli, B. Niederle, F. Tonelli, The surgical management of asymptomatic primary hyperparathyroidism: proceedings of the fourth international workshop. J. Clin. Endocrinol. Metab. 99, 3595–3606 (2014)