Familial multiple endocrine neoplasia type I: the urologist is first on the scene

Authors


Nikos Antoniou, Department of Urology, ‘A. Fleming’ General Hospital, Laskou 7, P. Psihiko, Athens 15452, Greece.
e-mail: chrada@ath.forthnet.gr

Abstract

OBJECTIVE

To study the urological manifestations of familial multiple endocrine neoplasia type 1 (MEN-1).

PATIENTS AND METHODS

The study included 26 adults (median age 38.5 years, range 18–80) from two unrelated MEN-1 pedigrees. In 15 of the patients the diagnosis was confirmed by genetic analysis, while in the rest the diagnosis was based on clinical criteria combined with genealogy data.

RESULTS

Urolithiasis associated with primary hyperparathyroidism was present in 65% of MEN-1 patients and in 77% of those who were symptomatic. In 68% of patients complications of urolithiasis (renal/ureteric colic, urinary tract infection) were the presenting clinical manifestations of MEN-1, whereas in 50% they constituted the only clinical manifestation of the syndrome. The mean time from the onset of symptoms of urolithiasis to the diagnosis of the polyendocrinopathy was 17.2 years. Initial failure to recognize the presence of MEN-1 in patients with primary hyperparathyroidism led to conservative parathyroid surgery, with subsequent relapse of the hyperparathyroidism, requiring re-operation. Serious renal morbidity included one case of pyonephrosis necessitating nephrectomy. While urolithiasis was a cardinal clinical manifestation of MEN-1, there was otherwise considerable phenotypic polymorphism, even among patients bearing the same MEN1 gene mutation.

CONCLUSION

In patients with familial MEN-1 the complications of urolithiasis are the commonest presenting clinical manifestations and the cause of significant morbidity. In the presence of a family history of renal stones, appropriate investigations may lead to the timely diagnosis of this important, albeit rare, disorder.

Abbreviations
MEN-1

multiple endocrine neoplasia type 1

HPT

hyperparathyroidism

INTRODUCTION

In 1939, Rossier and Dressler [1] described two sisters with nephrolithiasis combined with tumours of the parathyroid glands and the pancreatic islets. There was a strong paternal family history of peptic ulcers, but it took 22 years for it to be connected to the sisters’ endocrine neoplasms [2]. Meanwhile, in 1954, Wermer [3] had published his classic description of the familial syndrome comprising multiple parathyroid, pancreatic islet, and pituitary tumours, recognizing at the same time its autosomal dominant pattern of inheritance. Known originally as ‘Wermer's syndrome’ or ‘multiple endocrine adenomatosis’, this condition is now preferably termed ‘multiple endocrine neoplasia type 1’ (MEN-1). Beside the typical triad of tumours of parathyroid glands, endocrine pancreas, and anterior pituitary, its clinical manifestations may also include adrenocortical tumours, carcinoids mainly of foregut origin (bronchial, thymic, gastric, duodenal), and cutaneous tumours such as lipomas, angiofibromas and collagenomas [4,5]. The syndrome is thought to be caused by a defect in the MEN1 gene, a tumour-suppressor gene in the long arm of chromosome 11 (11q13), identified by positional cloning in 1997 [6]. The gene encodes a 610-amino acid nuclear protein, MENIN, which presumably has a role in regulating the transcriptional activity of the cell [7]. To date, more than 260 families with different germline MEN1 mutations have been described [8], and there is no evidence of a correlation between genotype and phenotype [9]. There is considerable phenotypic polymorphism even within the same kindred, but it appears that the most prevalent and sometimes the only [10] clinically evident abnormality is hyperparathyroidism (HPT), commonly presenting as chronic urolithiasis. Although the significant disease-specific mortality arises largely from pancreatic islet carcinoma and malignant thymic carcinoid, it is the urological morbidity that will often bring these patients to medical attention, and this is the object of the present analysis.

PATIENTS AND METHODS

The study included 26 patients (17 women and nine men, median age 38.5 years, range 18–80) from two unrelated pedigrees with familial MEN-1 syndrome. The diagnosis of familial MEN-1 was made when at least one of the following three criteria was met: (i) Typical lesions in at least two of the principal organs (parathyroid glands, endocrine pancreas, pituitary) involved in the syndrome plus at least one first- or second-degree relative with one such lesion; (ii) one such lesion plus a first- or second-degree relative with known MEN-1; and (iii) the presence of an inactivating mutation of the MEN1 gene in a blood relative of a person with known MEN-1 syndrome. In 15 of 20 patients belonging to the same large family (Family A) the diagnosis was confirmed by molecular genetic studies. Ten members of this family (six patients and four asymptomatic controls) were tested initially with full DNA sequencing of MEN1 (10 exons), as described elsewhere [11], and a mutation consisting of a single guanine base insertion was detected at position 1377 (exon 9) in all of the patients and none of the controls. This is a frameshift mutation resulting in the premature appearance of a stop codon predicting the formation of a truncated 447-amino acid MENIN, instead of the normal 610-amino acid protein. Subsequent testing of other family members for the presence of the 1377insG mutation involved limited sequencing of exon 9 combined with denaturing gradient gel electrophoresis of PCR products, using appropriate flanking primers, according to standard protocols. In the six members of a second MEN-1 family (Family B) no mutation was detected on gene sequencing and the diagnosis was based on clinical criteria alone. The search for the detection of alternative genetic abnormalities in this family is continuing.

When first diagnosed and at yearly intervals thereafter (or sooner if clinically indicated) MEN-1 patients had routine serum biochemical assessments, including calcium and phosphate levels, and a hormonal profile including serum parathormone, gastrin, insulin, C-peptide, glucagon, somatostatin, vasoactive intestinal peptide, chromogranin-A, pancreatic polypeptide, prolactin, growth hormone, adrenocorticotrophin, gonadotrophins, thyroid-stimulating hormone, triiodothyronine, free thyroxine, and cortisol. Endoscopic ultrasonography of the pancreas or thin-section CT of the upper abdomen were performed every 3 years and MRI of the pituitary every 5 years. Patients with HPT had Tc-sestamibi scintigrams to locate the abnormal glands, 24-h urine collections to confirm hypercalciuria, and plain radiographic and ultrasonographic studies of the kidneys and ureters to detect urolithiasis. IVU was used selectively to detect urinary obstruction. Stones were not routinely analysed, as practically all renal calculi in the setting of primary HPT are of calcium (calcium oxalate, calcium phosphate or both in the same stone).

Patients with renal and ureteric calculi were managed medically according to published guidelines [12,13] and had ESWL or surgical removal of stones when indicated [14]. Urolithiasis associated with HPT in the context of MEN-1 was considered as an indication for parathyroidectomy. Three glands and two-thirds of the fourth were removed when possible, and the remaining part of the fourth gland was either left in situ or implanted subcutaneously in the forearm. Parathyroidectomies performed before the diagnosis of MEN-1 were usually limited to removing macroscopically abnormal glands.

RESULTS

Of the 26 patients, 22 had clinical manifestations of MEN-1; in the remaining four who were asymptomatic the diagnosis had been made by genetic testing. The mean age at the diagnosis of MEN-1 was 39.8 years.

The individual results for urological morbidity are shown in Table 1. Complications of urolithiasis (renal/ureteric colic, UTIs) associated with primary HPT were present in 17 patients (65%, and 77% of those with symptoms) and were the first clinical manifestation of the syndrome in 15 (68%), while they were the only manifestation of MEN-1 in 11 (50%). The mean (range) age at the onset of symptoms of urolithiasis was 26.9 (20–53) years. The mean (median) time elapsing from the appearance of the first clinical manifestation of urolithiasis to the diagnosis of MEN-1 was 17.2 (15) years. There was no uniformity in the severity and time pattern of symptoms, the frequency of renal colic fluctuating from one or two episodes in a lifetime to several per month. In one case urolithiasis presented initially with pyonephrosis of a kidney containing a staghorn calculus.

Table 1.  Urological complications in patients with MEN-1
Patient No./sexAge at diagnosis of MEN-1, yearsComplications of urolithiasisAge at diagnosis of urolithiasis, yearsSurgical treatment
  1. PTH: parathyroid; *PTHectomy was performed because of persistent significant hypercalcaemia and hypercalciuria.

Family A
1/M50colic20lithotomy, PTHectomy
2/F42   
3/F19  PTHectomy*
4/M65colic29PTHectomy
5/F80   
6/F37colic25PTHectomy
7/F53pyonephrosis53PTHectomy, nephrectomy
8/F38colic, UTIs24 
9/F20   
10/F18   
11/F37  PTHectomy*
12/F36colic, UTIs26PTHectomy
13/F28colic27PTHectomy
14/M28colic28ESWL, PTHectomy
15/F29   
16/M33colic22ESWL, PTHectomy
17/M29colic26none
18/M49colic28none
19/M23  PTHectomy*
20/F19  PTHectomy*
Family B
21/M51colic20ESWL × 2, PTHectomy
22/F57colic, UTIs30lithotomy × 2, ESWL × 2 PTHectomy
23/F45colic22lithotomy, ESWL
24/M45colic20lithotomy
25/F55colic22lithotomy × 2, ESWL × 5 transurethral lithotripsy, PTHectomy
26/F50colic35none

Six of the patients (35%) with urolithiasis had a total of 12 sessions of ESWL. Surgical removal of stones was needed on eight occasions, in five patients (29%). The patient with pyonephrosis had a nephrectomy and on histological examination there was xanthogranulomatous pyelonephritis and changes of chronic pyelonephritis. Parathyroidectomy was performed in 15 patients (58%), in seven of whom the diagnosis of MEN-1 was unknown at the time of surgery and they were treated as cases of isolated primary HPT, undergoing resection limited to the glands which appeared macroscopically abnormal on neck exploration. In one case the abnormal (adenomatous) parathyroid was intrathymic in the thorax. In five of these patients the HPT relapsed a median of 7 (3–18) years after the operation. Only one re-operation after relapse has been recorded so far. Three of the eight patients who had various types of subtotal parathyroidectomy developed permanent hypoparathyroidism requiring long-term treatment with oral calcium and vitamin D. In all cases, parathyroidectomy was followed by a marked reduction in the frequency and severity of renal colic.

While urolithiasis was generally a cardinal clinical manifestation of MEN-1, there was otherwise considerable phenotypic polymorphism, even among patients bearing the same MEN1 mutation. Severe or refractory peptic ulcer disease was present in six patients (23%) and represented the commonest accompaniment to the urolithiasis. In two of these patients, a formal diagnosis of gastrinoma manifesting as Zollinger–Ellison syndrome (fasting hypergastrinaemia combined with an increased basal gastric acid output) was made. It was followed in frequency by cutaneous lipomatosis (five patients, 19%), non-functioning tumours of the pancreas (three, 12%), insulinomas (two, 8%), prolactinoma (one, 4%), non-functioning pituitary adenoma (one, 4%) and bronchial carcinoid (one, 4%). The most serious morbidity was in a patient with a malignant pancreatic tumour and hepatic metastases at the time of the diagnosis, which was made 30 years after the onset of frequent renal colic. Endoscopic ultrasonography showed the presence of small pancreatic adenomas in many of these patients, which were not detectable by CT. The clinical significance of these lesions remains unclear and, in the absence of hormonal overproduction, they were not investigated further.

DISCUSSION

Urolithiasis can be a manifestation of several non-urological diseases, including primary HPT, the latter accounting for 1–5% of cases with calcium stone disease [15] and in a minority of patients (<5%) is part of one of a variety of inherited syndromes, including MEN-1 [16]. In the present study we showed that, in members of two families with MEN-1, renal colic was usually the first clinical manifestation that would bring the patients to medical attention. Interestingly, in the case of the patient who developed pyonephrosis (the second reported case in the setting of MEN-1 [17]) there was no history of colic. Although there are few reports focusing specifically on the urological aspects of MEN-1, the present findings are in keeping with the reported high penetrance of primary HPT in the setting of MEN-1 syndrome. In a review of 143 MEN-1 patients diagnosed over 30 years in Japan, 90% had primary HPT, which was complicated by urolithiasis in 35% of cases [18]. In contrast to the dismal outcome of chronic urolithiasis in the days of Henry IV of Castille (reigned 1454–1474), the legendary MEN-1 sufferer who died from obstructive uropathy at the age of 49 years [19], the diligent 21st century urologist is in a position to not only treat the complications of renal calculi, but also play a key role in the early diagnosis of the underlying polyendocrinopathy.

Kidney stones are a frequent finding in the general population and are known to develop more frequently in individuals with a family history of urolithiasis than in those with no family history [20]. Against this background it can be difficult to distinguish the rare cases that are part of a polyendocrinopathy syndrome, especially when the latter presents clinically with isolated primary HPT where, as is often the case, serum calcium levels are only marginally elevated or even within the normal range [15]. Hospital admission is unnecessary for most patients with renal colic, so stone-formers are usually managed as outpatients and their treatment is often limited to control of the acute symptoms. A significant percentage will escape further investigation even in the setting of specialist clinics. In view of this, our finding of a long lag period (median 15 years) between the onset of colic and diagnosis of MEN-1 is not surprising. However, failing to diagnose MEN-1 at an early stage can have serious implications; MEN-1-associated primary HPT requires more aggressive surgery (resection of ≥ 3.5 parathyroid glands) than sporadic primary HPT. Relapse is known to occur even after subtotal parathyroidectomy, but the time to relapse is related to the amount of parathyroid tissue removed at the initial operation [21]. The short median time to relapse (7 years) in the present patients is explained in that almost half of them had a parathyroidectomy before the diagnosis of MEN-1. Moreover, beside the significant morbidity caused by renal stone events and other complications of primary HPT, failure to recognize MEN-1 in patients presenting with urolithiasis may lead to the delayed diagnosis of lesions carrying significant mortality, especially pancreatic malignancies, which represent the commonest cause of death. This is exemplified by the present patient with renal colic since the age of 20 years, whose MEN-1 syndrome was only diagnosed when he was found to have a metastatic neuroendocrine pancreatic tumour 30 years later. The findings from the history, physical examination and laboratory investigation that should alert the clinician to the possibility of an underlying polyendocrinopathy are:

  • • History: Personal or family history of peptic ulcer disease, chronic diarrhoea, pancreatic or pituitary tumours/operations, menstrual abnormalities, galactorrhoea, infertility.
  • • Physical examination: cutaneous lesions associated with MEN-1 (lipomas, angiofibromas, collagenomas).
  • • Serum biochemistry: high or high-normal calcium, low or low-normal phosphate; if there are marginal abnormalities, check parathormone levels.

At least one of these findings was present at the initial evaluation of all the patients who presented with urolithiasis and were subsequently found to have familial MEN-1 (sensitivity 100%). The full evaluation of primary HPT (including screening and follow-up for MEN-1) is certainly beyond the scope of standard urological investigation. Nevertheless, as most MEN-1 patients will initially present with renal colic, it is the urologist's responsibility to suspect primary HPT and refer appropriate patients for formal endocrinology consultation.

ACKNOWLEDGEMENTS

We thank Drs Manos Papadakis, Georgia Christopoulou, and Nikos Kastrinakis, who developed the DGGE method for 1377insG carrier screening. We are indebted to the members of the Greek MEN-1 Study Group (http://www.klinik.gr/men1) for their contribution to the care of our patients.

CONFLICT OF INTEREST

None declared. Source of funding: Greek state, French state.

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