Paediatric and Young Adult Manifestations and Outcomes of Multiple Endocrine Neoplasia Type 1

Madhuni Herath; Venkat Parameswaran; Michael Thompson; Michelle Williams; John Burgess

Disclosures

Clin Endocrinol. 2019;91(5):633-638. 

In This Article

Discussion

The Tasman 1 MEN1 kindred cohort provides a unique opportunity to understand the natural history of MEN 1 and its clinical and subclinical expression during childhood and adolescence. In this study, we found that MEN 1 did not adversely affect cohort-level survival to 22 years of age. However, we did identify the presence of potentially clinically relevant parathyroid-, pancreatic- and pituitary-related pathology and morbidity secondary to symptomatic manifestations of MEN 1 in adolescence. These findings strongly support the need for surveillance, investigation and judicious intervention in the context of MEN 1 during childhood and adolescence.

Although aggressive MEN 1–related neoplasms are uncommon, subclinical MEN 1–related pathology is highly penetrant by 22 years of age. Retrospective analysis of Tasman 1 kindred members who reached 22 years of age prior to the recognition of MEN 1 in Tasmania and prior to the institution of regular screening found no significant difference between the number of MEN 1–positive and MEN 1–negative offspring reaching adulthood. This finding offers reassurance that MEN 1 positivity during childhood does not significantly reduce survival even when engagement with routine surveillance is limited. These data are consistent with existing literature demonstrating that, while life-limiting aggressive MEN 1–related neoplasms may occur in the paediatric population, this is uncommon and must balance risk with an acceptable burden of patient surveillance.[12]

While childhood mortality secondary to MEN 1 is rare, biochemical abnormalities and clinically relevant disease are prevalent prior to 22 years and can be associated with significant morbidity. In the Tasman 1 kindred, the penetrance of MEN 1 was 54.8% by age 22 years. These rates are similar to published data for a French cohort of MEN 1 patients.[12] Bassett et al published a penetrance of 52% for patients under 20 years of age.[17] However, Manoharan et al described a penetrance of only 12% in patients aged <18 years in a German cohort.[11]

Symptomatic disease was present in 10.6% Tasman 1 cohort, comparable to other cohorts. Our data demonstrate primary hyperparathyroidism to be the most common paediatric manifestation of MEN 1 with significant heterogeneity in severity and clinical symptomatology. While no-one under 10 years of age experienced symptomatic disease, PHPT was diagnosed in one patient aged eight years. Pituitary and pancreatic diseases, while less prevalent than PHPT, were clinically more symptomatic, often functional and required directed intervention, albeit with good outcomes. There were no cases of Zollinger-Ellison syndrome, adrenal or thymic neoplasia prior to 22 years of age in the Tasman 1 kindred, reinforcing the rare nature of this paediatric presentation of MEN 1.[12]

Consistent with the experience of other MEN 1 kindreds, primary hyperparathyroidism was the most common paediatric manifestation of MEN 1 occurring in 50.0% of the patients, with only 4.8% of the affected patients symptomatic. It was the first identified manifestation in 33.3% patients and copresented with other pathology in further 7.2% patients. While the youngest age at detection of PHPT was eight years in our cohort, Goudet et al[12] have previously published the detection of PHPT in a 4-year-old patient in their cohort. Symptoms and manifestations of hypercalcaemia including nephrocalcinosis, abdominal pain, constipation and lethargy were present in 5.4% of the Tasman 1 population. The French and Belgian experience suggested a higher prevalence of symptomatic hypercalcaemia in their cohort, with 17.2% symptomatic.[12] While almost half of the Tasman 1 cohort (40.5%) affected by PHPT underwent parathyroidectomy, 50% experienced persistent or recurrent hypercalcaemia and one third protracted or permanent hypoparathyroidism.

The high frequency of suboptimal outcomes from parathyroidectomy in our paediatric MEN 1 population is similar to that observed in other MEN 1 cohorts.[11,12] Our experience, and that of others, emphasizes the need for careful consideration and counselling when selecting patients for surgical management of their PHPT.[14,15] This is especially important in a paediatric population due to the potential adverse effects of hypocalcaemia when skeletal maturation is incomplete.

Prolactinoma was the most common pituitary lesions, similar to findings in other MEN 1 populations.[16] While Cushing's disease was identified in two individuals, there were no cases of paediatric thyrotrophinoma or growth hormone excess, reinforcing the rare nature of these presentations.[11] In contrast to the experience of Groupe d' études Tumeurs de Endocrine, cosecretion of anterior pituitary hormones was not identified in the Tasman 1 paediatric population.[12] One nine-year-old patient died following possible pituitary apoplexy; however, all other patients were in their second decade of life at diagnosis. Our findings and that of others offer reassurance that while rare occurrences of pituitary disease can occur, pituitary pathology requiring intervention in the first decade of life is rare. Symptoms, biochemical investigations and imaging are appropriate for timely diagnosis of most MEN 1–related pituitary pathology.

The major forms of pNEN seen in the paediatric Tasman 1 cohort were nonfunctioning pNENs (66.7%) and insulinoma (33.3%). There were no cases of metastatic disease. Both nonfunctioning pNEN and insulinomas were identified from early in the second decade of life, consistent with existing published experience and reinforcing the importance of periodic abdominal ultrasonography screening in this young age group.[7,12] The incidence of insulinoma in our cohort was 3.6%, slightly less than that recorded by other groups (10%-12%). The low rates of incidence of pNENs make head-to-head comparison difficult.[11–13] Uncharacteristically, two of our patients were unable to identify clear symptoms prior to diagnosis of insulinoma on routine screening.

Subsequent to curative resection, the patients were able to retrospectively identify previous symptoms and reported improved quality of life following surgery. Although published data are only available for adult disease, our cure rate and absence of recurrence are similar to data published by the Vezzosi et al[18] for their French group. The prevalence of NFpNENs in our cohort was double that reported in the French group (9%). Similar to the findings of Goudet et al, none of our patients were symptomatic of their NFpNEN.[12] Our current practice includes yearly measurement of fasting glucose and second yearly abdominal ultrasound for patients with MEN 1 from age of 10 years.[18] We do not perform regular abdominal MRI or EUS for screening purposes in children and adolescents in an effort to minimize surveillance burden.

Enteropancreatic disease is a major cause of mortality in adult patients with MEN 1, with malignant disease and gastrin hypersecretion poor prognostic factors.[19,20] While advances in surgical care and pharmacotherapeutics in the form of somatostatin analogues have contributed significantly to reduce the life-limiting effects of enteropancreatic disease, quality of life can be significantly reduced.[10] While penetrance of gastrinoma in the second decade of life has been documented in other cohorts, this appears to be a rare occurrence, with none being identified in our cohort.[12] None of our patients had gastrinoma-range serum gastrin levels (>10-fold the upper limit of normal). Approximately 55% of patients with MEN 1 develop gastrinomas, the majority in the 5th decade of life.[21]

Highlighting the burden of MEN 1 for gene carriers, we found that MEN 1–related pathology was frequently co-manifested in our cohort (Figure 1). We identified 51 patients with data for concurrent parathyroid, pituitary and pancreatic screening. Of these, 17 patients (33.3%) were diagnosed with abnormalities of all three endocrine sites. Primary hyperparathyroidism was the sole pathology identified in only nine patients (17.6%), and two patients each (3.9%) were diagnosed with pituitary disease and pNENs. This highlights the unique challenges associated with management of paediatric and adolescent patients with this disease.

Figure 1.

Fifty-one patients with MEN 1 were assessed for parathyroid, pituitary and pancreatic diseases. Red denotes a diagnosis of pancreatic neuroendocrine (pNEN) disease, yellow a diagnosis of primary hyperparathyroidism (PHPT), and blue a diagnosis of pituitary disease

Paediatric MEN 1 age poses complex psychosocial challenges in addition to these typical childhood and adolescence. The previous experiences of other affected family members, the burden of medical care due to the need for frequent screening and medical visits, and possible fear of evolving malignancy are all relevant. Screening and management protocols need to consider the developmental age of the patient, burden of screening and risk of noncompliance and the psychological impact of the screening process for an asymptomatic young person. While less invasive methods of screening and more targeted therapies have improved patient outcomes, challenges remain.[10,22]

Our data also provide reassurance that commencement of biochemical screening at 10 years of age is sufficient in this cohort as the highest incidence of pathology occurred in the second decade of life. While younger patients may manifest pathology (PHPT), none required surgical intervention at prior to 10 years of age. Similarly, imaging of the abdomen and pituitary can be performed from 12 years of age to identify pathology in a timely manner. It seems reasonable that clinical assessment by history and examination take precedence in the first decade of life.

The retrospective nature of the data in our study restricts its interpretation and analysis. Symptomatology is less easily identified in historic documentation, and variability over time in the biochemical and radiological baseline screening studies will have also contributed to differences in sensitivity of identifying pathology. There is also a selection bias in relation to those patients attending screening, with those who are symptomatic or with a family history or existing complex comorbidities more likely to attend for screening.

In conclusion, our study demonstrates that while MEN 1–related mortality is rare in the paediatric and young adult age group, morbidity is not uncommon due to the frequent manifestation of PHPT, pNEN and pituitary disease, thus supporting the need for surveillance, investigation and intervention in MEN 1 patients older than 10 years. While parathyroid disease is more likely to cause biochemical abnormalities and expose patients to frequent monitoring, pituitary and pancreatic diseases are often symptomatic but may still require active intervention. An important consideration in supporting and managing these younger patients is a risk assessment of the likelihood of aggressive or incidental functional disease versus the burden of frequent medical surveillance.

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