Case-finding in Multiple Endocrine Neoplasia: clues for a timely diagnosis

Abstract

Multiple Endocrine Neoplasia (MEN) syndromes are rare, hereditary diseases, predisposing to the development of tumors in multiple endocrine organs and several non-endocrine features. Four distinct syndromes can be distinguished based on the underlying genetic defect and typical constellation of affected tissues: MEN1, MEN2A, MEN2B and MEN4. High penetrance of disease leads to high morbidity, decreased quality of life and reduced life expectancy in patients with all MEN subtypes.

The first part of this thesis focuses on ways to identify MEN syndromes in time without exposing (many) patients to harms related to extensive screening. Especially in sporadic patients with an atypical phenotype, high-level evidence on the use of DNA analysis is lacking. Pituitary adenoma can be a first sign of MEN1, but a hereditary underlying condition is only found in 5% of patients. By conducting a systematic review of literature (chapter 2), we illustrated that in sporadic patients, DNA screening for MEN1 syndrome appears mainly useful in patients < 30 years. In MEN2B, timely case-finding is even more challenging due to its extreme rarity (0.09-0.17 per 100,000) and de novo presentation in 75-90% of cases. Given the frequently early-onset of aggressive medullary thyroid carcinoma (MTC), many patients already suffer from advanced disease upon diagnosis. In a retrospective study (chapter 4), we demonstrated that premonitory non-endocrine (primarily gastrointestinal) signs can offer a window of opportunity for timely detection of MEN2B, leading to a better outcome. Additionally, the results described in chapter 5 shed new light on anthropometric features of MEN2B: in the existing literature marfanoid habitus (i.a. tall stature, long limbs) is supposed to be strongly linked to MEN2B, leading to the assumption that children with MEN2B have tall stature. Surprisingly, meticulous growth charts analysis revealed a short stature during childhood in most MEN2B patients instead. In chapter 3, we described the incidence trends of Dutch pediatric MTC over 30 years. Presumably due to the implementation of DNA mutation testing in families with MEN2A and subsequent prophylactic thyroidectomy before the development of MTC in mutation carriers, we found a decreasing incidence of pediatric MTC over time.

MEN patients are recommended to adhere to periodic biochemical and radiological surveillance in order to enable timely intervention if needed. The second part of this thesis concentrates on the occurrence and subsequent course of MEN1-related tumors. By studying the course of disease in the largest Dutch MEN1 families over a long period of time (chapter 6), we demonstrated that younger generations are diagnosed with MEN1-related tumors significantly earlier in life. Focusing on MEN1-related neuroendocrine tumors of the lung (chapter 7 and 8), we were able to show that these tumors generally have a good prognosis (also compared to sporadic neuroendocrine tumors of the lung) and are slow-growing, although sudden unpredictable aggressive tumor growth does occur rarely. By creating more insight into the natural course of MEN1-related manifestations, we aimed to contribute to more effective case-finding of MEN-related tumors with unfavorable course of disease in the future and to add to the development of personalized care.