Incidence of Medullary Thyroid Carcinoma and Hirschsprung Disease Based on the Cosmos Database

doi:10.21203/rs.3.rs-3101377/v1

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Incidence of Medullary Thyroid Carcinoma and Hirschsprung Disease Based on the Cosmos Database

https://doi.org/10.21203/rs.3.rs-3101377/v1

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Journal Publication

published 07 Jul, 2023

Read the published version in Pediatric Surgery International →

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Purpose

Multiple endocrine neoplasia Type 2A (MEN2A) can occur with Hirschsprung disease (HD) due to mutation in the RET proto-oncogene, with the majority developing medullary thyroid carcinoma (MTC). Given the comorbidity, many parents have contacted us to share concerns and unfortunate experiences about the prevalence rates of MEN2A/MTC in patients with HD. The aim is to determine the prevalence rate of patients with HD and MEN2A or medullary thyroid carcinoma, respectively.

Methods

This is a cross-sectional study of the COSMOS database from January 01, 2017, to March 08, 2023. The database was searched for patients diagnosed with MEN2A, MTC, and HD. IRB exemption was provided (COMIRB #23–0526).

Results

The database contained 183,993,122 patients from 198 contributing organizations. The prevalence of HD and MEN2A was 0.00002%, and for HD and MTC was 0.000009%. One in 66 patients (1.5%) with MEN2A also had HD. One in 319 patients (0.3%) in the HD group had MEN2A. One in 839 patients (0.1%) within the HD population had MTC.

Conclusion

The prevalence of MTC and HD or MEN2A and HD in the study population was low. Considering that almost all MEN2A patients have a positive family history, this data does not support the general genetic testing of HD patients.

Hirschsprung disease presents in newborns with distal intestinal obstruction. The aganglionic portion of the distal colon varies in length, which causes the colon to be spastic and fail to relax. During the fetal period, neural crest cells, which later differentiate into ganglion cells, migrate caudally. In Hirschsprung disease, the neural crest cells fail to reach the distal colon, causing the distal colon to be aganglionic. The incidence of HD is one to 5,000 live births with a preponderance towards males with a ratio of 4:1 [1–3]. HD is associated with various chromosomal anomalies and syndromes, most commonly with Trisomy 21 [1]. The predominantly affected gene in HD is the RET-proto-oncogene located on chromosome 10 [3].

As in HD, mutations of the RET proto-oncogene cause MEN2, inherited in an autosomal dominant pattern with high penetrance, resulting in a positive family history for MTC in over 95% of cases[4]. The estimated prevalence of MEN2 is 1:30,000–1:35,000 in the general population[5, 6]. It is subclassified into types 2A and 2B. One of the four variants of MEN2A is associated with HD[5]. The prevalence of HD in MEN2A patients ranges from 7.5% up to 42% in the literature, while the prevalence rate of patients with HD with associated MEN2A is reported to range from 2.5–5%[7–11].

Most patients with MEN2A will develop medullary thyroid carcinoma (MTC) in their lifetime [4, 12]. Therefore, genetic testing is recommended, and if a RET mutation with a known risk for aggressive medullary thyroid carcinoma is found, prophylactic thyroidectomy is recommended [6, 13, 14]. There are no universal recommendations for genetic screening in HD patients to identify those at increased risk for MTC due to MEN2A, but they have been proposed previously [2, 15–21]. In addition, after genetic RET proto-oncogene analysis confirmed high-risk gene carriers, prophylactic thyroidectomy in patients with MEN2A and HD, has been suggested[2, 8, 11].

This study aims to determine the prevalence rate of patients with HD and MEN2A or medullary thyroid carcinoma within the COSMOS database to provide insight into the prevalence rate of HD, MEN2A, and MTC. The COSMOS database reflects the unhealthy US population with a disease.

This is a cross-sectional study of the COSMOS database, a Health Insurance Portability and Accountability Act of 1996 (HIPAA) limited data set from 198 EPIC electronic health record (EHR) customers. At the time of the survey, COSMOS contained more than 183 million EHR, making it the most extensive integrated database, including patient data from all 50 states. In addition, the database claims to represent the United States population with patients of all races, sexes, and ages, independently of their residence or type of insurance.

The COSMOS database was then searched for the incidence rate of HD, MEN2A, and Medullary thyroid carcinoma. Medical Subject Headings (MeSH) Major Topics search of the database was done; we used: HD, MEN2A, and MTC to evaluate the prevalence rate. Additionally, the investigation was completed using the International Statistical Classification of Diseases, tenth revision diagnosis (ICD10 code) with Q43.1 for Hirschsprung disease and E31.22 for MEN2A.

Further, a search combination of MEN2A with HD and MTC with HD was performed, and the prevalence in the overall cohort was assessed. The data search was conducted on March 08, 2023. No demographic data were available within the COSMOS database; therefore, no basic demographic or disease-specific information was obtained. As no identifiable data was viewed, our Institutional Review Board deemed this study no human subject research (COMIRB #23–0526).

At the time of the study, the COSMOS database contained 183,993,122 patients from 198 contributing organizations (Table 1). The data search for HD diagnosis resulted in 13,436 patients and 2,755 diagnosed with MEN2A. Forty-two patients had MEN2A and HD listed at the time of the study; sixteen patients had MTC and HD listed within their electronic chart.

Table 1: Point prevalence of multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC), and Hirschsprung disease (HD) within the entire database.

	Study population	Ratio	Point Prevalence
Cosmos Population	183,993,122
HD	13,436	1: 13,694	7300:100,000,000
MTC	6,349	1: 28,979	3450:100,000,000
MEN2A	2,755	1: 66,785	1500:100,000,000
HD and MEN2A	42	1: 4,380,788	23:100,000,000
HD and MTC	16	1: 11,499,570	9:100,000,000

The overall prevalence within the COSMOS database of HD and MEN2A is 20 in 100,000,000 people (0.00002%), and for HD and MTC is 9 in 100,000,000 people (0.000009%) (Table 1). Within the subgroups, one in 66 patients (1.5%) with MEN2A also had HD (Table 2). One in 319 patients (0.3%) with HD had MEN2A. One in 839 patients (0.1%) within HD had MTC. One in 396 (0.25%) with MTC had HD.

Table 2: Point prevalence of multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC), and Hirschsprung disease (HD) within the subgroups.

	Affected patients within subgroup	Ratio	Point Prevalence
HD and MTC within HD group	16 of 13,436	1: 839	1 :1000
HD and MTC within MTC group	16 of 6,349	1: 396	2.5:1000
HD and MEN2A within HD group	42 of 13,436	1: 319	3 :1000
HD and MEN2A within MEN2A group	42 of 2,755	1: 66	15 :1000

Hirschsprung disease can co-occur with MEN2A due to a known mutation of the RET-proto-oncogene. The reported prevalence in the literature of HD in MEN2A ranges from 7.5–42%[7–9], with a risk as high as 5% of a RET mutation causative for MTC in HD families[15]. If a high-risk mutation for the development of MTC is found, prophylactic thyroidectomy is recommended[8, 15]. This led to the assumption by some physicians to perform genetic testing in patients with HD to screen for RET mutations known to be causative for MEN2A or MTC[15–18]. Our study showed that the prevalence rate, within the COSMOS database, including over 183 million people of HD and MEN2A or MTC, was exceedingly low, with 0.00002% for HD and MEN2A and HD and MTC 0.000009%. The prevalence found for HD in MEN2A patients is 1.5% which significantly differs from the majority reported in the literature, 7.5% up to 42%[7–11]. Similar findings were found for the prevalence rate of patients with HD with associated MEN2A. The COSMOS database prevalence was 10–16 times lower than reported in literature[9].

Genetic counseling and testing in patients with HD are becoming increasingly popular. The rationale is to diagnose a RET mutation causative for a metachronous formation of MTC due to MEN2A syndrome before neoplastic disease and to treat it by prophylactic thyroidectomy. Based on the high prevalence rate in the literature, our center receives frequent inquiries from parents and physicians about whether genetic testing is recommended in children with HD and if prophylactic thyroidectomy is warranted. We have information from personal communication of prophylactic thyroidectomies in a non-familiar HD patient without prior genetic testing in a foreign country. However, due to the low prevalence rate in the COSMOS database, thyroidectomy and comprehensive genetic testing are not supported by the data of this study. This varies according to family history.

The overall prevalence rate of HD, MTC, or MEN2A in the COSMOS database was very low compared to the published literature. Multiple MeSH Major Topics and ICD10 codes for MEN2A and HD searches were performed to exclude a search bias (missed patients, missed diagnosis). There is a chance that patients who underwent prophylactic thyroidectomies were cut within the data search since this was not a MeSH topic. Also, RET mutation was not a MeSH topic.

The weakness of this study is that this is a cross-sectional study, and no further information was collected regarding genetic testing and family history.

The prevalence of HD and MEN2A and HD and MTC was very low in this study population. Therefore, general genetic testing for the overall population of HD patients to screen for a RET proto-oncogene mutation known to cause MEN2A is not supported by the data found in this study.

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No competing interests reported.

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Journal Publication

published 07 Jul, 2023

Read the published version in Pediatric Surgery International →

Editorial decision: Accepted
29 Jun, 2023
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You are reading this latest preprint version

Incidence of Medullary Thyroid Carcinoma and Hirschsprung Disease Based on the Cosmos Database

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Abstract

Purpose

Methods

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Conclusion

Introduction

Methods

Results

Discussion

Conclusion

References

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Journal Publication

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