Clinical Features of a Family with Multiple Endocrine Neoplasia Type 2A Caused by the D631Y RET Mutation

Abstract

We describe a family with multiple endocrine neoplasia type 2A (MEN2A) caused by the D631Y RET mutation resulting in an atypical phenotype. The index case was a 24-year-old man with history of recurrent anaplastic ependymoma incidentally found to have the D631Y RET mutation. At first assessment, four family members had evidence of large pheochromocytomas. One patient was found to have micromedullary thyroid cancer at 79 years of age. None of the patients had primary hyperparathyroidism. Patients with MEN2A caused by a D631Y RET mutation most commonly present with pheochromocytomas. Medullary thyroid cancer is a less common part of the syndrome when compared with other RET mutations.

Introduction

Multiple endocrine neoplasia type 2A (MEN2A) is a rare autosomal dominant endocrine disorder caused by mutations of the RET proto-oncogene (1). The most common clinical feature of MEN2A is medullary thyroid cancer (MTC), with pheochromocytoma (PHEO) and primary hyperparathyroidism (HPT) affecting a smaller percentage of gene carriers (1). Although almost all patients will develop MTC, the penetrance of PHEO ranges from 25% to 88% according to age in patients with mutations in codon 634 and between 4% and 24% in patients with exon 10 RET codon mutations (1).

The most common mutations associated with MEN2A are those that affect codon 634, which accounts for ∼85% of cases (1,2). Mutations in RET codon 631 are rare, and in contrast to the classic presentation of MEN2A, ∼50% of the patients with the D631Y mutation previously reported presented with PHEO and only ∼30% with MTC (3,4).

Our aim was to summarize the clinical findings of a newly uncovered, single family with this rare mutation.

Methods

A retrospective review of the electronic medical records of a newly identified family with MEN2A caused by the D631Y mutation was performed. Mutation analysis was performed in 12 family members and was not completed in 15 family members (two were deceased and 13 did not agree to be evaluated).

This report was exempt from Institutional Review Board approval as a case series reporting on preexisting data. A general consent form for research is signed by patients in our institution according to Minnesota state law.

Mutation Analysis

Index case

The genetic mutation analysis in the index case was performed at Baylor College of Medicine, Medical Genetic Laboratories using whole exome sequencing on DNA extracted from tumor tissue of the ependymoma as well as peripheral blood.

Family members

DNA sequence analysis was used to test for the presence of the p.D631Y (c.1891G>T) mutation in exon 11 of the RET proto-oncogene from peripheral blood samples. Testing was performed at Mayo Medical Laboratory.

Results

Presentation of the index patient

A 24-year-old man with a complicated history of recurrent ependymoma was evaluated by genetic analysis in order to guide his oncology treatment. He was found to have a germline mutation in the RET gene, D631Y. Clinical and laboratory evaluation confirmed a secretory, benign pheochromocytoma with no evidence of primary HPT or MTC (Table 1).

Table 1.

Clinical Features of Members of a Single Family with MEN2A Caused by RET D631Y Mutation

No.	Age	Sex	PHEO (size)	PHEO biochemistry	Calcium level	Creatinine level	Kidney stones, fractures	Medullary thyroid cancer^a	Thyroid Ultrasound	Calcitonin^b	Carcino-embryogenic antigen^c	Other history
1	24	Male	4 cm	M 3.2 NM 3.5	9.8	1	No	No	3 mm cyst, no lymph nodes	<7	NA	History of hypertension with spells
2	27	Female	No	M 0.4 NM 0.6	9.1	0.8	No	No	Normal	<5	NA	Healthy
3	54	Male	1.8 cm	M 0.65, NM 0.63	9.5	1	No	No	Normal	<7	1.6	No symptoms
4	57	Male	No	M 0.26 NM 0.33	9.1	0.9	Incidental kidney stones	No	0.4 cm low suspicion nodule, no lymph nodes	<5	NA	Diabetes mellitus
5^d	53^d	Female	No	Urine MN 370	NA	NA	NA	No	Normal	<7		Healthy
6	56	Female	4.6 cm	M 7.8NM 3.0	9.6	0.9	No	No	Normal	<5	NA	Palpitations, normal blood pressure
7	24	Male	No	M 0.3NM 0.59	9.6	1	No	No	5 mm cyst, no lymph nodes	<5	1.9	Untreated hypertension, blood pressure 159/60 mm Hg
8	29	Female	2.7 cm	M 0.92NM 1.0	9.6	0.6	No	No	5 mm cyst, no lymph nodes	<5	0.9	Palpitations
9	26	Female	No	M < 0.2NM 0.26	9.2	0.8	No	No	Normal	<5	1.4	Palpitations
10	79	Female	No	M 0.42NM 0.81	9.6	0.6	No	0.2 cm	0.3 cm nodule	11	5.2	Healthy

The mean age at the time of MEN2A mutation diagnosis for the 10 family members found to be affected by the D631Y mutation was 43 years (standard deviation of 19, range 24–79 years), and 60% were women.

Only one patient underwent thyroidectomy.

Normal levels: males, <16 pg/mL; females, <8 pg/mL.

Normal level: <3 ng/mL.

Two centimeter adrenal mass, normal biochemical evaluation for PHEO.

Age, age at diagnosis in years; M, plasma metanephrines (normal, <0.50 nmol/L); NM, plasma normetanephrine (normal, <0.90 nmol/L); PHEO, pheochromocytoma; Urine MN, 24 hour-urinary metanephrines (normal, <400 μg/24 h).

Clinical features of the family members with D631Y mutation

At the time of this report, 12 family members have been comprehensively evaluated. The patient's sister and mother have tested negative for the RET D631Y mutation. The clinical features of the 10 family members affected by the mutation are found in Table 1 and Supplementary Figure S1 (Supplementary Data are available online at www.liebertpub.com/thy).

At first evaluation, 4 mutation carrier patients were found to have unilateral PHEO, with a mean size of 3.3 cm (standard deviation 1.3, range 1.8–4.6 cm) and positive biochemical parameters. MTC was found in the oldest patient in the family (79 years old). Her ultrasound showed a 3 mm lesion that was compatible with a 0.2 cm micromedullary thyroid cancer on histology after thyroidectomy. HPT was evaluated in 9 patients, without any family member having hypercalcemia (Table 1).

Discussion

Clinical evaluation of a family found to have MEN2A secondary to the D631Y mutation revealed large PHEOs in 4 out of the 10 affected family members at first evaluation, while only one patient (age 79) presented with MTC and none had HPT. To the best of our knowledge and investigation, there is no described association between RET mutations, including D631Y, and ependymoma, and no other family members or mutation carriers have had this tumor. Thus, we deem the finding of RET mutation and MEN2A in this patient to be incidental in nature.

When our findings are combined with previous reports (total of 29 mutation gene carries), 45% of D631Y mutation carriers had PHEO, while only 24% were found to have MTC. A summary of other clinical features of the reported families with D631Y mutation is found in Supplementary Table S1 (3,4). This contrasts with the expected prevalence for MTC of >90% in patients with MEN2A due to other RET mutations, which is often the first presentation of the syndrome within a family (1,2). However, only 1 out of 10 adult mutation carriers in this family have undergone thyroidectomy to date, as comprehensive evaluation using thyroid US imaging and biochemical evaluation did not reveal any evidence of MTC. These individuals will be followed closely for appearance of additional tumors.

Our study is limited by the small sample size and the fact that not all family members agreed to be evaluated. As a result, the description of the clinical features of this family can change if additional members proceed with evaluation.

In summary, patients with MEN2A caused by a D631Y mutation most commonly (and initially) present with PHEO. MTC is less commonly part of syndrome and/or appears to have a later onset when compared with other more common RET mutations.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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