Endocrine Journal
Online ISSN : 1348-4540
Print ISSN : 0918-8959
ISSN-L : 0918-8959
CASE REPORT WITH REVIEW OF LITERATURE
p.M918W, a novel RET germline variant: a case report and literature review of the possible association of multiple endocrine neoplasia type 2B and Charcot-Marie-Tooth disease
Mami Sato† , Rei Kubota†, Shinya Uchino, Takayuki Morita, Ryoyu Niikuni, Teruhisa Udagawa, Yoshiya Hagiwara, Miyako Tanaka, Miku Sato, Yuta Tezuka, Kei Omata, Yoshikiyo Ono, Kazuhiro Haginoya, Noriaki Nakashima, Keisei Fujimori, Takanori Ishida
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Keywords: RET, RET variant, Multiple endocrine neoplasia type 2B, Medullary thyroid carcinoma, Charcot–Marie–Tooth disease
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2025 Volume 72 Issue 7 Pages 839-845

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Abstract

Multiple endocrine neoplasia type 2B (MEN2B) is a rare autosomal dominant disorder caused by germline pathogenic RET variants. On the other hand, Charcot–Marie–Tooth disease (CMT) is a hereditary neurological disorder, characterized by distal muscle weakness and sensory loss, with approximately 100 identified causative genes. Herein, we report a de novo RET mutation in a patient presenting with clinical features of both MEN2B and CMT. The patient, a 22-year-old woman, had a history of lower limb muscle weakness, with no family history of MEN2B or CMT. The patient was being treated for a thyroid gland neoplasm. Genetic testing of the medullary thyroid carcinoma revealed a previously unreported RET germline variant, p.M918W (RET: c.2752_2753delinsTG, p.Met918Trp). The novel p.M918W RET variant was associated with concurrent MEN2B and CMT. This finding was unexpected as MEN2B typically manifests with distinct features, such as marfanoid habitus and mucosal neuromas, but not with muscle weakness, as seen in CMT. Based on this finding, the plausible role of the p.M918W mutation as a shared pathway for both MEN2B and CMT warrants further investigation.

Introduction

Multiple endocrine neoplasia type 2B (MEN2B), a rare autosomal dominant disorder characterized by medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism, is caused by RET germline pathogenic variants. MEN2B is one of the two types of MEN2 (i.e., 2A and 2B), with differences in clinical manifestation between the two types, based on the site of the mutated codon on the RET gene. On the other hand, Charcot–Marie–Tooth disease (CMT) is a hereditary neurological disorder, characterized by distal muscle weakness and sensory loss, with approximately 100 reported causative genes [1, 2]. The prevalence of MEN2B and CMT is very different. The incidence of MEN2B is very low, with an estimated prevalence of 1 in 500,000 to 4,000,000 individuals. Moreover, >75% of MEN2B cases result from de novo mutations [3-7]. By comparison, CMT is relatively common, with a prevalence of approximately 1 in 6,000 individuals [8, 9]. Herein, we describe a unique case in which a patient with a novel RET germline variant (codon 918 mutation) presented with concurrent features of both MEN2B (medullary thyroid carcinoma) and CMT (lower limb muscle weakness).

Case Presentation

The patient was a 22-year-old female born via vaginal delivery after full term pregnancy to un-consanguineous Japanese parents. She did not have any family history of neuromuscular diseases or thyroid, parathyroid, or adrenal disorders. At birth, she had bilateral congenital clubfoot, which was treated and followed up by an orthopedic surgeon. She started walking at the age of 16 months. At the age of 7 years, she developed leg muscle weakness and was referred to a pediatric neurologist at the age of 9 years. On examination, she presented with pes cavus, muscle atrophy, and profound weakness of the bilateral tibialis anterior and foot muscles. The vibration sense on her feet was also reduced. A motor nerve conduction study revealed no response of the bilateral peroneal nerves, while compound motor action potentials and conduction velocity of the bilateral posterior tibial nerves were within the reference range. Electromyography of the tibialis anterior muscle showed polyphasic giant potentials. These findings indicated the presence of axonal neuropathy. She also developed exaggerated patellar, Achilles tendon, and Babinski reflexes at the age of 12 years. The gait disturbance and foot deformity were progressive, which was compatible to that manifesting in CMT with pyramidal features [10]. During a routine checkup at the age of 22 years, thyroid nodules were identified, with a diagnosis of medullary thyroid carcinoma confirmed by fine-needle aspiration cytology. Findings on physical examination included multiple glossy nodules (neuromas) on the tongue (Fig. 1) and bilateral lower limb muscle atrophy. Marfanoid habitus was not observed.

Fig. 1  Photograph of the patient’s tongue, showing multiple glossy nodules that were diagnosed as neuromas.

Diagnostic investigations included ultrasound imaging, urine analysis, blood biochemistry tests, computed tomography (CT), and positron emission tomography (PET). As MEN was suspected, genetic counseling was provided, and RET genetic testing was conducted. Using DNA extracted from leukocytes in peripheral blood, Sanger sequencing of exons 10–16, except exon 12, of the RET gene was performed using an automated sequencer.

Diagnostic findings were as follows. On ultrasound imaging, lesions were identified in the right (10 mm) and left (30 mm) thyroid lobes, with evidence of coarse calcification in both lobes. Additionally, a hypoechoic, heterogeneous lymph node was identified in the right deep cervical region. Cytological results at these sites confirmed the diagnosis of medullary thyroid carcinoma (Fig. 2). Findings of elevated serum levels of calcitonin (974.10 pg/mL) and carcinoembryonic antigen (38.5 ng/mL) on blood analyses were consistent with the diagnosis of medullary thyroid cancer. In addition, urinary hormone analysis revealed mildly elevated metanephrine levels, considered as borderline for the presence of pheochromocytoma (Table 1).

Fig. 2  (A) Schematic representation of the location of tumors shown in (B–D). Thyroid ultrasound images, showing (B) the right deep cervical, (C) right thyroid lobe, and (D) left thyroid lobe regions.
Table 1 Results of blood and urine analyses

Biochemistry Reference range
 Human thyroid-stimulating hormone 2.20 μIU/mL 0.50–5.00 μIU/mL
 Free thyroxine 1.43 ng/dL 0.90–1.70 ng/dL
 Free triiodothyronine 3.35 pg/mL 2.30–4.00 pg/mL
 Calcitonin 974.10 pg/mL ≤3.91 pg/mL
 Carcinoembryonic antigen 38.5 ng/mL ≤5.0 ng/mL
 Adrenaline 0.05 ng/mL ≤0.17 ng/mL
 Noradrenaline 0.49 ng/mL 0.15–0.57 ng/mL
 Sodium 139 mmol/L 138–145 mmol/L
 Potassium 3.6 mmol/L 3.6–4.8 mmol/L
 Chlorine 102 mmol/L 101–108 mmol/L
 Calcium 9.1 mg/dL 8.8–10.1 mg/dL
 Inorganic phosphorus 3.9 mg/dL 2.7–4.6 mg/dL
 Whole parathyroid hormone 50.3 pg/mL 14.9–56.9 pg/mL
 Albumin 4.8 g/dL 4.1–5.1 g/dL
Urinary hormone Reference range
 Adrenaline 15.2 μg/day 1.1–22.5 μg/day
 Noradrenaline 62.2 μg/day 29.2–118.0 μg/day
 Metanephrine 0.19 mg/day 0.05–0.20 mg/day
 Normetanephrine 0.11 mg/day 0.10–0.28 mg/day

CT of the neck region revealed a 17 mm tumor in the left thyroid lobe and an 8 mm tumor in the right lobe, with no invasion into the surrounding organs. In the abdominal region, a 9 mm nodular lesion was visible in the right adrenal gland, with normal appearance of the left adrenal gland. There were no apparent signs of lymph node or distant metastasis from the medullary thyroid carcinoma (Fig. 3). PET-CT revealed increased radiomarker accumulation in the tumor in the left thyroid lobe and nodule in the right adrenal gland, with no other regions of abnormal accumulation (Fig. 4).

Fig. 3  Computed tomography images of the thyroid and adrenal glands showing (A) a carcinoma of the left lobe of the thyroid gland, (B) a carcinoma of the right lobe of the thyroid gland, and (C) a tumor of the right adrenal gland.
Fig. 4  Positron emission tomography-computed tomography images showing (A) transverse images of the cervical region and (B) full-body coronal images.

Family-based whole-exome sequencing identified a heterozygous de novo RET gene variant (c.2752_2753delinsTG p.Met918Trp), which was considered likely pathogenic according to the American College of Medical Genetics and Genomics guidelines (PM2 + PS2 + PM5) (Fig. 5). There were no other pathogenic variants.

Fig. 5  Genetic testing of the RET gene showing the p.M918W mutation (RET: c.2752_2753delinsTG p.Met918Trp.) located in exon 16.

Two different facilities independently detected an RET p.M918W-exon 16 mutation through genetic testing (RET: c.2752_2753delinsTG p.Met918Trp). Genetic testing of the patient’s parents confirmed that both parents had a normal sequence in codon 918 of the RET gene. This confirmed that the identified p.M918W mutation in our patient was a de novo variant (Fig. 5).

Based on these findings, a preoperative diagnosis of medullary thyroid carcinoma (cT2, N1b, M0, cStage4a) was made and the patient underwent total thyroidectomy and right-side neck lymph node dissection. Gross pathological findings of the resected thyroid gland (Fig. 6) confirmed the diagnosis—pT1b, pN1b, cM0, pStage4a medullary thyroid carcinoma. Immunohistochemistry was positive for calcitonin, chromogranin A, and synaptophysin. Generally, in cases of medullary thyroid carcinoma complicated by clinically evident pheochromocytoma, surgery for pheochromocytoma takes precedence over surgery for medullary thyroid carcinoma. In this case, however, the pheochromocytoma was still in its early stages and was considered to have little potential clinical impact; therefore, the medullary thyroid carcinoma was given priority.

Fig. 6  Photograph of the resected thyroid gland showing two medullary carcinomas, one in the mid-section of the left lobe (20 × 17 × 12 mm; black arrow) and the other in the upper right lobe (8 × 7 × 5 mm; white arrow).

The patient did not exhibit abnormally high blood pressure throughout the perioperative period, resumed oral intake on the first postoperative day, and was discharged on the fifth postoperative day. Compared to preoperative levels, calcitonin and carcinoembryonic antigen levels decreased post-surgery, with no increase over the first postoperative year (Fig. 7).

Fig. 7  Calcitonin and carcinoembryonic antigen levels post-surgery. CEA, carcinoembryonic antigen; Y, date of operation.

Discussion

In the present case, we identified a previously unreported germline RET variant, p.M918W. Although there are no prior reports on this variant, the p.M918T germline pathogenic variant, which occurs at the same position in the RET gene, is well documented and occurs at a high frequency; it is present in approximately 95% of patients with MEN2B [11]. Carriers of the p.M918T germline pathogenic variant have the highest malignancy grade of medullary thyroid carcinoma, as well as a higher incidence of pheochromocytoma, compared to carriers of other pathogenic variants [12]. Given that our patient had both lingual neuroma and medullary thyroid carcinoma in both thyroid lobes, as well as mild pheochromocytoma, there may be a phenotypic overlap between the p.M918W and p.M918T pathogenic variants.

In general, MEN2B presents with physical features such as marfanoid habitus, mucosal neuromas, and intestinal ganglioneuromatosis [13-15]. However, in our patient, although lingual mucosal neuromas were observed, marfanoid habitus and abdominal symptoms were absent. Clinically, it should be noted that not all individuals with MEN2B exhibit all three features; 50–60% of patients exhibit all three features [15]. The unique feature of the present case is the presence of CMT symptoms in a patient with MEN2B.

To our knowledge, only one previous case of concomitant MEN2B and CMT has been reported [16]. In that case, the identified p.M918T germline pathogenic variant is the typical variant expected. Generally, the relationship between MEN2B and CMT is considered weak as MEN typically involves abnormalities in hormone-secreting cells and does not possess the characteristic neural abnormalities observed in CMT [13-15, 17]. However, in MEN2B, mucosal neuromas, such as those observed on the tongue, have been associated with Schwann cell proliferation [18, 19]. If the p.M918W mutation also results in peripheral Schwann cell dysfunction, this may explain the CMT symptoms observed in the present case. The history of congenital clubfoot and gastric axis torsion is a strong congenital feature, but it is nonspecific, and the association is unknown; to the best of our knowledge, the combination of congenital clubfoot and CMT symptoms has also not been reported.

Although the causal relationship between the p.M918W germline variant and MEN2B and CMT remains unclear, it is possible that, similar to the more common p.M918T variant, the p.M918W variant may have a profound effect on homeostatic tyrosine kinase activation of the RET protein [13, 16]. These abnormalities in signaling pathways, which contribute to cell proliferation and differentiation, may play a role in the development of cancer and other nervous system manifestations.

The case summary has been provided in the Graphical Abstract.

Graphical Abstract

Conclusion

Herein, we identified a previously unreported germline variant in the RET gene, p.M918W. Although the relationship between the p.M918W variant and the concomitant development of MEN2B, CMT, and related diseases remains unclear, aberrant signaling caused by RET activation may lead to the development of medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and CMT symptoms. Based on this finding, the plausible role of the p.M918W mutation as a shared pathway for MEN2B and CMT warrants further investigation to elucidate the exact mechanism underlying the pathogenesis of these diseases and the relevance of each disorder.

Ethical Approval and Consent to Participate

Not applicable.

Consent for Publication

The patient provided consent for publication of this case study.

Availability of Data

The data used in this study are available from the corresponding author upon reasonable request. The data are not publicly available due to ethical restrictions.

Disclosure

None of the authors have any potential conflicts of interest associated with this research.

Funding

None to declare.

Author Contributions

Mami S and RK: Conceptualization, Formal analysis, Investigation, Project administration, Validation, Visualization, Writing—original draft, Writing—review & editing, SU: Investigation, Supervision, Validation, Visualization, Writing—review & editing, TM, RN, TU, YH, MT, Miku S, YT, KO, YO, KH, NN, KF, and TI: Writing—review & editing. All the authors have read and approved the manuscript.

References
Abbreviations

CMT

Charcot-Marie-Tooth disease

CT

computed tomography

MEN2B

multiple endocrine neoplasia type 2B (MEN2B)

PET

positron emission tomography

 
© The Japan Endocrine Society

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