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Multiple endocrine neoplasia type 2B: Frequency of physical stigmata—Results of the GPOH‐MET registry

Multiple endocrine neoplasia (MEN) 2B is characterized by early development of aggressive medullary thyroid carcinoma (MTC), visible physical stigmata, and associated symptoms. In most cases, de novo mutations are revealed. There are premonitory symptoms and stigmata that enable early diagnosis, before an inoperable MTC develops. The German Society for Paediatric Oncology and Haematology (GPOH)—Malignant Endocrine Tumours (MET) registry maintains records of children with MTC in Germany since 1997.

(familial MTC). In addition to calcitonin-producing thyroid tumors, pheochromocytoma, typical stigmata, and associated symptoms sometimes characterize children with MEN 2B. 2 MTC is usually the first tumor to occur and is the most common cause of death among these patients. 3 This malignancy is particularly aggressive in MEN 2B and may even occur in infancy. 4 Therefore, the current American Thyroid Association (ATA) guidelines recommend thyroidectomy in the first year of life, perhaps even in the first months. 5 The pathogenesis of MEN 2B involves the proto-oncogene rearranged during transfection (RET). 6 This gene encodes a transmembrane receptor tyrosine kinase that activates multiple downstream pathways, promoting cell growth, proliferation, and survival. The vast majority of patients with MEN 2B harbour de novo mutations and have no sign of predisposition in their family history. It is crucial to recognize typical stigmata before the patient develops advanced MTC with a poor prognosis. Detailed description of the phenotype and age-related appearance may help to recognize patients before the development of advanced MTC with a poor prognosis. 7 A recent international, multicenter, retrospective study highlights the importance of early diagnosis with impact on overall survival (OS). 8

METHODS
The GPOH-MET 97 study, conducted by the German Society for Otto-von-Guericke-University Magdeburg (174/12, 20.12.12), Germany. Written informed consent was obtained from either the parents of the patients or the patients themselves, if 15 years of age or older, and was necessary for registration and follow-up.
Records were retrospectively reviewed for children with a histological diagnosis of MTC in MEN 2B who had been admitted from January 1996 through May 2017. All patients with only somatic RET mutations were excluded. All clinical features mentioned in the medical charts were collected and summarized for each child. Morphologic features and associated symptoms were analyzed as described by Kahn et al. 9 Growth disturbances were included in this analysis because the musculoskeletal system is involved in MEN 2B. Disturbances of growth were defined as individual height below the third or above the 97th percentile for the corresponding mean height for a given age, sex, and population. If no precise body measurements were available, the diagnosis was made if it was mentioned by a physician or if hormonal therapy was provided. 10 The data of the German Health Interview and Examination Survey for Children and Adolescents (KiGGs 2003(KiGGs -2006 were used as reference population (Bundesblatt). Percentile curves and ranks were calculated using CrescNet. 11 Information regarding the heights of the parents was available in only a few cases. Weight for height percentage was used in children with short stature for nutritional assessment. The weight was compared with the weight (50th percentile) of a child of the same sex and height.
The time course of the disease and the development and recognition of the symptoms were not analyzed because the reporting was not sufficiently detailed in most cases. Pearson's chi-squared test was used to compare the frequency of categorical data. Student's t-test was used to compare the means of the two groups. OS was estimated using Kaplan-Meier survival analysis and compared using the log-rank test.
Data analysis was performed using SPSS 24.0. Any finding with a Pvalue less than .05 was considered significant.

Frequency of stigmata and symptoms associated with MEN 2B
The most frequent phenotypic characteristics affected the oral/dental (88.0%), musculoskeletal (79.2%), and gastrointestinal systems (70.8%) ( Table 1). Regarding the prevalence of single symptoms, neuromas of the lips (often described as "bumpy lips"), the tongue, and the buccal mucosa were mentioned most frequently. Chronic constipation, often since infancy, was the second most frequent finding. If histological investigations were performed, intestinal ganglioneuromatosis was diagnosed in these cases. Furthermore, marfanoid habitus was described with the same frequency.
In addition to marfanoid appearance, growth abnormalities, deformities of the foot and hip, muscle hypotonia, and malpositions of the spinal column were recognized. Ocular manifestations were reported in more than half of the children. Chronic or recurrent conjunctivitis, mucosal thickening, and neuromas were registered most frequently.
An inability to cry with tears was recognized by the treating physicians in four patients. Neuromas of the larynx were rarely detected.

Growth disturbances in MEN 2B
Growth disturbances were detected in 14 of 24 (58.3%) patients.
Eleven children showed heights below the third percentile and were

Age-related appearance of symptoms and stigmatas in MEN 2B
When examining the first evidence of symptoms, gastrointestinal disorders and musculoskeletal symptoms preceded with a significant margin the first symptoms of MTC (Breslau test, P = .001 and P = .027) (Figure 3). Chronic constipation or diagnoses of intestinal

Outcome by type of diagnosis
Clinical presentations and extent of disease by type of diagnosis are shown in Table Figure 4).

DISCUSSION
It is crucial to recognize children harbouring de novo RET protooncogene mutations that cause MEN 2B. 12 If affected children are identified before the development of advanced malignant disease, surgical cure is possible. 7 The aim of this retrospective analysis was to collect all the different characteristics in as much detail as possible. The impact on clinical course and outcome should also be determined.
In our data, oral and dental findings were the most frequent mani-

F I G U R E 4 Considerations leading to diagnosis and overall survival
have considered tearless crying a harmless feature and failed to report it to the treating physicians.
In the data from the GPOH-MET registry, oral and dental stigmata were the most common manifestations. Overall, 23 of 24 patients had conspicuous oral, dental, and/or facial symptoms. Among these findings, neuromas of the tongue, lips, and buccal mucosa were 2B and advanced MTC due to late diagnosis. 25 In all four patients, chronic constipation had been present since infancy. It cannot be stressed enough that severe chronic constipation since early infancy should be followed up and investigated. 26,27 Constipation is the second symptom appearing in the course of life, according to Brauckhoff et al. 13 Many patients report constipation during early childhood, later to be intermittently relieved by diarrhea. 15,21 Marfanoid habitus is assumed to be present in the majority of patients with MEN 2B. 23 The label "marfanoid habitus" is a collective, nonspecific term that is difficult to standardize. This manifestation is characterized among other manifestations by large hands and feet, long extremities, and an elongated face. Many of the patients included in the present study were described as marfanoid without a complete list of single symptoms. In addition to MEN 2B, marfanoid habitus is reported in Perrault syndrome, Lujan-Fryns syndrome, and Shprintzen-Goldberg syndrome, to name just a few. [28][29][30] In There are a number of case reports dealing with ophthalmologic signs of the disease. 35,36 Critical findings could be possible if the patient is examined by an ophthalmologist or an oculoplastic surgeon. 37 Prominent corneal nerves, thickening of the eyelids, and subconjunctival neuromas are frequently reported. In a review of 33 published cases, prominent corneal nerves were a striking ocular char-acteristic of MEN 2B. 38 In the present analysis, not all children were examined by ophthalmologists. Therefore, the incidence of ocular findings may be underestimated. Some of the ocular features are asymptomatic and may go unnoticed by the patient and the physician.
Laryngeal neuromas appear to be very rare in MEN 2B. Only a few patients have been reported in the literature. 39 43 It is possible that greater awareness of the phenotype led to earlier diagnosis and fewer patients with advanced disease.
In our data, among stigmata and associated symptoms, intestinal ganglioneuromatosis leading to chronic constipation was the most In this analysis of the clinical features of children included in the nationwide multicenter GPOH-MET registry over 20 years, oral/dental symptoms were most frequently detected, followed by musculoskeletal and gastrointestinal symptoms. Whether the diagnosis was based on symptoms of MTC or stigmata had a significant impact on outcome.
Furthermore, this report is the first to assess growth disturbances and their association with MEN 2B.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.