We report one of the youngest patients in the literature with MTC due to familial MEN 2B at 9 weeks of age. Histologically, the tumor was 2.5 mm in size and had infiltrating borders in focal areas, confirming the diagnosis of microscopic MTC and distinguishing it from C-cell hyperplasia . Other reports of early MTC in MEN 2B include a microscopic MTC in a 9-week-old infant, but with a de novo mutation , and metastatic MTC in a 3-month-old infant with familial MEN 2B .
Although extensive long term follow-up data is lacking in MEN 2B , the benefit of prophylactic thyroidectomy before the onset of metastatic MTC is well accepted . The current guidelines state that prophylactic thyroidectomy for ATA-D (highest risk) mutations must be undertaken "as soon as possible and within the first year of life" . Our case, together with these other reports, highlights the importance of early prophylactic surgery during infancy. However, while the guidelines allow for surgery up to a year of age, our case raises the question as to whether intervention should occur “as soon as possible” in earlier infancy. In familial cases, when the diagnosis is anticipated, thyroidectomy soon after the first month of life could be considered.
Current hurdles to performing prophylactic total thyroidectomy in the first few months of life include: 1) time delays in arriving at a diagnosis and scheduling surgery, 2) concern that surgical and anesthetic risks outweigh the benefits of surgery at that age, and 3) concern for iatrogenic hypothyroidism.
Any impediment to the multiple steps associated with the treatment of these patients, including genetic testing, referral to a pediatric thyroid surgeon, pre-surgical evaluation and procedure scheduling, could result in significant surgical delay. An early diagnosis should be made by genetic testing of at risk infants soon after birth, or even prenatally. The ATA guidelines recommend that all patients with MEN 2B of child-bearing age should be offered prenatal genetic counseling . This includes discussion of the options of pre-implantation genetic testing (enabling implantation of unaffected embryos using assisted reproductive techniques), chorionic villus sampling, and amniocentesis. Prenatal genetic counseling helps parents understand the risk of having an affected infant (50%) and the importance of prophylactic thyroidectomy in an asymptomatic baby, and facilitates RET testing early in the newborn period. In addition, if surgical referral and scheduling of anticipated thyroidectomy (contingent upon subsequent confirmation of the diagnosis) occur prenatally in familial cases, postnatal genetic confirmation may become the sole rate-limiting step. Of note, while pre-operative calcitonin measurement is recommended, calcitonin concentrations should be interpreted with caution in infants below 6 months of age and should not be used to dictate surgical decisions .
There are potential surgical and anesthetic risks associated with performing thyroidectomy during early infancy. Children younger than six years of age have the highest rate of complications following thyroidectomy as compared with adults, although outcomes may be improved by referral to high-volume surgeons . Significantly delaying prophylactic thyroidectomy may improve patient safety, but is not an option in MEN 2B when surgery has to be undertaken by a year of age, and possibly sooner. There are no formal studies of thyroidectomy outcomes in infants below a year of age. However, it is our opinion that there is little additional surgical risk for an infant one month of age compared with six months of age when performed by an experienced pediatric thyroid surgeon working in an environment with appropriate pediatric resources. Surgical complications include hypoparathyroidism and recurrent laryngeal nerve injury. Post-operative hypoparathyroidism does not appear to be related to the age of surgery in children with MEN , while the risk of both complications is increased by lymph node dissection . An added benefit of early surgery soon after a month of age in familial MEN 2B is that central neck dissection may be avoided. According to the ATA guidelines, “thyroidectomy prior to lymph node metastases obviates the need for central compartment lymph node dissection which is associated with a higher rate of hypoparathyroidism and vocal cord paralysis” .
There is evidence that the risk of general anesthesia is greater in a child under one year of age . However, anesthetic risk can be attenuated by carefully screening for children with a history of prematurity, congenital heart disease, or other congenital abnormalities . We typically wait until a full-term infant is one month of age before administering anesthesia for an elective procedure in order to minimize the risk of post-operative apnea. We therefore suggest that thyroid surgery be undertaken after 30 days of age in a child with MEN 2B.
Finally, the consequences of undertreating iatrogenic hypothyroidism are a potential problem. This concern should not warrant delaying thyroidectomy; instead, intensive monitoring and careful replacement of levothyroxine is essential .