This 13-year-old girl was admitted for evaluation of a 6month history of weight loss and fatigue. Despite a normal food intake, she has been losing weight and stopped menstruating several months earlier. Most recently, she had been complaining of weakness. She previously had been able to walk to school carrying her bag, but she was rapidly becoming unable to do so. She now complains of diffuse pain in all of her extremities and is unable to walk secondary to weakness and pain. Several days earlier, she noted the appearance of multiple masses in her breasts, which prompted medical attention.
Her past medical history is remarkable for having been diagnosed with bilateral slipped capital femoral epiphysis (SCFE) two years previously. At that time, she presented with a painful limp. Her mother states that the diagnosis was surprising to her doctors because she was tall and thin. She had a repair at an outside hospital and two subsequent surgeries to re-pin her right hip. She had her first menstrual period at age 1 1, and they had been regular for the next 18 months. She denied alcohol, drug, and tobacco exposure, and had no history of sexual activity. She's in a regular eighth-grade classroom. The family history was unremarkable.
On examination, she was markedly cachectic and in a great deal of pain. Temperature was 36.6° C, pulse 112, respiratory rate 26, blood pressure 108/79. Weight was markedly below the 5th percentile, and height was in the 90th percentile. She was obviously very tall and very thin. HEENT examination was unremarkable save for a slight nodularity to her Ups. In addition, her lips looked a little large, out of proportion to the rest of her face. There was a 2-cm, non-tender, non-mobile nodule on her right lateral neck. Lungs were clear. There were multiple large, firm masses in each breast. Abdomen was soft and non-tender without masses or organomegaly. Extremities were extremely tender to palpation, although there were no discreet masses or bruising. On neurologic examination, deep tendon reflexes were 2+ bilaterally. There was decreased muscle mass throughout with decreased strength.
Robert Listernick, MD, moderator: This is a very complicated case. Let's start with her past diagnosis of bilateral SCFE. What is a SCFE?
Eric King, MD, pediatric orthopedic surgeon: It's essentially a transphyseal fracture that occurs following low-energy trauma. Most other transphyseal fractures occur as a result of high-energy trauma, such as a car accident.
Dr. Listernick: How do children with SCFE generally present?
Dr. King: There are two classic presentations of SCFE: acute SCFE, in which children have pain or limp of less than three weeks' duration, and chronic SCFE, in which children have a longer history of symptoms. Children with chronic SCFE generally have a stable hip on which they can weight bear and walk; children with acute SCFE have an unstable hip that requires immediate treatment.
Dr. Listernick: In general, who gets an SCFE?
Dr. King: We tend to think of typical and atypical SCFEs. The typical presentation is a heavy child between 10 and 16 years. The incidence of typical SCFE is dramatically on the rise because of the obesity epidemic. Anyone else, such as this girl who is tall and thin, would be considered an atypical case. We actually have a chart that we use to distinguish between these two groups. Anyone less than the 50th percentile in weight or outside of the 10-to- 16-year range is atypical.
Dr. Listernick: Why is this distinction important?
Dr. King: Children who have atypical presentations are more likely to have an underlying disorder such as hypothyroidism, chronic renal failure, or a history of radiation therapy.
Dr. Listernick: How do you approach the treatment of SCFE?
Dr. King: Typical cases undergo repair of the SCFE, immediately if they have an acute SCFE, and at some point in the near future for á chronic SCFE. Atypical cases generally are referred to an endocrinologist for evaluation, and the SCFE is repaired. In the typical repair, we perform a gentle reduction of the fracture to reestablish anatomic normality and then place a pin in situ. In addition, we often prophylactically place a pin in the contralateral hip because of the markedly increased risk of bilateral disease in atypical cases.
Dr. Listernick: How does the endocrinologist approach a child who has an atypical SCFE?
Don Zimmerman, MD, pediatric endocrinologist: All of the children who have endocrine causes of SCFE have abnormal epiphyseal growth plates. It makes sense that children who have SCFEs after 16 years have a "growth" problem; most adolescents at 16 years have fused epiphyses and no growth plates. The most commonly associated endocrine disease is hypothyroidism, but SCFE can be seen in unusual cases such as hypogonadism of any etiology, rickets, or pseudohypoparathyroidism.
Dr. King: An underlying etiology is found in the majority of atypical cases.
Dr. Zimmerman: SCFE can also be seen in children who have growth hormone deficiency. It's unclear whether this is due to the underlying disease or to growth hormone replacement therapy itself. It's been shown that normal rats given pharmacologic doses of growth hormone develop less distensible growth plates that are prone to microfractures.
Dr. Listernick: Moving on, this is a horribly tragic case. I can't think of a way to segue to the correct diagnosis other than to say it. She actually has multiple endocrine neoplasia type 2B (MEN2B). The diagnosis was made after biopsy of one of the breast masses revealed metastatic medullary carcinoma of the thyroid.
Dr. Zimmerman: As a review, the tumors seen in MENI are the "three Ps:" tumors of the parathyroid, pituitary, and pancreas. The central feature of both MEN2A and MEN2B is medullary carcinoma of the thyroid. Those who have MEN2A also develop parathyroid hyperplasia and pheochromocytomas. Those who have MEN2B also develop pheochromocytomas as well as multiple ganglioneuromas throughout their gastrointestinal tract. Both of these conditions are inherited in an autosomal-dominant fashion.
Dr. Listernick: What is the molecular biology of MEN2A and MEN2B?
Dr. Zimmerman: Both are caused by mutations in the RET proto-oncogene. MEN2A is caused by a gain of function mutation, usually in the extracellular portion of the molecule; MEN2B is caused by an activating mutation in the intracellular tyrosine kinase domain. In MEN2B, one sees an over-migration (from the neural crest) and overproliferation of ganglion cells leading to multiple ganglioneuromas throughout the gastrointestinal tract. The nodularity and thickness of this child's lips are due to the presence of these ganglioneuromas. In Hirschsprung's disease, the ganglion cells often have inactivating mutations of RET. Some patients with MEN2A have Hirschsprung's disease because of to the inefficiency of trafficking their constitutively-activated RET molecules to the cell surface.
Dr. Listernick: Why do these people develop a marfanoid habitus, being tall and thin?
Dr. Zimmerman: That's not clear, but they can also develop a severe neuropathy that leads to their hyperextensibility. This girl has bilateral pes cavus, which are high arches that do not flatten with weight bearing and that are highly specific for the presence of a peripheral neuropathy.
Dr. Listernick: Let's discuss the medullary carcinoma of the thyroid.
Dr. Zimmerman: Medullary carcinoma of the thyroid is derived from the cells that comprise the ultimobranchial body. In many species, this is a separate organ in the neck. However, in humans, these neural crest cells migrate into the thyroid gland and begin producing calcitonin.
Anthony Chin, MD, pediatric surgeon: Medullary carcinoma of the thyroid accounts for 5% of childhood thyroid cancers. Once diagnosed, MEN2A and MEN2B should be suspected immediately. Unfortunately, most cases of medullary carcinoma of the thyroid that we see are diagnosed at the time of distant metastases, as in this child. If a child has MEN2A, we recommend thyroidectomy by age 5; for MEN2B, the recommendation is for thyroidectomy in the first year of life. This cancer is much more aggressive in children who have MEN2B.
Dr. Zimmerman: When seeing these children, you always have to ask the age-old question: "2B or not 2B."
Dr. Listernick: Ignoring the Bard of Chicago for the moment, once a molecular diagnosis of a MEN syndrome is made and thyroidectomy is undertaken, how should these children be followed?
Dr. Zimmerman: Most importantly, they should be screened yearly for the development of pheochromocytoma with plasma metanephrine and magnetic resonance imaging (MRI) scans of the chest and abdomen. Patients should be supine for 20 minutes before the blood is drawn for the metanephrine levels.
Dr. Listernick: Let's look at her radiographs.
Mary Wyers, MD, pediatric radiologist: On the computerized tomography (CT) scan, there are numerous low-density lesions within both lobes of the thyroid. In addition, there are multiple enlarged mediastinal lymph nodes. The CT scan of the chest demonstrates multiple enhancing breast nodules, as well as numerous pulmonary nodules, all most likely representing metastatic disease. Finally, she has multiple destructive lesions in various bones throughout her body with associated soft tissue masses.
Dr. Listernick: Can we see the pathology?
Pauline Chou, MD, pediatric pathologist: We received slides from the outside hospital of a lymph node biopsy. The lymph node structure has been completely replaced by neoplastic cells arranged in nests and ribbons forming trabecular patterns. On high power, there are extensive areas of necrosis, and the cells have large nuclei with frequent mitoses. The neoplastic cells stain positive for calcitonin as well as endothelial and neuroendocrine markers. Given the clinical history, these findings are most consistent with a malignant neuroendocrine carcinoma, most likely medullary carcinoma of the thyroid.
Dr. Listernick: So this child has widely disseminated metastatic disease that might have been prevented if she had been diagnosed as having MEN2B years earlier and had a prophylactic thyroidectomy. I imagine the parents must have been extremely angry. How did you approach them with this information?
Stanley Chaleff, MD, pediatric oncologist: There are really two issues. First, we needed to deal with the mother's guilt, unfounded as it may be, about the delay in diagnosis. We tried our best to reassure her that she had done everything possible, in that her daughter had had multiple physician visits throughout the past 5 years. After 1 week or so in the hospital, she also started asking questions as to why this diagnosis had not been made years earlier. I believe that we answered her honestly, saying that this is a rare disease and a difficult diagnosis to make, but that it certainly could have been diagnosed much earlier.
Dr. Zimmerman: I agree that, if she hadn't been, she should have been referred to an endocrinologist years earlier when the diagnosis of SCFE was made. However, with that said, it might have been a difficult diagnosis for some endocrinologists to make. The phenotype of the "bumpy lips" caused by the ganglioneuromas develops throughout years and might not have been present earlier. Very young children with MEN2B may develop "sentinel bumps," little protuberances on the buccal mucosa inside the comers of athe mouth. However, they are quite easily overlooked, and the physician has to know what he or she is looking for. In the absence of a family history, it's unusual to diagnose MEN2B before the patient has metastatic disease. However, if a prophylactic thyroidectomy is performed prior to the development of a metastatic disease, the patient's prognosis is excellent. They have to be screened periodically for the development of pheochromocytomas.
Dr. Listernick: Assuming she has an identifiable RET mutation, each parent would need to undergo mutation analysis as well.
Dr. Zimmerman: New mutations are fairly common. Given that neither parent is symptomatic in adulthood, her case is more likely the result of a spontaneous mutation.
Dr. Listernick: I understand that, despite her prognosis and the fact that her disease progressed rapidly, and she now is undergoing mechanical ventilation secondary to her parenchymal lung disease and extensive pleural involvement, she is receiving experimental chemotherapy.
Dr. Chaleff: We received compassionate use approval from the drug company to use an experimental tyrosine kinase inhibitor that targets the RET oncogene. We've offered its use for palliative care. Based on what we know of the drug, it does not have any significant adverse effects that would make this child feel worse, and it has the potential to stabilize the disease. We offered the family use of this drug before she became ventilator-dependent.
Dr. Listernick: Is this a rational, humane approach?
Joel Frader, MD, pediatric ethicist: I don't believe that we should be discussing rationality, as opposed to "feelings." This heavily-sedated child cannot enter into the decision-making process. The mother, who we have been told has already experienced significant guilt, has to live with whatever decisions she and clinicians will make. The use of "compassionate" therapy (an unfortunate misnomer, usually a euphemism for unproven intervention with a statistically tiny, if any, likelihood of clinical benefit) may not appear rational to many healthcare professionals. However, it may make perfect sense to family members who understand the patient will die but want to feel they have pursued all possible treatments. As long as the child is comfortable, it seems problematic to claim treatment is wrong.
Dr. Listernick: Thank you, everybody.