European Journal of Endocrinology (2004) 151 771–777 ISSN 0804-4643

CASE REPORT Multiple endocrine neoplasia 2A syndrome presenting as peripartum cardiomyopathy due to excess Jaime Kim1, Sirimon Reutrakul1, Dawn Belt Davis1, Edwin L Kaplan2,4 and Samuel Refetoff1,2,3 1Departments of Medicine and 2Pediatrics, 3the Committee on Genetics and the J P Kennedy Jr Mental Retardation Research Center and 4Department of Surgery, University of Chicago, Chicago, Illinois 60637, USA (Correspondence should be addressed to J Kim; Email: [email protected])

Abstract We report the case of a 24-year-old female with a history of medullary thyroid who presented at 38 weeks gestation with acute chest pain and shortness of breath. She was found to be in pulmonary edema and respiratory failure. An emergency cesarean section was performed. Subsequently, an echocardiogram revealed an ejection fraction of 10%. After medical therapy with digoxin, milrinone, captopril and diuretics, her condition improved rapidly and a repeat echocardio- gram showed that the left ventricular function had normalized. Diagnosis of was made by urine and plasma catecholamine measurements. Magnetic resonance imaging revealed a 3.7 cm left adrenal mass. Increased uptake activity was seen in the same region by an 131I-metaio- dobenzylguanidine (MIBG) scan. The patient underwent successful surgical resection of the pheochromocytoma. Subsequent DNA analysis revealed that the patient had a mutation of the RET proto-oncogene. The same mutation was also found in several of her family members. In summary, we report a case of multiple endocrine neoplasia 2A presenting as peripartum cardio- myopathy and cardiovascular collapse. Pheochromocytoma should be considered as a potential cause of peripartum cardiomyopathy.

European Journal of Endocrinology 151 771–777

Introduction for a missed abortion one year earlier. Medication con- sisted of L-thyroxine (L-T4; 150 mg/day) and cholestyra- Pheochromocytoma presenting as cardiogenic shock is mine. She had no allergies and denied , alcohol, a recognized but relatively uncommon occurrence, and illicit drug use. Significant family history revealed a with only a few published cases (1, 2). We report an mother who died during childbirth. unusual case of a 24-year-old pregnant woman with The patient was brought in to the labor and delivery a history of medullary thyroid carcinoma who pre- suite; however, she was found not to be in labor. She sented with peripartum cardiomyopathy as a result of was afebrile with a pulse of 84 beats/min, a blood press- catecholamine release from a pheochromocytoma. ure of 124/84 mmHg, and a respiratory rate of 28 She had a rapid resolution of her cardiac dysfunction breaths/min. Wheezes and rales were present through- after only 5 days of medical therapy. Further investi- out both lung fields, with poor air movement. Initial gations confirmed the diagnosis of multiple endocrine arterial blood gas measurement, while on 6 liters of neoplasia 2A (MEN-2A). oxygen by nasal cannula, showed pH of 7.43, PaCO2 of 29 mmHg, PaO2 of 105 mmHg, and oxygen satur- Patient report ation of 96%. An electrocardiogram revealed sinus tachycardia with diffuse ST depression anterolaterally The patient was a 24-year-old Hispanic female (grav- in leads V2 through V6. Despite being given nebulized ida2, para1), who presented at 38 weeks gestation to albuterol treatments, her respiratory distress worsened another hospital with complaints of acute chest pain and she was intubated. A chest x-ray revealed bilateral and shortness of breath. In addition, she had neck pulmonary edema. Fetal bradycardia prompted an pain, and nausea with vomiting. Her pregnancy had emergency cesarean section. A liveborn female weigh- thus far been complicated only by cholestasis during ing 3660 g was delivered, with Apgar scores of 4 at her third trimester, for which she was taking 0 min, 6 at 1 min, and 6 at 5 min. The patient was cholestyramine. then taken to the intensive care unit. It was found that the patient had had medullary Her initial blood analysis at the outside institution thyroid carcinoma at age 21 for which she had had a was remarkable for a glucose of 18.4 mmol/l (normal thyroidectomy. Her obstetrical history was significant 4.2–6.4) and a calcium of 1.7 mmol/l (normal

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2.2–2.6). Urinalysis showed 300 mg/l protein and Upon arrival at our institution, the patient was .10 g/l glucose. Total creatine kinase was slightly elev- afebrile, with a heart rate of 120 beats/min, and ated at 350 IU/l (normal 22–269), with a creatine blood pressure of 80/50 mmHg. Pulmonary capillary kinase MB isoenzyme fraction of 10.8 mg/l (normal wedge pressure was 13 mmHg, cardiac output was 0–4) and a troponin I level of 0.97 mg/l (normal 0– 5.5 l/min/m2, and systemic vascular resistance was 0.5). The thyrotropin level was elevated at 31.4 mU/l 1152 dynes/s/cm. The patient was intubated and (normal 0.35–5.5). Hepatic function panel was sedated, but arousable. Her neck examination revealed remarkable for a serum glutamic oxaloacetic transam- no jugular venous distension, and a well-healed thyroid- inase (SGOT) level of 79 IU/l (normal 0–40), serum ectomy scar with no palpable thyroid tissue or other glutamic pyruvic transaminase (SGPT) of 128 IU/l masses. Diffuse rhonchorous breath sounds were (normal 0–50), and alkaline phosphatase of 227 IU/l present bilaterally. Abdominal examination showed a (normal 25–115). clean, dry cesarean section wound. A repeat echocardio- After the cesarean section, the patient became hypo- gram again revealed a moderately dilated left ventricle tensive and tachycardic. An echocardiogram revealed with severe global systolic dysfunction with an ejection poor left ventricular function with an ejection fraction of 10%. Captopril was started, milrinone was continued, of approximately 10%. Coronary angiography showed and L-T4 was given intravenously. no abnormalities. An intra-aortic balloon pump (IABP) Given the history of medullary thyroid carcinoma, and a Swan Ganz catheter were placed, but she contin- the possibility of pheochromocytoma and MEN-2A ued to be tachycardic at 140 beats/min and hypotensive was considered. The patient and her family were with systolic blood pressures of 70–80 mmHg, not further questioned, and it was discovered that the augmenting with the IABP. Pulmonary capillary patient’s mother had died during childbirth under wedge pressure was 15 mmHg. The patient was given circumstances that were very similar to the current furosemide, digoxin and milrinone, but her oxygenation situation. The patient did acknowledge having rare on mechanical ventilation remained poor. She was then episodes of intermittent diaphoresis, palpitations and transferred to our institution with the diagnosis of weakness lasting a few minutes over the last few possible peripartum cardiomyopathy. years. Therefore, urine was collected for immediate

Figure 1 T2-weighted MRI reveals a 3.7 cm high signal intensity mass in the left adrenal gland, with a central cystic area, characteristic of a pheochromocytoma.

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Downloaded from Bioscientifica.com at 09/28/2021 07:08:30AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151 Pheochromocytoma presenting as peripartum cardiomyopathy 773 catecholamine determination, and a 24 h urine collec- Ten days later, she returned for a left adrenalectomy. tion was begun. The spot urine showed elevated norepi- During the operation, the right adrenal gland was nephrine of 93.4 mg/g creatinine (normal level 7–65) palpated and felt to be normal. During manipulation of and epinephrine of 58.2 mg/g creatinine (normal the left adrenal mass, the patient became slightly 2–16), and a normal of 92.3 mg/g creatinine hypertensive with 160 mmHg systolic pressure and (normal 40–390). While awaiting the results of the was given nitroglycerin. Upon clamping of the mass, 24 h urine collection, an abdominal ultrasound was the patient had an immediate hypotensive response carried out that revealed a left suprarenal mass pos- with a systolic pressure of 80 mmHg, requiring an epi- terior to the splenic vein, measuring 3.2 £ 4.6 cm. nephrine drip. Postoperatively, the patient did well. The Blood pressure remained stable and milrinone was patient was weaned off the epinephrine drip on the discontinued on hospital day 2. The patient was same day. She was discharged on postoperative day 4. extubated on the third day. A repeat transthoracic Pathology revealed a benign pheochromocytoma, echocardiogram carried out on the fifth hospital day weighing 27 g and measuring 6.5 £ 5.0 £ 1.5 cm revealed normal left ventricular systolic function and (Fig. 3). Results of repeat urine catecholamine measure- wall motion. Given the remarkable resolution of her ments 1 month later were normal. cardiac function, peripartum cardiomyopathy was Commercial polymerase chain reaction (PCR)-based deemed unlikely, and the suspicion for a pheochromo- assay and DNA sequence analysis were used to search cytoma increased. An abdominal magnetic resonance for the presence of a mutation in exons 10, 11, 13, imaging (MRI) scan revealed a left-sided, 3.7 cm 14 and 16 of the RET proto-oncogene. A mutation adrenal mass with low signal intensity on T1- and was identified in codon 634 (TGC ! TAC) with pre- high signal intensity on T2-weighted images, consistent dicted amino acid change Cys ! Tyr. The presence of with a pheochromocytoma (see Fig. 1). The patient’s this mutation was consistent with the diagnosis of urine and plasma laboratory values confirmed the MEN-2A. Additional genetic screening was performed diagnosis of pheochromocytoma (Table 1). Addition- on her brothers and sisters (Fig. 4). Four of her six sib- ally, her parathyroid hormone (PTH) level was found lings were found to have the same mutation. to be 9 ng/l (normal ,60) with a simultaneous cal- cium level of 1.85 mmol/l (normal 2.2–2.6). Her Discussion plasma level was 2.89 nmol/l (normal 0–0.49) and plasma normetanephrine level was Several cases of catecholamine-induced cardiomyopa- 2.9 nmol/l (normal 0–0.89). level was thy as well as pheochromocytoma in pregnancy ,0.03 ng/l. have been described. However, pheochromocytoma- A computerized tomography (CT) scan again induced cardiomyopathy in the peripartum period, as revealed the left adrenal mass, and there was no seen in our patient, has only been described in fewer evidence of extra-adrenal involvement. An 131I-metaio- than ten cases (2, 3–7). Furthermore, our patient’s dobenzylguanidine (MIBG) scan revealed markedly pheochromocytoma was part of the MEN-2A syn- increased activity in the left suprarenal region and a drome, with implications for her and her first-degree mild focus of activity in the right suprarenal region relatives, as we will review below. (Fig. 2). While the activity in the left adrenal area can cause both dilated or hypertropic corresponded with the mass, there was no mass seen cardiomyopathy (8–11); however the specific mechan- on MRI or CT scans in her right suprarenal region. ism is not known. It has been suggested that elevated Captopril was discontinued and a-blockade with catecholamines and/or their oxidation products cause phenoxybenzamine was initiated. The genetic counsel- increased permeability of the sarcolemmic membrane, ing service was consulted and the patient’s DNA was which causes an influx of calcium that results in myo- collected and sent to test for mutations known to cardial necrosis (12–14). Others suggest that excess cause the MEN-2 syndrome. The patient was then adrenergic stimulation causes vasoconstriction that discharged home with the dose of medication gradually leads to decreased coronary perfusion resulting in increased to 20 mg b.i.d. myocarditis (11, 12, 14, 15). It is likely that both

Table 1 Twenty-four hour urine catecholaminess and on hospital days 1, 5 and 8. Abnormal values are shown in bold type.

Day 1 Day 5 Day 8 Normal values

Norepinephrine 103 54 30 15–80 mg/day Epinephrine 72 40 21 0–20 mg/day Dopamine 69 92 95 65–400 mg/day Normetanephrine 2002 967 773 ,900 mg/day Metanephrine 3978 1775 1696 ,400 mg/day Total metanephrines 5980 2742 2469 ,1300 mg/day

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Figure 2 Chest and abdominal images were acquired 48 h after the administration of 2.11 mCi 131I-MIBG. The image demon- strates markedly increased activity in the left suprarenal region corresponding to the site of the 3.7 cm adrenal mass identified on MRI. There is also a mild focus of activity in the right suprarenal region. Figure 3 Left adrenal containing the pheochromocytoma. mechanisms contribute to myocardial injury. Histologi- (A) Gross appearance of 26.7 g of tissue containing a nodule with cally, focal myofiber necrosis, myofibrillar degeneration, a peripheral rim of normal adrenal tissue. (B) Microscopic appear- ance of the pheochromocytoma with typical uniform cells contain- myocardial fibrosis, and mononuclear infiltration have ing abundant cytoplasm and small, central nuclei. Note that the been observed (1, 3, 6, 7, 10, 13). Pulmonary edema cells are separated into clusters by fibrovascular stroma. seen in pheochromocytoma may be cardiogenic, but there may also be a noncardiogenic component. Cat- echolamines are thought to cause pulmonary capillary and even vigorous fetal movement, may play a role membrane damage leading to increased microvascular in initiating symptoms of pheochromocytoma in permeability, coupled with postcapillary venule con- pregnancy (3, 16), and perhaps these instigated our striction. This leads to increased pulmonary capillary patient’s acute event. hydrostatic pressure and pulmonary edema (15). Pheochromocytoma during pregnancy is potentially Pheochromocytoma-induced postpartum cardio- very dangerous to both mother and fetus, due to the myopathy has been reported by two groups (3, 5). effects of catecholamines on blood pressure and utero- Another report described a case that presented with placental blood flow (16, 17). Antenatal recognition severe hypertension, cardiomyopathy, and pulmonary reduces maternal mortality from 17% to 0% and fetal edema during the first trimester (4). Our patient, mortality from 50% to 15% (17). However, given the however, did not present with a hypertensive crisis similarity of many of the symptoms to pre-eclampsia, but rather a low/normal blood pressure, possibly due such as hypertension, headache, postural hypotension, to the predominantly epinephrine secreting nature of and heart failure, many cases remain undiagnosed. In her tumor. It has been hypothesized that uterine con- addition, the occurrence of hypertension and classical traction, as well as increased intra-abdominal pressure symptoms of catecholamine excess are less frequent

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Figure 4 Pedigree of the patient. Numbers below the symbols are the age of the subject, and known causes of death are indicated. than in non-pregnant women (16). These cases may resulting in earlier detection, improved management, also be discovered when there are unusual responses and lower mortality (23). This has led to the rec- to drugs that affect catecholamines, or as reactions to ommendation that anyone diagnosed with medullary anesthesia, labor, or delivery. The possibility of pheo- be screened for the RET proto-oncogene chromocytoma should be entertained in any pregnant and for pheochromocytoma (23), even before surgery woman with intermittent hypertension occurring for is performed (24). during the first half of pregnancy or accompanied by There are several unique features of pheochromocy- headache, palpitations, tachycardia, diaphoresis, and toma that occur in MEN-2A compared with sporadic impaired glucose tolerance or diabetes. In addition, sug- cases. Early symptoms in familial pheochromocytoma gestive family history for pheochromocytoma or famil- include intermittent palpitations, tachycardia, and ner- ial syndromes associated with the tumor or sudden vousness, rather than diaphoresis or headache (26). collapse should also raise suspicions (16). Also, hypertension is less common in pheochromocy- Another unusual aspect of this case is the rapidity of toma associated with MEN-2, occurring in only a the reversal of the cardiomyopathy. In most reported third of patients (27) compared with the usual 72% cases, post-resection resolution of cardiomyopathy (28). In addition, the tumor has an increased takes several months to occur (1, 2, 10, 18–20). How- production of epinephrine, with an increased urinary ever, medical therapy with an a-blocker, angiotensin epinephrine as well as an increased ratio of epinephrine converting enzyme (ACE) inhibitor, and/or b-blocker to (29). Finally in MEN-2 patients who has been reported to reverse the condition in 3–14 have a unilateral pheochromocytoma, the unaffected days (3, 6, 11, 13, 21). Our patient’s left ventricular adrenal gland has a 50% chance of developing function improved from 10% to 60% in 5 days. The pheochromocytoma in 10 years (16, 30). improvement could not be attributed to a-blockade, Mutations of the RET proto-oncogene, found in which was started after resolution of the cardiomyopa- MEN-2 syndromes, are gain-of-function mutations, thy had already been demonstrated. Rather, it was causing activation of the receptor, kinase. This likely due to the administration of captopril alone, as results in hyperplasia of calcitonin-producing parafolli- described previously (22). cular cells and adrenomedullary chromaffin cells, and Our patient’s pheochromocytoma is familial, as part a subsequent neoplastic transformation (31). The of the MEN-2A syndrome, an autosomal dominant con- specific RET mutation correlates with the MEN-2 variant dition that includes medullary thyroid carcinoma, and the aggressiveness of the medullary thyroid cancer pheochromocytoma, and hyperparathyroidism. Medul- (23), and can thus be used to stratify risk and guide lary thyroid cancer is usually the first manifestation of tumor screening in carriers. A mutation in codon 634 MEN-2A due to its earlier occurrence and higher pene- places this family in level two, which is described as trance (23). Before MEN-2A was recognized as a syn- ‘high risk’ for medullary thyroid cancer. It is rec- drome, one of the most frequent causes of death in ommended that the affected individuals have a total patients with medullary thyroid cancer was sudden thyroidectomy before the age of five, yearly screening death from pheochromocytoma (24, 25). With the for pheochromocytoma starting at age five, and recognition of MEN-2A as a syndrome, screening for annual monitoring of calcium and PTH levels. Pheo- pheochromocytoma has become more widespread, chromocytomas occur more frequently in codon 634

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Downloaded from Bioscientifica.com at 09/28/2021 07:08:30AM via free access 776 J Kim and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151 mutation carriers (up to 50%) and also occur at an ear- 4 Hermayer KL & Szpiech M. Diagnosis and management of pheo- lier age and are more likely to be bilateral (in about 25%) chromocytoma during pregnancy: a case report. The American Journal of the Medical Sciences 1999 318 186–189. (23, 32). All female MEN-2 carriers should be screened 5 Satani O, Katsuragi M, Hano T, Tomobuchi Y, Arita M & Nishio I. for a pheochromocytoma prior to or early during Pheochromocytoma-related myocardial damage following deliv- pregnancy (23), as antenatal diagnosis decreases ery. Hypertension Research 1996 19 291–293. both fetal and maternal mortality. 6 Nanda AS, Feldman A & Liang CS. Acute reversal of pheo- Our patient had surgery for medullary thyroid cancer chromocytoma-induced catecholamine cardiomyopathy. Clinical when she was 21 years old. 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