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A 30-year-old
woman was seen because of persistent right flank soreness and
pain and blood urine for one month. She also complained of
thirst and intermittent constipation. There was no abdominal
pain, diarrhea, vomiting, fever, cough, dysuria, sweating,
palpitation or headache. Urinalysis disclosed hematuria and
sonography of the abdomen revealed right renal stones. A
serial studies reported serum calcium concentration 3.14
mmol/L, phosphate 2.0 mg/dL, chloride 114 mmol/L, alkaline
phosphate 158 U/L, intact parathyroid hormone (i-PTH) 569.9
pg/mL(reference:15-65), and calcitonin 135.1 pg/mL (reference:
<100). Sonography of the neck showed a left parathyroid
cyst and a multi-nodular goiter (Fig 1
). Cytology of the
thyroid and parathyroid glands by aspiration reported
medullary carcinoma of the thyroid and parathyroid adenoma,
respectively. Because of highly suspicious multiple endocrine
neoplasia, type 2A, she was admitted for further evaluation
and treatment.
She had no other systemic disease
and did not consume alcohol, medicine or tobacco. She had no
history of animal contact or travel recently. She had three
brothers and one sister. Her father had undergone total
thyroidectomy for medullary carcinoma of the thyroid and
excision of the left adrenal tumor for pheochromocytoma. Her
sister had undergone left inferior parathyroidectomy and total
thyroidectomy.
On examination, she had clear
consciousness but was ill-looking. Her height was 160 cm and
weight 56 kg. The temperature was 37.1°C, the pulse rate, 82
beats per minute and the respiratory rate, 22 breaths per
minute. Blood pressure while in supine position was 132/64
mmHg. The skin was dry and there was no cyanosis, petechiae,
purpura or pigmentation. Her conjunctivae were pink, the
sclerae anicteric and the pupils isocoric with prompt light
reflexes. The neck was supple without lymphadenopathy,
engorged jugular veins, palpable goiter or carotid bruits. The
chest wall expansion was symmetric and breath sounds were
bilaterally clear. The heart beats were regular without
audible murmur. The abdomen was soft and bowel sounds were
normoactive. The liver and spleen were impalpable. The liver
span was estimated 10 cm at the right mid-clavicular line. Her
extremities were freely movable without edema.
<
Laboratory Data >
1. CBC
|
WBC |
RBC |
HB |
HCT |
MCV |
MCHC |
PLT |
|
K/μL |
M/μL |
g/dL |
％ |
fL |
g/dL |
K/μL |
|
5.24 |
4.06 |
12 |
34.8 |
85.7 |
31.4 |
152 |
2. BCS + e-
|
ALB |
TP |
T-Bil |
AST |
ALT |
ALP |
LDH |
Glucose |
|
g/dL |
g/dL |
mg/dL |
U/L |
U/L |
U/L |
U/L |
mg/dL |
|
3.7 |
6.9 |
1.0 |
13 |
16 |
158 |
215 |
90 |
|
UN |
CRE |
Na+ |
K+ |
Ca2+ |
Cl- |
P |
Mg2+ |
|
mg/dL |
mg/dL |
mmol/L |
mmol/L |
mmol/L |
mmol/L |
mg/dL |
mmol/L |
|
12 |
1.1 |
143 |
4.2 |
3.18 |
110 |
2.1 |
0.83 |
3. Other tests
|
hsTSH |
free T4 |
ACTH(A) |
Cortisol(A) |
i-PTH |
Calcitonin |
|
0.4- 4
μIU/mL
|
0.60-1.75
ng/dL
|
10-65
pg/mL
|
5-25
μg/dL
|
15-65
pg/mL
|
<100
pg/mL
|
|
0.76 |
1.25 |
12 |
7.9 |
569.5 |
170 |
|
hGH |
Prolactin |
IGF |
VMA |
E |
NE |
Dopamine |
|
0.06-5
ng/mL
|
2.2-19.2
μg/L |
160-510
ng/mL
|
<7
mg
|
<22.4
μg
|
<85.5
μg
|
<450
μg
|
|
2.5 |
11.2 |
206 |
6.1 |
22.1 |
39.3 |
176.7 | *hs TSH = high sensitivity
thyroid-stimulating hormone; freeT4 = free thyroxine; ACTH =
corticotrophin; A = AM; hGH = growth hormone; IGF =
insulin-like growth factor; VMA = vanillylmandelic acid; E =
epinephrine; NE = norepinephrine.
< Treatment and Course
>
During the hospitalization, a
24-hour-urine exam revealed normal catecholamine levels.
Computerized tomography of the abdomen showed negative
finding. She underwent total thyroidectomy with central lymph
node dissection and left upper and right lower
parathyroidectomy. The pathology revealed medullary carcinoma
of the thyroid and parathyroid adenoma. She had no
complications related to the operative procedures. She started
to receive thyroid hormone treatment for suppression. She was
followed up regularly as an outpatient with normal serum
calcitonin levels.
< Discussion
>
多發性內分泌腺瘤(multiple endocrine
neoplasia，MEN)是指患有兩種以上內分泌腺腫瘤的疾病，包括第1型及第2型，皆屬於體染色體顯性遺傳。多發性內分泌腺瘤第2型(MEN
2)分為A型和B型，流行率約為十萬分之一到十，發生率無性別之分，30歲為好發年齡高峰。MEN
2A的表現為甲狀腺髓質癌(medullary carcinoma of the thyroid，MCT)，嗜鉻細胞瘤
(pheochromocytoma)，副甲狀腺機能亢進(hyperparathyroidism)，是MEN
2中最常見的一型，佔75%與RET gene的codon
609、611、618、602、634、790、791突變有關，其中codon
634的突變佔了85%，大部份是使原本應該製造出的cystein變成argine，導致RET tyrosine
kinase的活性增加，進而致病；MEN 2B的表現是甲狀腺髓質癌、嗜鉻細胞瘤、類馬方氏症體型(marfanoid
habitus)、黏膜神經瘤(mucosal neuromas)、腸道神經結細胞瘤(ganglioneuromatosis
of
bowel)。通常不會在同一個人同時發生所有腺體之病灶，但同一腺體卻可為多發性(multicentric)，因此同時左右兩側腺體皆產生病變是很常見的，在檢查及治療時皆必須特別留意。
甲狀腺髓質癌是由甲狀腺C細胞不斷地增生而演變成髓質癌，髓質癌佔所有甲狀腺惡性腫瘤的10%，是MEN
2最常見的表現，約佔百分之八十至一百，通常多中心且集中在甲狀腺的上三分之一，可能會蔓延到局部淋巴結，或轉移到肝、肺和骨頭，血中抑鈣素(calcitonin)濃度升高是甲狀腺髓質癌最好的腫瘤標記。嗜鉻細胞瘤約佔MEN
2 的百分之五十，常為雙側，少惡性，雖然90%嗜鉻細胞瘤的患者有高血壓，但是，MEN
2病人血壓卻常常是正常而沒有症狀。副甲狀腺機能亢進佔MEN
2的百分之二十五，以增生為最常見，極少出現在MEN 2B，表現較MEN
1良性，病理、生化、臨床方面的變化皆比甲狀腺的變化晚出現，開刀效果很好。
MEN 2 的基因突變位於第10對染色體的c-ret
proto-oncogene，此基因負責製造 tyrosine kinase
receptor，雖然大部分的甲狀腺髓質癌或嗜鉻細胞瘤為偶發性(sporadic，分別佔75%和90%)，但是所有罹患甲狀腺髓質癌或嗜鉻細胞瘤的病人還是都應該接受RET基因的檢查，一旦發現有突變，就應該對家屬做基因檢查，然後對有相同基因突變的家屬做相關腫瘤及疾病的篩檢追蹤。據統計，以分子生物技術篩選出陽性基因之病患追蹤至70歲前有60%產生甲狀腺髓質癌，20%到50%產生單側或雙側之嗜鉻細胞瘤，10%到20%產生副甲狀腺增生或腺瘤。
MEN 2
病患若已確診有甲狀腺髓質癌者應接受開刀，至少要做全甲狀腺切除和中央淋巴結群廓清術，所有的病患於手術前都應該篩檢是否有嗜鉻細胞瘤，且應該先處理嗜鉻細胞瘤(包括藥物治療及手術切除)，以防發生高血壓危象或休克。一旦有新病例發現時，其近親往往可以在密切的追蹤檢查下找出具有潛伏性危及生命的甲狀腺髓質癌及嗜鉻細胞瘤，早期發現並早期手術切除，對於病人之預後及存活率有極大的影響。根據目前的研究，tyrosine
kinase inhibitor在未來可能可以用來治療這類與RET
proto-oncogene相關的癌症，這對MEN 2A的家族來說無疑是個很好的消息。
< References
>
- Gardner DG. Multiple endocrine
neoplasia. In Greenspan FS, Grardner DG (eds). Basic and
Clinical Endocrinology. New York: McGraw Hill, 2004:829-840.
- Brandi ML, Gagel RF, Angeli A, et
al. Guidelines for diagnosis and therapy of MEN type 1 and
type 2. J Clin Endocrinol Metab 2001; 86:5658-5671.
- Machens A, Ukkat J, Brauckhoff M,
Gimm O, Dralle H. Advances in the management of hereditary
medullary thyroid cancer. J Intern Med 2005; 257:50-59.
- Bugalho MJ, Domingues R, Sobrinho L. Molecular diagnosis
of multiple endocrine neoplasia Type 2. Expert Rev Mol Dian
2003;3:769-779.
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Case Discussion
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