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[Case
Presentation]
A 21-year-old woman sought medical
attention at an endocrinology clinic in March 1999 due to
weight gain, hypomenorrhea and hypertension. Physical
examination revealed freckles over the bilateral cheeks (figure 1
), moon face, buffalo hump, hirsutism, and purple stria over
the abdomen and thighs. Blood tests were performed, which
revealed elevated plasma cortisol (28.2 μg/dl; reference
values, 5 ~ 24 μg/dl in the morning and 2.5 ~ 12.5 μg/dl in
the afternoon) and depressed adrenocorticotropic hormone
(ACTH, 3.0 pg/ml; reference, 10 ~ 65 pg/ml). Both low-dose and
high-dose dexamethasone suppression tests failed to suppress
the cortisol level. ACTH-independent Cushing’s syndrome was
suspected. Computed tomography of the abdomen after
administration of contrast medium revealed multiple hypodense
nodular lesions at the bilateral adrenal glands, which
suggested adrenal cortical hyperplasia (figures 2 and 3). Bilateral
adrenalectomy was performed after complete evaluation to
reveal bilateral pigmented nodular cortical hyperplasia (figure 4
). Residual adrenal tissue was
transplanted to the left inguinal area. However, functional
evaluation performed in August 1999 revealed graft failure. In
the follow-up period, she received regular steroid supplement
and remained free of symptoms suggestive of adrenal
insufficiency.
In July 2007, she began to experience progressive anorexia,
dizziness, lethargy and exercise intolerance, for which she
was hospitalized. Orthostatic hypotension was noted and blood
tests revealed elevated liver enzymes (AST 106 U/L; ALT 92
U/L) and hyperbilirubinemia (total bilirubin, 2.16 mg/dl), and
a serum sodium and potassium level of 132 mmole/l and 5.2
mmole/l, respectively. Abdominal sonography revealed mild
fatty liver, a hepatic cyst and bilateral pleural effusions.
Serological markers of viral hepatitis and autoimmune profile,
including anti-nuclear, anti-smooth muscle and
anti-mitochondrial antibodies, were all negative. A
gastrointestinal consultant suggested drug-related hepatitis
due to the previous history of use of herbal remedies.
Treatment with stress-dose hydrocortisone was began, resulting
in gradual alleviation of the symptoms. Follow-up liver
function tests also showed improvement. A diuretic was
prescribed for pitting edema and weight gain. Steroids were
gradually tapered to physiological dose, and she was
discharged.
About two months later, she was taken
to the emergency department due to progressive dyspnea,
orthopnea and bilateral lower leg edema for 2 days. Her
temperature was 37.0℃, pulse rate 92 beats per minute,
respiratory rate 20 breaths per minute, and blood pressure
78/58 mmHg. Physical examination revealed jugular vein
distention, pitting edema of bilateral lower limbs and
positive hepatojugular reflex. Auscultation revealed grade II
diastolic murmur at the cardiac apex. The electrocardiogram
showed right atrial enlargement and right ventricular
hypertrophy. Chest X-ray showed cardiomegaly (figure 5).
Laboratory tests revealed normal cardiac enzyme levels and an
elevated B-type natiuretic peptide level (BNP, 1089 pg/ml).
Echocardiogram showed a large left atrial tumor with its stalk
attached to the intra-atrial septum (figure 6
),
mitral flow obstruction, tricuspid regurgitation and pulmonary
hypertension. Emergent tumor excision was performed while she
was receiving supplement of stress-dose hydrocortisone. A
fragile red-yellowish tumor, originating from the dorm of the
left atrium, was found to occupy the left atrial chamber and
extend into the left ventricle through mitral annulus, with
severe distension of the right ventricle. The symptoms
improved dramatically after the operation, and the BNP level
also dropped to 140 pg/ml. Pathology of the excised tumor
showed an atrial myxoma. With the presentation of bilateral
adrenal nodular cortical hyperplasia and cardiac myxoma, the
diagnosis of Carney complex was made. The steroid supplement
was tapered gradually to a physiological dose, and the patient
was discharged under a stable condition.
[Discussion]
自1980年代初期，即有病例報告指出，在一些患者的身上，會同時出現皮膚色素沉著及黏液瘤（myxoma）的病變：如Atherton等人於1980年所發表的NAME症候群（N-
nevi：痣；A- atrial myxoma：心房黏液瘤；M- myxoid
neurofibroma：黏液樣神經纖維瘤；E-
ephelide：雀斑），及Rhodes等人於1984年所發表的LAMB症候群（L- lentigines：斑；A-
atrial myxoma：心房黏液瘤；M- mucocutaneous myxoma：黏膜及表皮的黏液瘤；B- blue
nevi：藍痣）。而在1985年，Carney等人發表了40人的病例系列，其同時出現的症狀，包括了皮膚色素沉著、內分泌功能亢進、及黏液瘤。次年，此一表徵即被統稱為卡尼氏複合症（Carney
complex, CNC）。而先前所發表的NAME或LAMB症候群，也被認為可能是卡尼氏複合症的表現。
卡尼氏複合症為一相當罕見的疾病：每個患者身上受到影響的器官或組織，都不盡相同。若患者符合兩個以上的主要診斷條件，或是僅符合一個主要診斷條件，但一等親屬亦有此症，或是被偵測出有PRKAR1A基因的突變時，則可確定診斷（見附表）。
皮膚病灶
卡尼氏複合症的皮膚病灶以雀斑、藍痣、交界痣（junctional nevi）、複合痣（compound
nevi）及表皮黏液瘤為表現；其中，以雀斑最為常見。皮膚病灶可出現在體表各個不同的位置，如：臉頰、上下唇、眼瞼、耳朵、會陰部、甚至是口腔或是生殖器的表皮黏膜處。
內分泌功能亢進
在卡尼式複合症的患者身上，最常出現的內分泌功能異常，為非促腎上腺皮質素依賴性之庫欣氏症（adrenocorticotropic
hormone-independent Cushing’s
syndrome），其發生率可達25~30%。與其他原因引起的庫欣氏症相較，卡尼氏複合症的庫欣氏症是由極少見的腎上腺皮質病變-原發性色素結節腎上腺病（primary
pigmented nodular adrenocortical
disease）-所引起；而發病時間則集中在2~3歲及20~30歲這兩個年齡帶。然而，在一些病人身上，皮質素過量的表現可能為亞臨床、非典型或著是週期性的，使得診斷較為困難。至於在影像學方面，雖然患者的腎上腺會有典型的多發性色素結節，但整個腎上腺的體積卻不一定有顯著的變化。因此，即便是最常用於評估腎上腺的影像學檢查-
電腦斷層，在此類病人身上，也僅能偵測出約70%的腎上腺病灶。除了庫欣氏症之外，其他與內分泌系統有關的病變，諸如因腦垂腺之分泌生長激素（growth
hormone）腺瘤所引起的肢端肥大症（acromegaly）、良性或惡性的甲狀腺腫瘤、男性的睪丸腫瘤（如大細胞鈣化性史托利細胞腫瘤，large
cell calcifying Sertoli cell
tumor）、及女性的卵巢囊腫或囊腺瘤（cystadenoma）等，亦都曾在卡尼氏複合症的患者身上被發現過。
心臟黏液瘤
心臟黏液瘤，可說是卡尼氏複合症最嚴重的併發症：因其可以造成心臟血流輸出的阻塞、血管栓塞、中風、甚至死亡。與偶發性的病例相較，卡尼氏複合症的心臟黏液瘤之發病年齡呈平均分佈，且其病灶可在心臟的任何一個房室中多次發生；也因為這樣的特性，故卡尼氏複合症的患者，應定期接受心臟超音波的篩檢及追蹤。而在一些較為困難的病例中，經食道心臟超音波（trans-esophageal
echocardiogram）及心臟核磁共振造影（cardiac magnetic resonance
imaging）亦可幫助相關的診斷。
其他病變
除了上述各項併發症之外，其他像是黑色素性史旺細胞瘤（melanotic schwannoma）、乳管腺瘤（breast
ductal adenoma）、乳房黏液瘤（breast
myxoma）及骨軟骨黏液瘤（osteochondromyxoma）等，都曾在卡尼氏複合症的病例中被報告過。
基因
在遺傳性的病例中，卡尼氏複合症呈現出顯性遺傳的型態。就目前所知，與此症有關的染色體位置（locus）主要有兩個：分別是位在17q22-24的CNC1及位在2p16的CNC2。而這兩處變異所呈現的表現型（phenotype）並無顯著的不同。CNC1所含的基因，為cAMP訊息傳遞路徑中的關鍵角色-protein
kinase A-之調控1-alpha次單元（regulatory subunit
1-alpha），即PRKAR1A。一些病例報告指出：PRKAR1A基因的去活化突變（inactivating
mutation），與內分泌腫瘤的發生有關，意味著PRKAR1A可能為一腫瘤抑制基因（tumor suppressor
gene）。在遺傳性的病例中，約有45~60%的患者均帶有PRKAR1A的異合子型（heterozygous）去活化突變。另一方面，在CNC2所含有的基因變異，至今仍未完全釐清。
臨床處置
由於卡尼氏複合症的臨床表現十分多樣化，因此，無論是已經確定診斷的患者，或是檢測出帶有好發基因（即PRKAR1A突變）的人，都應接受相關症狀的篩檢。特別是心臟黏液瘤，由於對患者預後有顯著的影響，因此心臟超音波的篩檢應盡早開始；如確實有發現病灶，即可以手術方式加以切除。而在術後，仍因進行定期的追蹤，因黏液瘤終其一生都有可能再發。如患者因原發性色素結節腎上腺病而引起庫欣氏症，可以兩側腎上腺切除術治療；對於無法接受手術的病患，則可使用藥物（如：ketoconazole或mitotane）來治療。至於其他較少見的病變，則應視其臨床表現及對患者的影響來給予適當的處理。
結論
卡尼氏複合症為一包括了皮膚色素沉著、內分泌功能亢進、黏液瘤等臨床表現的症候群。儘管罕見，但如遇到有疑似病史或病徵的患者時，仍因謹慎地考慮其可能性，並安排基因篩檢或其他相關的檢查。一旦確定診斷，患者則應接受關於心臟黏液瘤、內分泌腫瘤及其他病灶的定期追蹤，以期能即時發現問題，並即時進行適當的處理。
[Reference]
- The complex of myxomas, spotty pigmentation, and
endocrine overactivity. Medicine (Baltimore), 1985. 64(4):
p. 270-83.
- Carney complex (CNC). Orphanet J Rare Dis, 2006. 1:
p. 21.
- Carney complex, a familial Cushing's syndrome due to
primary pigmented nodular adrenocortical disease: a case
report. Kaohsiung J Med Sci, 2002. 18(12): p. 627-31.
- Carney complex with primary pigmented nodular
adrenocortical disease and bilateral papillary thyroid
carcinoma occurring 11 years apart: a case report.
Endocrinologist, 2005. 15(4): p. 243-247.
- Clinical and molecular features of the Carney
complex: diagnostic criteria and recommendations for patient
evaluation. J Clin Endocrinol Metab, 2001. 86(9): p. 4041-6.
- Carney complex: pathology and molecular genetics.
Neuroendocrinology, 2006. 83(3-4): p. 189-99.
- Mutations of the gene encoding the protein kinase A
type I-alpha regulatory subunit in patients with the Carney
complex. Nat Genet, 2000. 26(1): p. 89-92.
- Minireview: PRKAR1A: normal and abnormal functions.
Endocrinology, 2004. 145(12): p. 5452-8.
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Case Discussion
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