Virilizing adrenocortical carcinoma in a child with Turner syndrome and somatic TP53 gene mutation
Jung-Hee Ko . Hyo Sung Lee . Jeong Hong . Jin Soon Hwang
Received: 12 July 2009 / Accepted: 12 August 2009 /Published online: 25 August 2009 C Springer-Verlag 2009
Abstract Virilizing adrenocortical carcinoma and Turner syndrome have opposite clinical manifestations in some aspects. Here, we report on the first case of virilizing adrenocortical carcinoma in a girl with Turner syndrome. A 2 10/12-year-old girl presented pubic hair of Tanner stage III with clitomegaly, deepening of her voice, and tall stature. No other morphologic anomaly was found. Bio- chemical assessment revealed normal electrolytes with pronounced elevation of adrenal androgens. She was found to have a large mass of the left adrenal gland on abdominal computed tomography scan. She underwent complete resection of the mass, and pathology was consistent with adrenocortical carcinoma. She was tested for TP53 gene mutation, and we found a de novo TP53 gene mutation (Val143Ala) as well as a 45,X karyotype.
Keywords Adrenocortical carcinoma · Turner syndrome . TP53 gene mutation
Introduction
Adrenocortical carcinoma (ACC) is known to be a very rare tumor type with estimated annual incidence of 0.3 cases per million children younger than 15 years of age except in Brazil where the annual incidence has been reported to be
10~15 times more than that observed in the other regions of the world [11, 17]. Incidence of ACC in children under 15 years old in Korea from 1999 to 2002 is reported to be 0.2 cases per million by the national cancer information center in Korea.
Symptoms and signs of overproduction of adrenocortical
hormones are present in more than 90% of children with
adrenal tumors. Virilization is the most common presenting
sign in children with adrenocortical tumors occurring alone
(5080%) or in combination with hypercortisolism (20
40%). Virilizing adrenal tumors show growth acceleration,
deepening of voice, premature pubic and axillary hair
development, and clitoral or penile enlargement. Isolated
Cushing syndrome, Conn syndrome, and pure feminization
occur very rarely in children [6, 13, 18, 24].
Turner syndrome, one of the most common chromosom- al abnormalities, affects approximately one in 2,500 live female births. Turner syndrome is characterized cytogenet- ically by X chromosome monosomy, the presence of an abnormal X chromosome, or mosaicism of a 45,X cell line, which might be 46,XX, 46,XY, or might have an abnormal sex chromosome rearrangement. There is a wide variation of clinical features seen in females with Turner syndrome, ranging from the severe phenotype with short stature, gonadal dysgenesis, lymphedema, and characteristic dys- morphic features (micrognathia, low posterior hairline, short neck, webbed neck, and high-arched palate), to women with only a mild reduction in final height or premature ovarian failure. The diagnosis of Turner syn- drome may be delayed until adulthood in up to 10% of women because pathognomonic clinical features are often not present, and patients often show normal phenotype. The diagnosis is made on the basis of a chromosomal analysis [3, 7]. The patient described below had no phenotypic abnormalities to suggest Turner syndrome. Here, we
J .- H. Ko . H. S. Lee . J. S. Hwang Department of Pediatrics, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon 443721, South Korea e-mail: pedhwang@ajou.ac.kr
describe the first case of virilizing adrenocortical carcinoma in a child with Turner syndrome.
Case report
A 2 10/12-year-old girl was referred for evaluation of clitomegaly with pubic hair in Tanner stage III. Her parents noticed clitomegaly when she was about 2 years of age, and pubic hair started to grow 4 months later. Deepening of her voice was another change. No other symptoms or morpho- logic anomaly was found. Vital signs showed blood pressure of 116/65 mmHg (>95 percentile), heart rate of 120/min, and respiratory rate of 30/min. Her height was 100 cm (90~97 percentile) and weight was 19 kg (>97 percentile). Her bone age was approximately 9 years advanced.
Biochemical assessment revealed normal electrolytes
and elevated adrenal androgens. Luteinizing hormone
(LH) and follicle stimulating hormone (FSH) were
2.3 mIU/ml (age-adjusted range, 00.5 mIU/ml) and
1.1 mIU/ml (age-adjusted female range, 17 mIU/ml),
respectively. Estradiol level was 34 pg/ml (age-adjusted
female range, <5 pg/ml). The 17-hydroxyprogesterone
(17-OHP), androstenedione, testosterone, and dehydroe-
piandrosterone (DHEA) sulfate were noticeably elevated to
29.89 ng/ml (reference range, 0.22.6 ng/ml), 36.6 ng/ml
(reference range, 1.72.7 ng/ml), 7.12 ng/ml (reference
range, 00.8 ng/ml), and 1,629 ug/dl (reference range, 120
360 ug/dl), respectively. Urine level of 17-ketosteroids was
28.12 mg in 24 h (reference range, 0~3 mg/24 h).
Urine levels of epinephrine, norepinephrine, dopamine,
vannilyl mandelic acid (VMA), and homovanillic acid
(HVA) were all in normal range. Other results (and
reference ranges) were adrenocorticotropic hormone
(ACTH), 36 pg/ml (1060 pg/ml); morning cortisol,
7.9 ug/dl (9.426 ug/dl); morning cortisol after a 1 mg
overnight dexamethasone suppression test, 6.3 ug/dl; and
urine free cortisol, 41.2 ug/24 h (2090 ug/24 h). Plasma
rennin activity was 7.97 ng/ml/h (age-adjusted range,
supine for 1 h, <10 ng/ml/h) and aldosterone was
166.60 pg/ml (age-adjusted range, 0.23.7 pg/ml) [10].
As part of the evaluation, adrenal computed tomogra- phy (CT) scan was performed, revealing a well-defined mass at the left suprarenal region measuring about 7×6× 4 cm (Fig. 1). Localized tumor was confirmed by fluorodeoxyglucose-positron emission tomography imag- ing. Left adrenalectomy of the mass measuring 7.5×6.5x 4.5 cm and weighting 102 gm was done with resection margins free of tumor. Microscopically, the tumor showed 40 mitoses per 50 high power microscopic fields, high nuclear grade, atypical mitotic figures, and sinusoidal invasion. Immunohistochemical staining showed reactivity
1
for vimentin and MIB-1, but not for cytokeratin AE1/AE3, chromogranin A, or S100 protein.
Postoperative day 1, serum level of androgens were 17- hydroxyprogesterone, 0.22 ng/ml; androstenedione, 0.3 ng/ml; testosterone, <0.2 ng/ml; and DHEA sulfate, <5 ug/dl. Her blood pressure decreased to 90/60 mmHg. She is currently being followed up by endocrinologist and oncologist with regular hormone level test and imaging study.
Methods and results
Pubertal stage was assessed according to Tanner [22]. Bone age was assessed from left hand and wrist radiographs by the method of Greulich and Pyle [5]. Serum steroid hormones (LH, FSH, estradiol, 17-OHP, androstenedione, testosterone, DHEA sulfate, ACTH, cortisol), plasma renin activity, aldosterone, and urine free cortisol were deter- mined by radioimmunoassay. Serum and urine levels of epinephrine, norepinephrine, dopamine, and VMA were measured by high-performance liquid chromatography. Urine level of 17-ketosteriods was measured by ultraviolet visible spectrophotometry. Urine level of HVA was mea- sured by gas chromatograph and mass spectrometer.
Previously known strong association between TP53 gene mutation and adrenocortical carcinoma prompted us to examine the status of TP53 gene of the patient [4, 17, 20,
23]. Informed consent was obtained before the sampling of blood. Genomic DNA was isolated from peripheral blood lymphocytes. In the patient, all exons (exon 1-11) and the intronic flanking regions of the TP53 gene were ampli- fied by the use of polymerase chain reaction (PCR). Subsequently, PCR products were purified, and DNA sequencing was performed. Direct DNA sequencing of the PCR product revealed that the patient was heterozygous for a T-to-C transition at nucleotide 428 (c.428T>C, p. Val143Ala; Fig. 2). This missense sequence alteration was already reported as a disease causing mutation in human cancers, but this is the first report in pediatric adrenocortical carcinoma [2, 8, 25]. Mutation analysis of exon 5 of TP53 gene of both parents failed to detect the same mutation suggesting that the V143A mutation arose de novo in the proband.
The chromosome analysis of cultured peripheral leuko- cytes stimulated by phytohemagglutinin revealed 45,X, Turner syndrome.
Discussion
The patient described above had two genetic abnormalities, Turner syndrome and a somatic mutation of the TP53 gene. When the patient first visited our clinic, we suspected of androgen producing tumor but not Turner syndrome. This is the first report of virilizing adrenocortical carcinoma in a child with Turner syndrome to the best of our knowledge, although Pivnick et al. reported nonfunctioning adrenocor- tical carcinoma in a girl with Turner syndrome [16].
Clinical presentation of adrenocortical carcinoma seen in the adult group is different from that observed in the younger groups. Virilizing features are seen in approxi- mately 90% of pediatric patients with adrenocortical carcinoma, whereas, Cushing syndrome or nonfunctional tumors are the most common tumor type seen in adoles- cents and young adults at the time of diagnosis. Moreover, constitutional TP53 gene mutations are frequently involved in pediatric patients, but are relatively rare in adults [23]. The frequency of adrenocortical carcinoma is 0.4 per
TGCCCTOCGCAGCTG’
million during the first 4 years of life, and it decreases to 0.1 per million during the subsequent 10 years. It then rises to 0.2 per million during the late teens and reaches another peak during the fourth decade of life. From these observations, it has been thought that pediatric adrenocor- tical carcinoma comprises at least two subtypes [18].
During gestation, the adrenal cortex is subdivided into the outer definitive and inner fetal zones. The fetal zone comprises 85% of the adrenal cortex during fetal develop- ment and is oriented toward dehydroepiandrosterone production. After birth, the adrenal gland rapidly loses 50% of its volume by apoptosis within the first 2 weeks. Subsequently, adrenal cortex develops into three regions which are zona glomerulosa, zona fasciculata, and zona reticularis by remodeling. In the pediatric patients, the predominance of virilizing tumor arises from the fetal zone of the fetal adrenal cortex, whereas, adrenocortical carci- noma of adolescence and adulthood may originate from the definitive adrenal cortex [9]. The presence of a TP53 gene mutation may increase the penetrance of adrenocortical carcinomas in the fetal adrenal cortex but not in the definitive adrenal cortex [19].
The tumor suppressor protein TP53 is a transcription factor of 393 amino acids which is located on 17p13.1. In response to oncogenic and other stresses, TP53 induces the transcription of regulatory genes resulting in cell-cycle arrest until the damage is repaired and activates additional factors that induce apoptosis, thus, playing a key role in prevention of cancer development. When TP53 gene is inactivated, most commonly by a single missense mutation, cell growth can proceed without regulation, thus, causing tumor growth [8, 25]. Somatic TP53 gene alterations are frequent in most human cancers and germline TP53 mutations predispose to a wide spectrum of early-onset cancers, Li-Fraumeni, and Li-Fraumeni-like syndromes. The most frequent cancers associated with TP53 germline mutations are breast cancer, bone and soft tissue sarcomas, brain tumors, and adrenocortical carcinomas. Other less frequent cancers include leukemia, stomach cancer, and colorectal cancer [15].
Early in embryogenesis, there is inactivation of one X chromosome in each cell in female. An increasing number of genes that escape inactivation have been identified, and the Turner syndrome phenotype is considered to be the result of haploinsufficiency of these genes. It has been proposed that the genes that escape inactivation are potentially involved in oncogenesis and underlie the relationship between Turner syndrome and malignancy, although, there is only limited number of published reports to establish a definite relationship [1]. Gonadoblastoma may develop in a female with Turner syndrome karyotype that includes a Y chromosome, such as 45,X/45,XY mosaicism. Increased susceptibility to neuroblastoma and
related neurogenic tumors in childhood and early adulthood has been reported. Case reports have shown that patients with Turner syndrome are at increased risk of endometrial cancer due to estrogen replacement treatment, although endometrial cancer in untreated patients has also been reported. The association between central nervous system tumors including meningioma and pituitary adenoma, colon cancer, corpus uteri cancer, bladder and urethral cancer, cutaneous melanoma, and leukemia with Turner syndrome has also been reported [12, 14, 21, 26].
Michalkiewicz et al. reported that patients reported from other countries rarely had been tested for constitutional or somatic TP53 mutation except Brazilian patients [13]. We recommend the patients with adrenocortical carcinoma, especially the girls to be tested for the status of TP53 gene. The bone age of the patient above was approximately 9 years advanced due to the virilizing adrenocortical carcinoma which could result in adult short stature in addition to the effect of haploinsufficiency of the genes that escape X inactivation shown in Turner syndrome. The effect of 45,X chromosomal complement on the expression of neoplasm seen in patients with TP53 gene mutations remains to be determined.
Conflict of interest The authors of this manuscript have no relevant financial relationship to declare.
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