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Paper text:
adrenocortical carcinoma is a rare malignancy comprising only about 0.2% of all cases of childhood cancer .
this rare malignancy is associated with a high rate of recurrence and mortality with a reported 5-year event - free survival estimate of 54.2% in children .  
pediatric adrenocortical tumors ( acts ) occur most commonly in females and in children less than four years .  
eighty to ninety percent of patients have functional tumors with endocrine manifestations at diagnosis and the majority present with virilization , alone or in combination with overproduction of other adrenal hormones .
we report an infant with cushing syndrome without the clinical features of androgen or mineralocorticoid excess , consequently diagnosed with adrenocortical carcinoma .
the patient is a caucasian female born at term with a birth weight of 3.06  kg ; pregnancy and delivery were uncomplicated . at six months of age
her linear growth apparently had been arrested between three and six months of age , although she gained weight at an accelerated rate ( figure 1 ) .  
prior to referral , laboratory evaluation by her primary care physician revealed serum cortisol of 240  mcg / dl ( normal , 4.522.7  mcg / dl ) ;   total testosterone of 185  ng / dl ( normal , 677ng / dl ) , and dhea - s of 401  mcg / dl ( normal , 1696  mcg / dl ) .
serum acth was less than 5  pg / ml ( normal , 1060  pg / ml ) .   
her weight at initial evaluation in our clinic at six months of age was 7.52  kg ( 6075th percentile ) and length was 59.1  cm ( < 5th percentile ) .
physical examination showed cushingoid facies , buffalo hump , facial acne , and poor muscle tone ( figure 2 ) .
an mri of the abdomen showed a heterogeneous right adrenal mass measuring 3.6  5.4  3.8  cm ; this mass was found to extend as a tumor thrombus into the inferior vena cava .
the tumor thrombus appeared to extend to approximately 2  cm from the right atrium .
a doppler ultrasound showed minimal , but present flow around the ivc tumor thrombus which measured 2.5  0.9  1  cm .
laboratory evaluation showed serum cortisol 70.8  mcg / dl ( normal , 4.522.7  mcg / dl ) ; aldosterone 4.2  ng / dl ( normal 6.586.0  ng / dl ) ; testosterone 59  ng / dl ( normal , 677  ng / dl ) ; acth   < 5 ( normal , 1060  pg / ml ) .
she was prescribed ketoconozole prior to surgery due to moderately elevated blood pressure . however ,
surgical resection was undertaken and intraoperative findings showed a large , well - circumscribed mass in the right adrenal gland measuring 5.2  4.0  3.5  cm mass which did not invade the liver , kidney or other surrounding soft tissues .   on intraoperative transesophageal echocardiography , there appeared to be thickening of the wall of the superior vena cava of unknown significance .
the intracaval clot did not extend to the right atrium and cardiopulmonary bypass was not required .
blood flow was visualized around the caval clot with no evidence of adherence to the caval wall .
the adrenal mass and thrombus were removed en bloc ( figure 3(a ) ) .  
the mass showed five to ten percent necrosis of the mass with spotty calcifications ( figures 3(b ) and 3(c ) ) .
she received stress dosing with hydrocortisone during and after surgery ; she was reduced to a physiologic replacement dose by 15 days postoperatively .
she was considered to have stage 1 adrenocortical carcinoma based on the relatively small tumor size , complete surgical resection , lack of metastases , and normalization of hormonal markers postoperatively .  
the tumor cells demonstrated a low mitotic count ( < 1 to 2 per 50 high power fields and no atypical mitoses ) .
in addition , the mib-1 index was low at   < 1% to 12% with regional variability .  
tumor immunohistochemistry for p53 protein showed weak staining with no accumulation in the nucleus ; when p53 amplification is present , the defective proteins accumulate within the nucleus due to abnormal cellular processing . to evaluate for a germline p53 mutation in the patient ,
whole gene sequencing was performed for the tp53 gene and did not reveal any known mutation .  
quarterly pet scanning to monitor for recurrence is underway , and has been negative for 24 months post - operatively .
two months after surgery , laboratory evaluation showed total testosterone level of   < 7.0  ng / dl ( normal , 677  ng / dl ) ; dhea < 1.0ng / ml ( normal ,   < 2.9  ng / ml ) ; dhea - s < 15.0  ng / dl ( normal , 1696  mcg / dl ) .
acth was 7.6  pg / ml ( normal , 1060  pg / ml ) .  
growth velocity began to increase within two months after surgery , and five months after surgery was 25  cm / year consistent with catch - up growth .
our patient demonstrated classic features of glucocorticoid excess including growth failure , hypertension , acne , plethora and a buffalo hump with excessive weight gain .
the differential diagnosis of cushing syndrome in an infant includes adrenocortical tumors ( carcinoma or adenomas ) , as well as multinodular adrenal hyperplasia .
in addition , cushing disease , ectopic acth production , and iatrogenic cushing syndrome should be considered .
miller et al . , demonstrated that of 60 infants with cushing syndrome , 48 had adrenal tumors .
two had ectopic acth production , five had nodular adrenal hyperplasia , four had undefined adrenal hyperplasia and one had an acth producing tumor .
therefore , first an adrenocortical tumor should be excluded in an infant with cushing syndrome as long as there is no history for exposure to exogenous glucocorticoids . in our case ,
the unilateral adrenal mass in the mri indicated an adrenal tumor and histopathological findings confirmed an adrenocortical carcinoma .
pediatric adrenocortical tumors have distinct clinical and biological features in comparison to those which occur in adults .
it is estimated that there are 1920 new cases of adrenocortical carcinoma in children and adolescents per year in the united states according to the surveillance , epidemiology and end results program .
most of these patients are either toddlers , early school age children or in their late teens as pediatric adrenocortical tumors have a bimodal age distribution .
there is a peak in incidence before four years of age ( 0.4 cases per million ) which then declines during the subsequent ten years .
interestingly , the majority ( 60% ) of pediatric adrenocortical tumors occur in children less than five years which is similar to the distribution seen with tumors of embryonic origin .
although our patient fits the common age distribution for an adrenocortical tumor , her presentation with cushingoid features alone is unusual especially at such a young age .
although biochemically she demonstrated elevations in both androgens and cortisol , she had no evidence of virilization on physical examination .
michalkiewicz et al . , found in a registry of 254 pediatric patients with acts that 55% presented with virilization alone .
only 5.5% percent of this group presented with isolated cushing syndrome , and this tended to occur in older children ( median age , 12.6 years ) .
in addition , lefevre et al . , showed similar results in their analysis of 42 children with acts in france .
therefore , our patient is remarkable in that she presented with cushingoid features alone during infancy .
the tendency for adrenocortical tumors to occur in younger age groups and to be predominantly androgen - producing could be linked to their relationship to the fetal adrenal cortex .
the fetal adrenal cortex is composed of two distinct zones : the outer definitive zone which is steroidogenically quiescent until late gestation and an inner zone which appears to produce steroid hormones throughout gestation .
the inner fetal zone makes up 8590% of the total fetal adrenal cortex at birth from which time it begins to undergo apoptosis .
the histopathologic features of acts in young children suggest that they arise from the fetal zone which has a tendency towards androgen production due to differential expression of steroidogenic enzymes at different times in development .
the primary steroid product of the fetal adrenal cortex is dehydroepiandrosterone sulfate ( dhea - s ) which is the precursor of placental estrogen .
thus , the derivation of adrenocortical tumors of infants , and young children from the fetal zone of the adrenal cortex could help to explain their preferential elaboration of androgens .
our patient 's tumor was negative for p53 mutation which is estimated to occur in 8090% of all pediatric adrenocortical tumors .
interestingly , a distinct germline p53 mutation , tp53 r337h , has been described in brazilian patients with adrenocortical tumors [ 5 , 6 ] .  
this mutation leads to an abnormal folding of the tp53 protein and accumulation in the nucleus ; loss of heterozygosity at this locus is though to be involved in tumorigenesis . in a study evaluating penetrance of this mutation ,
our patient has a favorable prognosis given complete surgical resection , small tumor size , lack of metastasis and young age
. from the international pediatric adrenocortical tumor registry report including data from 254 patients , those with completely resected tumors weighing less than 200  gm and without metastasis , had a five year event free survival rate of 91% .
this study also showed that age less than four years was independently associated with better prognosis ; multivariate analysis showed adjusted odds ratio of 2.6 for age less than four years .
as mentioned earlier , her follow - up pet scans and hormonal markers have remained negative for 24 months postoperatively . in conclusion , although rare , acts should be considered in the differential diagnosis of cushing syndrome in the pediatric age group . while virilizing features are typically dominant , acts may present with isolated cushing syndrome .
early diagnosis , adequate perioperative management with specific emphasis on postoperative glucocorticoid replacement , complete excision of tumor and close follow - up for recurrence and metastases are crucial to improve survival .
cushing syndrome is rare in infancy and usually due to an adrenocortical tumor ( act ) . 
 
 we report an infant with cushing syndrome due to adrenocortical carcinoma . 
 the patient presented at six months of age with a three - month history of growth failure , rapid weight gain , acne , and irritability . 
 physical examination showed obesity , hypertension , and cushingoid features . 
 biochemical evaluation showed very high serum cortisol , mildly elevated testosterone , and suppressed acth . 
 abdominal mri revealed a heterogeneous right adrenal mass extending into the inferior vena cava . 
 evaluation for metastases was negative . 
 the tumor was removed surgically en bloc . 
 pathologic examination demonstrated low mitotic rate , but capsular and vascular invasion . 
 she received no adjuvant therapy . 
 her linear growth has improved and cushingoid features resolved . 
 hormonal markers and quarterly pet scans have been negative for recurrence 24 months postoperatively . in conclusion , 
 adrenocortical neoplasms in children are rare , but should be considered in the differential diagnosis of cushing syndrome .