Hepatic Adenomatosis in Aicardi Syndrome: a Clinical Report and Review of the Literature


 Aicardi Syndrome is a rare X-linked dominant genetic disorder characterized by callosal agenesis, generalized seizures, chorioretinal lacunae and vertebral anomalies. Uncommon neoplasms have been previously observed in affected patients. We describe the case of a 19-year-old woman with Aicardi Syndrome developing multiple giant mass lesions in the liver. Histopathology revealed hepatic adenomas.


Introduction
Jean Aicardi in 1965 described a syndrome of spasms in flexion, callosal agenesis, and ocular abnormalities [1]. In the following years, other findings were identified, in particular porencephalia, facial asymmetry, and vertebral dysplasia [2]. Aicardi syndrome (AS) is an X-linked dominant genetic disorder, observed almost exclusively in female patients, being lethal in males; rare XXY male cases have been described [3]. Extensive genetic studies have been performed but the mutation has not yet been identified [4]. Some reports describe rare neoplasms complicating with AS [5,6]; here, we report the case of a young AS woman developing multiple giant liver adenomas.

Case Description
A 19-year-old woman was referred to our center due to abdominal pain and US finding of multiple large mass lesions in the liver. The patient had a known diagnosis of AS, with severe scoliosis, agenesis of the corpus callosum ( Fig. 1), central chorioretinal lacunae (round depigmented areas in the retina), spasms, and mental retardation. Her regular anticonvulsant medications were felbamate and rufinamide; 4 years before, because of severe pelvic pain occurring during each menstrual period, she had started estrogen-progestin oral therapy (ethinylestradiol/drospirenone). When the woman presented to our attention, she complained new onset of severe abdominal pain in the upper abdomen; US revealed large liver lesions (maximum diameter 13 cm), irregularly hypoechoic, with hyperechoic foci, and diffused in both lobes. At physical examination, the liver was markedly enlarged. Significant serum laboratory test results were hemoglobin 10 g/dL, bilirubin 1.2 mg/dL, AST 16 U/L, ALT 56 U/L, and alpha fetoprotein level 1.1 ng/mL. No serologic markers of viral hepatitis were present. Abdominal CT confirmed multiple solid liver masses, with spherical shape, pseudocapsule appearance, early contrast enhancement, and inhomogeneous washout. The biggest lesion was located in the right lobe with diameter of 13 cm; it presented both fluid areas and spontaneously hyperdense foci, suggesting necrosis and hemorrhagic phenomena (Fig. 2). Percutaneous liver biopsy of the largest mass was performed, with US guide and under local anesthesia (Fig. 3). At histopathological examination, cells presented reticulin pattern similar to that of normal liver, with steatosis, mild nuclear atypias, and high glycogen content, depicted in PAS stains; HepPar1 marker was positive, CD34 mildly positive, and MART-1 negative. The samplings lack mutations in hepatocyte nuclear factor-1 alpha or betacatenin genes. These features were typical for hepatic adenoma. After multidisciplinary discussion, because of the high number of large lesions, no surgical therapy was performed; the estrogen-progestin therapy was stopped. At 3-month follow-up, reduction in size of all the lesions was observed, with resolution of abdominal discomfort.

Discussion
Our patient presented typical characteristics of Aicardi syndrome (AS): callosal agenesis, generalized seizures, chorioretinal lacunae, and vertebral anomalies [2,7]. Moreover, she developed multiple hepatic adenomas. These rare benign liver tumors arise in noncirrhotic liver; they occur predominantly in young women who take oral contraceptives or other steroid medications [8]; the annual incidence is 3 per 100,000 in women who have used oral contraceptives over years [9]. A small part of of patients have multiple lesions; > 3 lesions are defined as liver adenomatosis [8]. Its development is associated with some genetic syndromes, in particular glycogen storage diseases [10]. The risk of adenoma malignant transformation is supposed to be 5-6%, but it is difficult to distinguish between adenoma and welldifferentiated hepatocellular carcinoma both in imaging and histopathologically; the most useful criteria is the reticulin pattern, in adenoma similar to that of normal liver [8][9][10]. Because of its rarity, the natural history of adenoma-carcinoma progression is still unclear [11].
Among previously reported patients with AS, increased incidence of rare neoplasms was observed: choroid plexus papilloma, teratoma, embryonal carcinoma, and angiosarcoma [6,12,13]; Tanaka et al. in 1985 described a case of young AS girl with hepatoblastoma [5]. Our patient presented with multiple large liver adenomas developed after 4 years of estrogenprogestin therapy, a relatively limited period of time. This may suggest a genetic tendency in AS woman to develop liver neoplasms, making oral contraceptive therapy contraindicated. Further studies are necessary to confirm and understand the tendency to develop tumors in AS patients.

Declarations
Ethical Approval All procedures performed were in accordance with the ethical standards of the Institutional Research Committee and with the 1964 Helsinki Declaration and its later amendments.
Informed Consent Informed consent was obtained from the patient.

Consent for Publication
Consent for publication was obtained for the patient's data.