This was a 29-year-old male with a medical history of gout for over 6 years. He was once admitted to our hospital in 2019 due to gastrointestinal bleeding. An abdominal magnetic resonance imaging (MRI) showed multiple abnormal signal lesions in the liver (Fig. 1a). Biochemical assays showed increased uric acid (UA, 768.6 umol/L, reference range: 208-428 umol/L), decreased hemoglobin (39.1g/L, reference range: 130-175g/L). The liver biopsy was performed and showed normal hepatocellular differentiation and hepatocytes were arranged in plated with 1-2 cells thickness (Fig 2). Steatosis was absent. Periodic acid-Schiff stain (PAS) was negative and reticulin staining showed normal liver plate. It was highly suspicious for hepatic adenomas. No gastrointestinal biopsy was obtained. After the hemostasis under endoscopy, he was discharged and was ordered to follow up every six months. No prominent changes have been identified with his liver nodules and laboratory testing during the past two years. However, the abdominal MRI showed the mass was enlarged in 2021 compared to the previous images (Fig. 1b). Then he was admitted to hospital again for surgery.
The patient had short stature with 160cm in height and 50kg in weight. There were multiple palpable tophi in the proximal interphalangeal joints, wrist and knee joints (Fig. 3). Pre-surgical laboratory examinations showed hypoglycemia (3.57 mmol/L, reference range: 3.9-6.1 mmol/L) and decreased creatinine (52.7 umol/L, reference range: 64-104 umol/L) increased uric acid (559.1 umol/L, reference range: 208-428 umol/L) , free fatty acids (1139.1 umol/L, reference range: 129-796 umol/L), and urea nitrogen (9.83 mmol/L, reference range: 2.8-7.6 mmol/L), but tumor markers were negative. It was indicating that his liver function and renal function were abnormal besides his blood glucose. Multiple mass lesions were found in the liver during the operation. Nine nodules were ablated and the other four were resected and sent for pathology examination.
On gross inspection, all of 4 nodules in the liver were well demarcated and soft, the cut surface appeared pale and yellowish. One of them showed necrosis and hemorrhage. No fibrous capsule was seen (Fig. 3). Microscopically, the boundary of the tumor was clear, but fibrosis was typically absent. There was hemorrhage in some of the tumors, which suggested peliosis. The hepatocytes in three tumors were uniform in size and shape without mitosis, but the hepatocytes in the other one was slightly atypia (Fig 4a). Immunohistochemical (IHC) markers of Hepatocellular carcinoma (HCC) panel and reticulin staining denied the diagnosis of HCC with this nodule. Small bile ducts hyperplasia was evident around the tumors (Fig 4b) The cytoplasm of some peri-tumor hepatocytes was abundant, pale or clearing, and glycogen nuclei were observed, showing features with subtle glycogenosis. They were positive on PAS-stained tissue section (Fig 4c) and negative for D-PAS.
This case was discussed by multidisciplinary team. After reviewing his clinical history, GSD Ia was suspected for the underlying disease and complicated with multiple hepatic adenoma (adenomatosis). Then WES was performed to detect the possible gene variations of the patient. As shown in table 1, the results of WES suggested that there were mutations on G6PC and PGAM2 genes of the patient, the former was related to GSD. To be specific, there are 3 mutations through the WES of this patient, including 2 missense mutations, namely mutation c.964T>G (p. F322V, NM_000151.4) on exon 5 of G6PC gene (Chr17: 41063333) and c.290G>A (p. G97D, NM_000290.4) variation on exon 1 of phosphoglycerate mutase 2 (PGAM2) gene (Chr7: 44104839). Both of them showed deleterious variations according to function prediction tools, such as SIFT, Polyphen2, LRT, Mutationtatser, Gerp++, CADD, etc and had no relative research in Clinvar database. Thus, comprehensive analysis defined the mutation as uncertain significance. The mutation c.262del (p. V88Ffs*14, NM_000151.4) on exon 2 of G6PC gene (Chr17:41055977) may lead to the early coding of termination codon and truncated Glucose - 6 - phosphatase catalytic subunit 1 (G6pase-α), which is the pathogenic mutation and related to glycogen storage disease type Ia (GSD1A). Therefore, both pathologic examination and WES results verified the diagnosis.
Table 1
The results of the whole exome sequencing (WES)
Genes
and transcripts
|
Chromosomes
|
Exons
|
Variations
|
Diseases
|
variant assessment
|
G6PC
(NM_000151.4)
|
Chr17:
41055977
|
2
|
c.262del
(p. V88Ffs*14)
|
GSD1A
|
pathogenic
|
G6PC
(NM_000151.4)
|
Chr17:
41063333
|
5
|
c.964T>G
(p. F322V)
|
GSD1A
|
uncertain significance
|
PGAM2
(NM_000290.4)
|
Chr7:
44104839
|
1
|
c.290G>A
(p. G97D)
|
GSD10
|
uncertain significance
|