Classically, the diagnosis of NPDB biochemically relies on the determination of acid sphingomyelinase activity in leukocytes, dried blood spots or cultured skin fibroblasts. Activity in patients is less than 15% of the normal value . However, we were unable to measure acid sphingomyelinase activity in our patient because too few laboratories currently offer this assay. Therefore, advanced determination methods, such as bone marrow cell biology and gene sequencing analysis, are helpful in further clarifying the final diagnosis. In this case, we report that the patient was misdiagnosed with BCS for three years because the diagnosis was based only on the clinical characteristics of hepatosplenomegaly and hepatic vein imaging. Gene sequencing analysis with parental study further determined the final diagnosis of NPDB. The c.1805G > A (p.Arg602His) mutation in exon 6 of the SMPD1 gene has been reported in the relevant scientific literature [6, 7]. It has been included in the ClinVar database. In a study of 118 Chinese patients with NPA/B, 92 different SMPD1 variants were identified. The most prevalent mutation was p.Arg602His, which accounted for 9.3% of alleles . We also found another mutation locus, c.829 T > C, in exon 2 of the SMPD1 gene. The pathogenicity of this locus has not yet been reported, and the frequency of this mutation locus in the normal population is zero. SIFT and Polyphen-2 predicted the novel mutation to be disease causing.
Hu et al. found a link between BCS and SBH in one case, but the patient refused liver biopsy. Thus, whether SBH was the exact cause of BCS could not be determined. SBH can be a secondary cause of NPDB, BCS, or multiple myeloma, which may make this case more complicated in clinical settings . There is also a link between BCS and lipid storage diseases. Some researchers have found that lipid storage diseases should be included as a risk factor for BCS. They found that three Egyptian children with BCS had lipid storage diseases, of which one is Niemann Pick Disease . Gaucher’s cells focally infiltrate the liver parenchyma at the hepatic venous confluence. This compromises the hepatic veins and the inferior vena cava and causes BCS . The above connections provide us with ideas for differential diagnosis in many aspects. In this case, the major clinical characteristics are abdominal distension and hepatosplenomegaly, which make it difficult to differentiate NPDB from BCS without further advanced examinations. Thus, it had been misdiagnosed as BCS for three years.
Imaging findings showed that the thinner hepatic vein merged into the inferior vena cava with increased blood flow following her admission. Hepatosplenomegaly can be observed in a variety of diseases, including NPDB, BCS, Gaucher disease, leukaemia, lymphoma, multiple myeloma, hepatic venous-occlusive disease, and primary liver tumours. If patients present with hepatosplenomegaly, haematological anomalies, and dyslipidaemia, the diagnosis should be cautiously considered. Further advance examinations, such as bone marrow cell biology and gene sequencing analysis, should be performed to reduce misdiagnoses and to provide an optimal therapeutic option. The novel mutation site (c.829 T > C in exon 2 of the SMPD1 gene) in this case has not been reported in the literature thus far and needs to be further confirmed. Of note, specific enzyme replacement therapy for NPDB may soon become available since clinical trials using olipudase alfa in adult and paediatric patients have shown significant improvements across several clinically relevant endpoints, particularly spleen size and DLCO [12,13,14]. This treatment, however, is currently not approved by regulatory agencies, except in Japan. In the future, specific enzyme replacement therapy with NPDB deserves our attention.