Diagnosis of 5α-reductase 2 deficiency: is measurement of dihydrotestosterone essential?

BACKGROUND: 5α-Reductase 2 deficiency (5ARD) is a known cause of 46,XY disorders of sex development (DSD). Traditionally, the diagnosis relies on dihydrotestosterone (DHT) measurement, but the results are often equivocal, potentially leading to misdiagnosis. We reviewed alternative approaches for diagnosis of 5ARD. METHODS: We conducted a retrospective review of the results of urinary steroid profiling (USP) by GC-MS and mutational analysis of SRD5A2 [steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)] by PCR and direct DNA sequencing of all 46,XY DSD patients referred to our laboratory with biochemical and/or genetic findings compatible with 5ARD. We also performed a literature review on the laboratory findings of all 5ARD cases reported in the past 10 years. RESULTS: Of 16 patients diagnosed with 5ARD between January 2003 and July 2012, 15 underwent USP, and all showed characteristically low 5α- to 5ß-reduced steroid metabolite ratios. Four patients had DHT measured, but 2 did not reach the diagnostic cutoff. In all 12 patients who underwent genetic analysis, 2 mutations of the SRD5A2 gene were detected to confirm the diagnosis. Twenty-four publications involving 149 patients with 5ARD were published in the review period. Fewer than half of these patients had DHT tested. Nearly 95% of them had the diagnosis confirmed genetically. CONCLUSIONS: 5ARD can be confidently diagnosed by USP at 3 months postnatally and confirmed by mutational analysis of SRD5A2. Interpretation of DHT results may be problematic and is not essential in the diagnosis of 5ARD. We propose new diagnostic algorithms for 46,XY DSD.

A novel nonsense mutation in the LPL gene in a Chinese neonate with hypertriglyceridemia.

BACKGROUND: Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive disorder characterized by hypertriglyceridemia. The genetic defect lies in a mutation of the LPL gene. METHODS: A Chinese neonate with non-consanguineous parents was incidentally found to have hypertriglyceridemia. Mutation in her LPL gene was screened by using polymerase chain reaction and direct DNA sequencing. RESULTS: Homozygous missense mutations (L252V) were detected in the LPL gene of the patient. A novel nonsense mutation (C27X) was also identified. CONCLUSION: Our finding supports L252V mutation in the LPL gene is a common mutation in Chinese with familial hyperchylomicronemia syndrome. DNA-based diagnosis in this syndrome is definitive. It saves the need for heparin-infusion test, which carries the risk of hemorrhage, and the measurement of LPL activity, which is tedious and is not widely available.