A-318 Pseudo-hypertriglyceridemia in a 2-year-old Male with Global Developmental Delay, Myopathy and Adrenal Hypoplasia
Authors: Fu X R , Williamson C P , Bosfield K P 
Published: September 2023

Background

Pseudo-hypertriglyceridemia is an overestimation of serum triglyceride levels due to laboratory assays that measure free glycerol concentrations instead of triglycerides directly. Consequently, conditions presenting with elevated levels of endogenous or exogenous free glycerol, such as glycerol kinase deficiency, result in an overestimation of serum triglycerides. Glycerol kinase deficiency (GKD) is caused by pathogenic variants of the GK gene on chromosome Xp21. Three forms of GKD are recognized, characterized as infantile, juvenile, and adult forms. While the juvenile and adult forms are recognized as isolated GKD, the infantile form manifests itself as part of the Xp21.3 contiguous gene deletion syndrome, also known as complex GKD. This syndrome is composed of genes associated with Duchenne muscular dystrophy (DMD), X-linked congenital adrenal hypoplasia (NR0B1), and intellectual disability (IL1RAPL1). GKD is characterized biochemically by hyperglycerolaemia and glyceroluria.

Case Description

A 2-year-old male presented to the genetics clinic with a history of global developmental delay (gross motor and speech), axial hypotonia, poor head control and inability to sit unassisted or walk. Significant findings on examination included a startled appearance, absent eyebrows and temporal thinning, high forehead, frontal bossing, axial hypotonia and peripheral hypertonia. Laboratory findings included elevated creatine kinase (CK) of 14809 units/L (normal 27–160 units/L), aspartate aminotransferase (AST) of 307 (normal 20–60 units/L), alanine aminotransferase (ALT) 265 (normal 15–45 units/L), Adrenocorticotropic Hormone (ACTH) 156 (normal 6–48 pg/mL), and elevated triglycerides at 683 (normal 44–157 mg/dL). There was also a family history of developmental delay and intellectual disability in patient's mother and younger sister.

Method

Triglycerides are commonly measured indirectly with different enzyme reagents. The Triglycerides in this boy were measured by an automated chemistry analyzer based on a colorimetric serial enzymatic reaction including lipase, glycerol kinase and L-α-glycerol-phosphate oxidase1. Urinary organic acids profile including glycerol was extracted from acidified urine (pH 1-2) using diethyl ether. Organic extracts are then evaporated to dryness under nitrogen and trimethysilyl derivatized by the addition of N, O-bis (trimethylsilyl) trifluoroacetamide with 1% trimethylchorosilane (BSTFA/TMCS) and analyzed by gas chromatography-mass spectrometry (GC-MS).

Results

A comprehensive work-up including qualitative urinary organic acid analysis and chromosomal microarray was carried out. Urinary organic acids analysis revealed very abnormal accumulation of glycerol. Chromosomal microarray results showed a 4.2 Mb deletion of Xp21.3p21.1 (29296579-33551038) including complete copies of GK, DMD, and NR0B1 genes as well as multiple exons of IL1RAPL1. This confirmed his GKD as part of the Xp21 continuous gene deletion syndrome. Elevated triglycerides were then recognized as pseudo-hypertriglyceridemia after the diagnosis. Mild glyceroluria is also observed in the younger sister of this patient.

Discussion and Conclusion

This case highlights the importance recognizing pseudo-hypertriglyceridemia and diagnostic challenges. Earlier identification through urine organic acid analysis could have been made. The combination of clinical presentations and increased glycerol should cause suspicion for GKD. Female carriers of this X-linked disorder need to be evaluated for intellectual disability, as seen in this patient's mother and younger sister.