Glycerol kinase deficiency (GKD) is a rare X-linked metabolic disorder often presenting in infancy or childhood. In adults, it may remain undiagnosed due to nonspecific symptoms or incidental biochemical findings. We report a case of incidental GKD diagnosis in an adult male presenting with hyponatraemia and acute kidney injury (AKI). Discrepancies between triglyceride concentrations and lipaemic indices prompted further investigation, revealing severe hyperglycerolaemia due to GKD. This case highlights the importance of considering GKD in adults with unexplained hypertriglyceridaemia, especially when triglyceride concentrations are discordant with lipaemic indices and other lipid profile parameters. Genetic testing confirmed that the patient was hemizygous for a likely pathogenic variant in the GK gene, consistent with a genetic diagnosis of glycerol kinase deficiency.

X-linked adrenal hypoplasia congenita (AHC) is a rare, life-threatening disorder caused by pathogenic variants in NR0B1 (DAX1), leading to adrenal insufficiency and hypogonadotropic hypogonadism. AHC is often associated with Xp21 contiguous gene deletion syndrome, which involves the deletion of multiple genes, including NR0B1, GK, DMD, and IL1RAPL1, resulting in a spectrum of phenotypic manifestations, such as glycerol kinase deficiency (GKD), Duchenne muscular dystrophy (DMD), and neurodevelopmental disorders. We report two cases of AHC with neurodevelopmental delays due to contiguous Xp21 deletions involving NR0B1 and IL1RAPL1, each diagnosed through distinct clinical pathways. Case 1 involved a neonate with adrenal insufficiency, persistent hyperCKemia, and excessive urinary glycerol excretion, leading to a diagnosis of Xp21 deletion syndrome with DMD and GKD. The patient's sister, an asymptomatic carrier, exhibited elevated CK levels and mild developmental delays. Array comparative genomic hybridization identified a novel complex structural variation, including duplication-deletion-duplication rearrangement, which may have modified clinical manifestations. Case 2 involved a 10-year-old boy with AHC and developmental delay that was initially considered a consequence of adrenal crises. Genetic analysis confirmed an Xp21 deletion, including IL1RAPL1, implicating it in his intellectual disability. A literature review reveals that Xp21 deletions involving IL1RAPL1 are strongly associated with neurodevelopmental delays, suggesting a distinct phenotype within Xp21 deletion syndromes. Early genetic diagnosis via chromosomal microarray analysis facilitates precise delineation of deletion regions, aiding in clinical management, genetic counseling, and early intervention strategies. Further studies are needed to elucidate genotype-phenotype correlations in Xp21 deletion syndromes and optimize individualized medical care.

Glycerol kinase deficiency is an X-linked disorder and can occur in isolation or combined as part of the Xp21 continuous gene deletion syndrome. We report the first offspring of a non-consanguineous couple with this contiguous gene deletion syndrome. There was a family history of short stature and learning difficulties, and a personal history of two hospitalizations due to prostration, hypoglycemia, and metabolic acidosis, the first of which occurred at six months of age. The patient was referred to a neurodevelopment consultation due to a global developmental delay detected at two years of age and a genetic consultation at four years old. The array comparative genomic hybridization study identified a maternally inherited hemizygous deletion of the Xp21 region of approximately 6.08 Mb that included both Duchenne muscular dystrophy and glycerol kinase genes, confirming the diagnosis. The patient was referred to metabolic and neurology consultations. Motor examination revealed a waddling gait when running, calf hypertrophy, and a positive Gower's sign. Laboratory evaluation was notable for elevated creatine kinase, hyperglyceroluria, pseudohypertriglyceridemia, and increased transaminases. The patient had a normal adrenocorticotropic hormone stimulation test and normal aldosterone and renin levels. Currently, he has a multidisciplinary team follow-up, including therapies. He maintains deflazacort therapy and follows a nutrition plan based on a fat-restricted diet and avoidance of prolonged fasting to prevent further metabolic crises. This case highlights the importance of identifying the exact genetic defects, in addition to a global picture of symptoms. In our case, it was possible to diagnose complex kinase deficiency along with Duchenne muscular dystrophy. Consequently, it was optimal for multi-profile medical care accompanied by an adequate nutritional plan.

Xp21 contiguous gene deletion syndrome is a rare X-linked disorder involving deletions of DMD, GK, and NR0B1 (DAX1), leading to a combination of Duchenne muscular dystrophy, glycerol kinase deficiency, and congenital adrenal hypoplasia. Diagnosis can be delayed due to overlapping symptoms, especially in critically ill infants. We describe two male infants presenting in early life with adrenal insufficiency, electrolyte imbalance, hyperpigmentation, and hypotonia. Biochemical findings included elevated ACTH, low cortisol, high CK, and pseudo-hypertriglyceridemia. In the first case, delayed diagnosis led to sudden death at 7 months. In the second case, early clinical suspicion enabled timely genetic testing and family screening. MLPA revealed DMD gene deletion in both cases. In the second case, molecular karyotyping confirmed deletion at Xp21.3-p21.1; the mother and sister were also carriers. Clinicians should consider Xp21 syndromes in male infants with adrenal insufficiency and neuromuscular or metabolic signs. Early recognition and genetic testing are crucial for accurate diagnosis, effective management, and informed family counseling.

Hyperglycerolemia is a rare X-linked inborn error of metabolism whose prevalence is currently unknown. Whether extreme glycerol levels are associated with atherosclerosis is still unknown. The aim of this study was to assess subclinical atherosclerotic cardiovascular disease (ASCVD) in hyperglycerolemia. We performed a retrospective analysis in a cohort of patients referred to a tertiary referral center for dyslipidemia between 2000 and 2011. We assessed plasma glycerol levels in all subjects exhibiting hypertriglyceridemia (defined as triglyceride levels > 200 mg/dL). Genetic testing was performed in patients with confirmed hyperglycerolemia. Over 314,268 lipid profiles, 11.8% had hypertriglyceridemia, of whom 13 patients had biological hyperglycerolemia. Genetic tests showed 7 previously undescribed variants of the X-linked glycerol kinase gene. None of the hyperglycerolemic patients presented carotid atherosclerosis at baseline. After a median 11.5 years follow-up, none of the hyperglycerolemic patients developed clinical ASCVD, although noninvasive coronary and carotid imaging revealed the incidence of subclinical atherosclerosis for three of the hyperglycerolemic patients with concomitant classical cardiovascular (CV) risk factors together with an unhealthy trajectory in body weight. Hyperglycerolemia per se is not associated with premature ASCVD. Its screening should be considered only in patients with persistent hypertriglyceridemia unresponsive to treatment. The confirmation of hyperglycerolemia can help the clinician reassure the patient concerning his CV risk, as no further assessment is required other than common CV risk factors monitoring, including body weight increase and insulin resistance that may appear over the life course.