A Sri Lankan boy was first admitted to the paediatric ward at the age of 3 years with complaints of difficulty in feeding, failure to thrive and global developmental delay. He was born to non-consanguineous parents at term with a birth weight of 2.5 kg and did not have significant neonatal complications. On examination, he was drowsy, had hyperpigmentation involving perioral, buccal and palmar areas and showed evidence of hypovolaemia with tachycardia and low volume pulse.
Investigations performed at that time revealed; serum sodium 120mmol/L, potassium 7.1mmol/L, glucose 30 mg/dL, cortisol 4nmol/L (normal 120-626), ACTH 343pg/mL (normal 7-41), aldosterone 0.97ng/dL (normal 1.76-23.2), plasma renin concentration 254µIU/mL (normal 2.8-32.9), plasma renin activity 21ng/mL/hr (normal 1.9-5.2), cholesterol 153 mg/dL (normal 125-170), 17-hydroxyprogesterone 1.1ng/dL (normal 3-90) and dehydroepiandrosterone sulphate 0.08µmol/L (normal 0.7-5.7). Serum levels of thyroid stimulating hormone and abdominal ultrasonography were normal. Based on the biochemical features of hyponatraemia, hyperkalaemia, hypoglycaemia, low cortisol, low aldosterone, high ACTH in the presence of low 17-hydroxyprogesterone and dehydroepiandrosterone sulphate levels, he was diagnosed to have primary adrenal insufficiency due to a defect in the initial steps of adrenal hormone biosynthesis or congenital adrenal hypoplasia. He was commenced on oral hydrocortisone and fludrocortisone.
At the age of 5 years, he was admitted again with a history of difficulty in walking and getting up from the seated position, which was gradually worsening. Physical examination at this point revealed bilateral calf hypertrophy, waddling gait, positive Gower’s sign, hypotonia of both lower limbs, muscle power of grade 4 and normal tendon reflexes suggestive of a classical proximal myopathy (Fig. 1). His creatine kinase was 12,395U/L (normal 38-174), and electromyography showed evidence of myopathy. His electrocardiography and echocardiogram were normal. Genetic mutation analysis using multiplex ligation-dependent probe amplification method revealed hemizygous deletion encompassing final 35 exons (exon 45 to 79) of the dystrophin gene confirming the diagnosis of Duchenne muscular dystrophy.
Due to the co-occurrence Duchenne muscular dystrophy and primary adrenal insufficiency probably due to congenital adrenal hypoplasia, Xp21 contiguous gene deletion syndrome was suspected. Further investigations revealed hypertriglyceridemia (4.0 mmol/L), which was associated with non-turbid serum leading to the suspicion of pseudohypertriglyceridemia due to the presence of free glycerol in serum (Fig. 2). This was confirmed by the detection of a large glycerol peak on the urinary organic acid analysis using gas chromatography-mass spectrometry (Fig. 3). Genetic mutation testing by next generation sequencing based copy number variation analysis confirmed glycerol kinase deficiency due to hemizygous deletion encompassing the entire glycerol kinase gene (exons 1 to 21). Genetic testing for congenital adrenal hypoplasia was not done due to unavailability.
Based on the presence of Duchenne muscular dystrophy, glycerol kinase deficiency and probable congenital adrenal hypoplasia along with genetic confirmation of deletions involving dystrophin and glycerol kinase genes, the diagnosis of Xp21 contiguous gene deletion syndrome was made. He was started on oral prednisolone 0.75 mg/kg daily as a treatment for Duchenne muscular dystrophy; oral hydrocortisone was discontinued, but fludrocortisone was continued. Family screening revealed intellectual disability and elevated creatine kinase level [1108 U/L (normal 26-140)] in his mother suggesting heterozygous carrier state. His only sibling, who was a 13-year old boy was clinically normal and none of the member in the extended family were affected.