An 8-year-old boy was referred for evaluation of fatigue.
He was born at term weighing 4 kg to non-consanguineous parents and attained normal early developmental milestones.
Height and weight were on the 10th and 50th centiles, respectively.
Preliminary examination was remarkable only for hepatomegaly extending 3.5 cm below the right costal margin.
Initial laboratory evaluation revealed normochromic normocytic anaemia (haemoglobin 7.8 g/dL (11.5–16), mean corpuscular volume (MCV) 85.8 fL (75–87) and mean corpuscular haemoglobin (MCH) 25.4 pg (25–35)) with marked anisocytosis (red-cell distribution width (RDW) 29% (11–14.5)).
Hypochromia and teardrops were evident on a blood film.
Leucopoenia was also a feature (white cell count 2.9×109/L (4.5–13.5), neutrophils 1.7×109/L (2–7.5) and lymphocytes 0.8×109/L (1.5–4)).
A bone marrow aspirate and biopsy revealed a hypercellular marrow with erythroid hyperplasia.
An iron stain revealed that approximately 50% of erythroblasts were ringed sideroblasts.
Marrow cytogenetics were normal including fluorescence in situ hybridisation studies of chromosomes 5q, 7 and 8 and flow cytometry did not detect a blast population.
Serum copper and lead were normal, as were blood smears on the proband’s parents and sister.
Analysis of several genes responsible for hereditary SA (ALAS2, ABC7, FECH and PUS1) revealed no reported pathogenic variants.
Fasting lactate was elevated at 3.8 mmol/L.
Neurological examination identified upper motor neuron signs in the lower limbs bilaterally; however, cerebellar signs were negative.
MRI of the brain demonstrated volume loss with slight prominence of the cerebellar folia.
Urine organic acids revealed elevated 3-methylglutaconate and 3-methylglutarate.
The lactate:pyruvate ratio was elevated (30:1).
Muscle biopsy revealed a structurally normal muscle and biochemical assay of respiratory chain components resulted in a diagnosis of partial complex IV deficiency.
He subsequently commenced a high-fat diet and coenzyme Q with a resultant improvement in energy.
Analysis of mtDNA in leucocytes and muscle utilising PCR did not reveal a deletion.
Carnitine, vitamin A, thiamine, pyridoxine, folate and uridine were supplemented without improvement in his anaemia.
Haemoglobin levels fell to 4.4 g/dL, leading to occasional and then regular three-weekly red cell transfusions.
With repeated transfusions, ferritin rose to 1700 µg/L, necessitating iron chelation.
Peak growth hormone and cortisol to insulin-induced hypoglycaemia were 30.9 mU/L (normal >20) and 447 nmol/L (normal >500), respectively, at age 13 years.
Thyroid function was normal.
Repeat peak cortisol was 384 nmol/L following adrenocorticotropic hormone (ACTH) stimulation.
Plasma renin activity was elevated to 15 ng/mL/h, and adrenal androgens were below the lower limit of assay detection.
A urinary steroid profile was qualitatively normal, as was an abdominal ultrasound.
Hydrocortisone 5 mg twice daily and fludrocortisone 100 µg daily were initiated.
Adrenal autoantibodies to 21-hydroxylase were negative and very-long-chain fatty acids were normal.
The patient has recently developed a renal tubular Fanconi syndrome including glycosuria, hypokalaemia, hypophosphataemia with low maximal tubular reabsorption of phosphate and a generalised aminoaciduria.
In addition, he was incidentally noted to have hyperglycaemia during an admission for percutaneous endoscopic gastrostomy insertion.
Glycated haemoglobin was elevated to 62 mmol/mol (7.8%) despite rapid red cell turnover.
Pancreatic autoantibodies were negative (glutamic acid decarboxylase, anti-insulin, anti-islet antigen 2 and pancreatic islet cell antibodies).
He is maintained on twice daily insulin detemir with satisfactory glycaemic control with fructosamine 161 µmol/L (205–285).