Inherited tubulopathies: Case

This infant has nephropathic cystinosis presenting as Fanconi syndrome. The failure to thrive, the polyuria and polydipsia, the hypophosphataemic rickets with frontal bossing, widened wrists and bowed tibiae, the normal anion gap metabolic acidosis, the hypokalaemia, and the glycosuria with a normal blood glucose together signal a generalised failure of the proximal tubule. Cystinosis is the commonest inherited cause of Fanconi syndrome in children, and without cysteamine it progresses to end-stage kidney disease in the first decade. [1]

Clinical findings

The clinical picture is one of global proximal tubular dysfunction with its metabolic consequences. The proximal tubule normally reabsorbs the bulk of the filtered load, and its failure spills glucose, phosphate, amino acids, low molecular weight proteins and bicarbonate into the urine. The glycosuria with a normal blood glucose, the hypophosphataemia with rickets, and the normal anion gap acidosis from bicarbonate wasting are the hallmarks. The polyuria from the osmotic diuresis and the concentrating defect drives the dehydration and the vomiting that contribute to the failure to thrive. [2]

The rickets is the skeletal expression of the phosphate wasting. The chronic hypophosphataemia, compounded by the acidosis that leaches mineral from bone, produces the bowing of the legs, the widened wrists and the frontal bossing. The child is reluctant to walk because of bone pain. In cystinosis there may be added photophobia from corneal crystal deposition and a fair complexion, and the candidate should ask about these and examine the eyes, because the corneal crystals are a defining feature that the slit lamp reveals before any blood test returns. [1]

Investigations and staging

The Fanconi screen confirms the proximal tubulopathy. I would send a urine sample for glucose, amino acids, phosphate and low molecular weight proteins, alongside a normal blood glucose, and the combination of glycosuria with euglycaemia, phosphaturia, aminoaciduria and low molecular weight proteinuria with a normal albumin establishes the generalised proximal wasting. The venous blood gas confirms the normal anion gap metabolic acidosis, and the serum shows the low potassium and the low phosphate. [2]

The cause workup is the next step, and cystinosis leads it. I would measure the leukocyte cystine, which is markedly raised in cystinosis, and arrange a slit-lamp examination for corneal crystals, which are pathognomonic. I would confirm genetically with a CTNS analysis, because the diagnosis carries specific therapy and counselling. I would also screen for the other inherited Fanconi causes where the history fits, including galactosaemia, hereditary fructose intolerance, tyrosinaemia and Lowe syndrome, and take a careful drug history to exclude acquired causes such as ifosfamide, tenofovir and valproate. [3]

The renal function assessment tracks the progression. I would monitor the creatinine and the estimated glomerular filtration rate through the course, because cystinosis progresses to renal failure despite Fanconi therapy, and the rate of decline is what guides the timing of renal replacement planning. The bone mineralisation is assessed with radiographs of the wrists and knees for rachitic changes, and the growth is plotted at every visit, because growth recovery is the marker of adequate treatment. [4]

Management and outcome

The management has two strands, replacing what the proximal tubule wastes and treating the underlying cystinosis. The acidosis is corrected with high-dose bicarbonate at 10 to 20 mEq per kg per day in divided doses, because the kidney keeps wasting bicarbonate above the lowered threshold. Potassium is added, because the increased distal bicarbonate delivery drives potassium wasting. Phosphate is replaced for the rickets, with calcitriol to support the bone mineralisation, and the dose is titrated to the serum phosphate and the alkaline phosphatase. [2]

The disease-modifying therapy is cysteamine, and it is the determinant of the long-term renal survival. Cysteamine depletes the lysosomal cystine and dramatically slows the progression to end-stage kidney disease, which is why early diagnosis by leukocyte cystine matters. I would start cysteamine as soon as the diagnosis is confirmed, titrated to the leukocyte cystine target, and accept that the frequent dosing and the gastrointestinal side effects test the adherence, because adherence is the single biggest determinant of the outcome. Topical cysteamine eye drops address the corneal crystals. [1]

The long-term outlook depends on the cysteamine and the renal surveillance. Without cysteamine this child would reach end-stage kidney disease in the first decade, but with cysteamine the progression is dramatically slowed and renal survival into adulthood is achievable. I would involve the paediatric nephrology and metabolic teams early, monitor the growth, the biochemistry and the renal function, and begin planning for renal replacement therapy if the function declines, with pre-emptive transplantation the goal. The family needs genetic counselling about the autosomal recessive inheritance and the 25 percent recurrence risk, and I would offer cascade testing and preimplantation genetic diagnosis for future pregnancies. [3]