Fanconi syndrome-associated interstitial lung disease

Background

Fanconi syndrome is a rare global dysfunction of the proximal tubule leading to excessive urinary excretion of amino acids, glucose, phosphate, bicarbonate, uric acid and other solutes normally reabsorbed by the proximal tubule.1 The diagnosis of Fanconi syndrome is made based on tests documenting excessive loss of substances such as phosphate, amino acids, glucose, bicarbonate in the urine and the absence of high plasma concentrations in the respective substances. Urinary hyperexcretion of amino acids of all classes, evidence of type 2 renal tubular acidosis with metabolic acidosis or decreased serum phosphate on unrestricted dietary intake are among the most common signs that should fuel meticulous evaluation for Fanconi syndrome. Aetiology differs depending on the age of diagnosis. In childhood, inborn errors of metabolism consist of the principal cause, while in adults, the disease is acquired and usually caused by toxins or drugs.2 3 Treatment is not specific and mainly consists of replacement of substances lost in the urine.1 Pulmonary manifestations are not common in Fanconi syndrome, as progressive renal impairment resulting in metabolic acidosis, aminoaciduria, phosphaturia and proteinuria is the representative manifestation of the syndrome. Nevertheless, several familial cases of Fanconi syndrome may lead to both kidney and lung injury with relatively unknown pathogenic mechanisms.4

We report a case of interstitial lung disease (ILD) in a patient with Fanconi syndrome. Multidisciplinary discussion (MDD) between pulmonologists, nephrologists and internists suggested ILD as a rare complication of Fanconi syndrome. The following report presents in detail patient’s management and clinical course as well as highlights the cardinal role of MDD in diagnosis and management of rare causes of ILDs.

Case presentation

A middle-aged man, never smoker, presented to our department with rapidly progressive dyspnoea on exertion and non-productive cough over the past 8 months. Chest high-resolution CT (HRCT) revealed multiple bilateral consolidations, traction bronchiectasis, reticular pattern and honeycombing with basal and peripheral predominance. He denied the presence of fever, night sweats or weight loss. The patient reported a medical history compatible with Fanconi syndrome diagnosed almost 40 years ago, hypothyroidism and atrial fibrillation treated with ablation in 1997. The patient was receiving phosphate, potassium bicarbonate and cholecalciferol, since childhood as a replacement treatment for Fanconi syndrome and oral prednisolone as therapeutic option for ILD first identified in HRCT 12 months ago. The patient reported no occupational or environmental fibrogenic exposures.

Physical examination revealed the following vital signs: blood pressure of 135/70 mm Hg; heart rate, 67 beats/min; temperature, 36,7 °C and oxygen saturation, 97% on ambient air. Lung auscultation revealed bibasal end-inspiratory crackles (velcro type). Heart and abdomen examination was unremarkable. Clubbing was present. There were no palpable lymph nodes. Timeline of clinical features is depicted in figure 1.

Figure 1

Depiction of timeline of clinical features from childhood to adult life (created by Theodoros Karampitsakos).

Investigations

At the time of referral to respiratory department, HRCT revealed multiple bilateral consolidations, traction bronchiectasis, reticular pattern and honeycombing with basal and peripheral predominance indicative of indeterminate for Usual interstitial pneumonia (UIP) pattern (figure 2A). The complete blood and metabolic panel revealed renal impairment (serum creatinine: 3 mg/dL), while complete serology profile was negative. The patient did not undergo conventional bronchoscopy due to non-compliance and informed consent withdrawal. Pulmonary function tests (PFTs) showed moderate restriction and severe reduction in diffusing lung capacity for carbon monoxide (Forced vital capacity: 57%, Tiffeneau: 91, Total lung capacity: 65%, Diffusing capacity for carbon monoxide: 41%). Echocardiogram was normal with no signs of pulmonary hypertension.

Figure 2

(A) Chest CT of the patient receiving MMF plus corticosteroids for ILD as a complication for Fanconi syndrome showing bilateral consolidations, traction bronchiectasis and fine reticulation of subpleural distribution. (B) Radiologic progression 12 months after MMF discontinuation. ILD, interstitial lung disease; MMF, mycophenolate mofetil.

Differential diagnosis

On the basis of a compatible clinical (cough and dyspnoea on exertion), functional (restrictive pattern with diffusing capacity impairment) and radiological features (fibrotic pattern indeterminate for UIP) in the context of negative serology and absence of bacterial infection as well as familial history or major fibrogenic exposures, MDD work-up set a working diagnosis of Fanconi syndrome-associated fibrotic ILD.

Treatment

Following MDD, the patient was commenced on mycophenolate mofetil (MMF) (2 g/day) plus low doses of oral prednisolone (10 mg/day).

Outcome and follow-up

In a follow-up appointment after 6 months, the patient presented with no radiologic and functional improvement on HRCT and PFTs, respectively. MMF was discontinued on the basis of patient’s preferences and close monitoring was decided. Unfortunately, 6 months later, the patient presented with clinical, functional and radiological deterioration (figure 2B) and we commenced nintedanib in the context of progressive-fibrotic ILD (PF-ILD). Nintedanib was discontinued due to severe gastrointestinal disorders and excessive diarrhoeas leading to further renal function impairment. The patient remained at baseline supplementation treatment for Fanconi syndrome. Eight months later, the patient presented with fever, productive cough, worsening of dyspnoea and severe respiratory failure and was admitted to the intensive care unit, intubated and finally passed away. Thorough microbiology and virology investigation was negative. Overall course of PFTs is shown in figure 3.

Figure 3

Overall course of PFTs (created by Theodoros Karampitsakos). PFT, pulmonary function test; FVC, Forced vital capacity; DLCO, Diffusing capacity for carbon monoxide.