Cystinosis is the major cause of inherited Fanconi syndrome, and should be suspected in young children with failure to thrive and signs of renal proximal tubular damage. Nephropathic (infantile) cystinosis is the most common and the most severe clinical expression of the disease. It clinically presents with growth failure, proximal tubular Fanconi syndrome at 6–12 months of age, glomerular failure by the age of 10 years, and various non-renal complications including a distal vacuolar myopathy, decreased pulmonary function, swallowing impairment, and deterioration of the central nervous system (CNS), endocrinopathies, vascular calcifications, retinal damage, and other ophthalmic complications [6].
One set of complications targets the respiratory system which are respiratory failure from muscle weakness, aspiration because of swallowing abnormalities, and sleep apnea.
Therefore, the current study aimed to evaluate pulmonary complications among pediatric patients with nephropathic cystinosis.
The study was conducted on 15 patients (from 15 families) with confirmed nephropathic cystinosis and included 9 males (60%) and 6 females (40%). Although the mean age at onset of symptoms was 0.5 years, consistent with infantile onset, yet the mean age at diagnosis was late at 3.6 years, in contrary to the recent recommendations by Nesterova and Gahl for early diagnosis and early treatment [7].
As a result of being relatively late in diagnosis and thus treatment, 40% of studied patients were CKD stage 5, 13% were CKD stage 4, 20% were CKD stage 3 and 26% were CKD stage 1.
The age of ESRD ranged from 3 to 8 years with mean 4.5 years which is lower than that described by Starlen and his colleagues who studied 134 cystinosis on RRT and reported age of RRT at 10.8 years. This is presumably a reflection of the relatively late diagnosis coupled with inconsistent cysteamine therapy [8].
Gahl study reported that every month of treatment prior to 3 years of age, worth 14 months of preservation of renal function. This emphasizes the need for early diagnosis and early initiation of treatment to preserve renal function and prevent complications [9].
Oral cysteamine therapy was available in Egypt since June 2004 with interrupted periods due to financial constraints and lack of governmental and health insurance support. The mean dose of oral cysteamine used, which was solely supplied by charity organizations, was 35.3 mg/kg/d (range 10–55 mg/kg/d).
Our study showed that 67% of our patients were non-compliant to cystagon with no significant relation between cystagon compliance, CKD stage and mode of renal replacement therapy, this may be due to small size of studied group and their young age, time gap between presenting symptom and age of diagnosis. There were no sufficient data to determine if long-term cysteamine therapy was correlated with better pulmonary function. Similar to Anikster 2001 who studied 12 adult patients who lived at least 17 years without being compliant to cysteamine therapy [10].
The clinical presentation of our patient fit the broad definition of Fanconi syndrome as the leading symptom for diagnosis was polyuria and dehydration representing 80% followed by rickets representing 13% and finally failure to thrive representing 7%.
The rate of consanguineous marriage in Egypt is still high, thus autosomal recessive inherited disorders are common as positive consanguinity was detected in 87% of patients, 8 families had other affected siblings with cystinosis.
Growth was greatly affected in our patients but, height was affected more than weight as median weight was − 2.9 ranging from -3SD to − 0.78SD with while median height − 4.3 ranging from − 9.6SD to-0.49SD. This is partly due to metabolic bone disease including active rickets and renal osteodystrophy in patients with ESRD.
Out of 15 cystinosis patients, only 3 patients received renal allograft. Anikster studied 12 adult patients with nephropathic cystinosis and 3 patients with ocular, non-nephropathic cystinosis and all the nephropathic cystinosis patients had previously received a renal allograft [10].
Our patients underwent a thorough pulmonary evaluation that included a clinical assessment, pulmonary function tests in the form of IOS/ Spirometry and chest x-ray. But not all our patients were able to perform spirometry which is more sensitive in detecting restrictive lung disorder expected to be found in cystinosis patients due the young age of our studied patient (ranging from 3 to 15 years with mean of 8.6 years) and the need of patients’ cooperation and revealing no significant relation between pulmonary function affection and age, sex, age of diagnosis, consanguinity, immune suppression medication or chest symptoms and chest wall shape.
Out of the 6 patients performing spirometry,3 patients showed restrictive pattern with mean age predicted value of FEV1 and FVC were 82.8 and 75.8 respectively compared to mean FEV1 and FVC 57 and 58 respectively in an adult study including 12 nephropathic cystinosis patients (age ranged from 21 to 40 years) and detected decreased values for mean FVC, FEV1, and total lung capacity but there was no correlation between impaired pulmonary function and age, gender, or immunosuppressive medications [10]. This difference attributed to predict value to age and age difference in both studied group as cystine crystals continue accumulation in tissues including muscles as age progress.
This is the first study to evaluate the pattern of lung dysfunction in Egyptian children affected by nephropathic cystinosis. There was no available study in nephropathic cystinosis to compare IOS values with data received from our study.
Clinically all our recruited patients had normal respiratory rate for age, normal breath sound without adventitious sounds, but by chest inspection (10 patients) showed increment in AP diameter of the chest while (5 patients) showed normal chest wall. This due to rickets associated with renal disease and renal osteodystrophy proven by statistically significant relation between calcium level and chest wall shape with p value 0.04. Eighty six percent (86%) of our studied patients did not show symptoms suggestive for chest affection, 1patients (7%) had recurrent aspiration while another one (7%) had pneumonia requiring hospital admission. In contrast to an adult study showing that 9 patients had no respiratory complaints, 6 complained of dyspnea at night and 2 patients died of respiratory insufficiency [10].
Chest radiograph done for our studied patients did not show any abnormality except for conical chest configuration. In contrary to Anikster study, which performed chest radiography for 11 patients showing normal lung parenchyma in 9 patients but slightly increased interstitial markings in 1patient and left base atelectasis in 1 patient. In addition, seven patients exhibited a conical chest cavity thin-section. CT scans of the chest was also performed for 11 patients. The lung parenchyma was normal in nine patients, while 1 patient exhibited a punctate density in the pleura of the right upper lobe and 1 patient showed minimal scarring of the left lower lobe. This difference can be attributed for younger age where pulmonary affection known to be a late complication of the disease [10].
Our study showed no significant relation between CKD stage or mode of renal replacement therapy and pulmonary complication which was similar to Anikster study that showed no relation of pulmonary disease with renal failure, as indicated by the normal serum creatinine values in 10 out of 12 patients [10].
Patients in our studied group did not show symptoms suggestive of myopathy in the form of dysphagia or recurrent aspiration so no EMG was performed, therefore; we lack relation between pulmonary functions and myopathy. In contrast to the adult study which proved that the extent of pulmonary dysfunction correlated directly with the severity of myopathy. The respiratory muscle seems not to be involved in the myopathic process, although recruitment of the intercostal muscles during quiet respiration was noticed. Limited EMG examination detected evidence for irritability of the biceps and intercostal muscles, typical of the primary muscle disorder seen in nephropathic cystinosis [10].