Samardzic et al. Journal of Medical Case Reports 2011, 5:400 http://www.jmedicalcasereports.com/content/5/1/400 Case presentation A 7-year-old Montenegrin boy was initially referred to the pediatric endocrinology ward because of short sta- ture. His height was 2.93 standard deviations (SD) below the mean. His mid-parental height was 181.6 cm (+1 SD). Our patient was born at term following an uneventful pregnancy with a birth weight of 3.95 kg and a birth length of 57 cm. His family history was negative for short stature, delayed puberty and renal disease. Except for dental caries, high palate and slight genus valgus, he had no other abnormalities. His blood pres- sure was normal and his bone age was 5 years. A laboratory test was positive for proteinuria. He had an elevated urinary calcium level and b2-microglobulin excretion. A renal ultrasound showed early medullary nephrocalcinosis. His levels of serum calcium, phos- phorus and alkaline phosphatase were normal. His tubu- lar reabsorption of phosphate (TRP) was decreased. His creatinine clearance test [7] was normal (92.8 ml/min/ 1.73 m2). No other electrolyte or metabolic abnormal- ities were observed. His overnight growth hormone (GH) profiles were normal (> 3 peaks of > 10 μg/L). An audiometry test was also unremarkable. In order to con- firm a diagnosis of Dent’s disease, molecular genetic analysis was performed one year later and showed a mutation in the CLCN5 gene, leading to S244L amino acid substitution. The mutation carrier, the patient’s mother, was asymptomatic with slight hypercalciuria. After two years of conventional treatment with hydro- chlorothiazide, our patient was referred for a new endo- crine evaluation because of a failure to catch-up growth. Laboratory tests showed more prominent urinary pro- tein excretion, whereas the level of calciuria remained unchanged. Clinical, radiological and laboratory signs of hypophosphatemic rickets became noticeable. We found hypophosphatemia (0.74 mmol/L), elevated serum alka- line phosphatase activity (926 U/L), and a nearly normal level of parathyroid hormone. X-rays showed enlarge- ment of his wrists and knees and fraying of the meta- physes of his distal ulna and radius. Our patient’s growth velocity was 4.7 cm/yr (-1 SD). His parental adjusted height at that time was -3.11 SD; his pubertal status was Tanner stage one. A height prediction based on his recent growth was approximately 160.7 cm (Sta- tistical program: SAS v9.13). At the age of nine years and three months we initiated recombinant human growth hormone (rhGH) therapy. The indication for GH therapy was markedly short stature and chronic renal disease stage one [8]. The average dose of rhGH was 0.04-0.05 mg/kg per day. Because of the overt hypo- phosphatemic rickets and hypercalciuria, in addition to hydrochlorothiazide we started him on calcitriol 20-40 ng/kg/day in two divided doses, phosphorus 20-40 mg/ kg/day, maximum 2.5 g/day in 3-5 divided doses and Page 2 of 6 potassium citrate. A follow-up was performed at three- month intervals. We followed his growth velocity, serum phosphate, serum creatinine, creatinine clearance, TRP, protein and calcium excretion, insulin-like growth factor 1(IGF-1), insulin-like growth factor-binding protein 3 (IGFBP-3) and other laboratory tests in relation to growth hormone therapy (Table 1, Table 2). In the first two years, our patient grew at an average rate of 9 cm per year (> 95c), and in the third year he grew 6 cm (50c) (Figure 1). His bone age remained retarded. Dur- ing rhGH treatment and other therapies, there were no relevant changes in his creatinine clearance or the degree of nephrocalcinosis on renal ultrasonograms. His cystatin C level was also normal at -0.85 mg/L (normal range 0.53-0.95 mg/L). His level of proteinuria remained stable whilst urinary calcium excretion was reduced. Despite continued phosphaturia, his serum phosphate level increased gradually, and his serum alkaline phos- phatase returned to normal. No acceleration in bone age or increase in glucose intolerance was noted. After sus- pending GH therapy for two months, GH secretion was re-evaluated: IGF-1 level was under the normal range and a clonidine stimulation test showed a peak serum GH concentration of 16.5 μg/l, again confirming the absence of a GH deficiency. Discussion Dent’s disease is an inherited tubulopathy caused by CLCN5 gene mutations. To date, more than 80 distinct CLCN5 mutations have been reported [9]. S244, is the most common mutation in CLCN5 thus far described. In our patient’s family we also identified this mutation. Tosetto et al. found that approximately 48% of patients with Dent’s disease had rickets, which correlates with only one mutation, S244L [10]. It is not completely clear how the loss of function in the endosomal chloride channel leads to a decrease in brush-border sodium/ inorganic phosphate co-transport. However, not all patients with Dent’s disease show a decrease in phos- phate reabsorption [9]. Hoopes et al., found that hypo- phosphatemic patients were not always affected by rickets. Also, some patients with Dent’s disease have been observed to have extrarenal manifestations such as mild intellectual impairment, hypotonia and cataracts, and such patients have been reported to share a muta- tion in OCRL1 with the oculocerebrorenal syndrome of Lowe. The occurrence of these extrarenal manifestations with mutations relating to Lowe syndrome is referred as Dent’s disease type 2 [11]. The most striking physical sign in the first described patient with Dent’s disease and hypophosphatemic rick- ets was the shortness of stature [12]. At the time of set- ting the differential diagnosis our patient also had growth failure (-2.89 SD), although he had normal