Intestinal mucosa in nephropathic cystinosis

The major manifestations of nephropathic cystinosis are renal tubular acidosis, vitamin D-resistant rickets, and dwarfism. Cystine crystals are deposited in a variety of cells, mainly phagocytic, including macrophages of the intestinal lamina propria. Previously, ultrastructural changes were suggested to occur in the absorptive epithelium as well, possibly as a result of local cystine toxicity. We report here on the light- and electron-microscopic findings in the jejunal mucosa of two patients, aged 4 and 9 years with nephropathic cystinosis. Cystine crystals were easily identified in semithin sections of plastic-embedded specimens as brick- and hexagon-shaped spaces in macrophages. Electron microscopy showed that all crystals were in single-membrane-limited bodies (lysosomes), within phagocytic cells, and exclusively located in the lamina propria. In contrast to previous findings, the absorptive epithelium showed no abnormalities. We conclude that the growth failure in cystinosis is not a consequence of morphological toxic alterations in the intestinal epithelium, but is related to the known metabolic abnormalities of this condition. The use of rectal suction biopsy as a means of diagnosing cystinosis is also suggested as an alternative to other diagnostic methods.     

Hypothyroidism in children with cystinosis

Eight children with cystinosis (3 with renal transplants, 2 on maintenance haemodialysis, 2 with chronic renal failure, and one with normal renal function) were studied for evidence of hypothyroidism, and compared with a control group of children with chronic renal failure due to other causes. Abnormal thyroid function was present in all the cystinotic patients: thyroxine (T4) low in 1, free thyroxine index (FTI) low in 2, thyroid-stimulating hormone (TSH) raised in 6; all had a supranormal TSH response to thyrotrophin-releasing hormone (TRH) stimulation, indicating impaired thyroid reserve compared with patients in the control group who had a depressed or normal TSH response. Increased growth velocity with thyroid supplementation occurred in only 2 patients, and the onset of puberty may have contributed to this improvement. Hypothyroidism is a common finding in cystinosis, and it is suggested that thyroxine treatment be started when the TSH concentration becomes raised.     

Hypothyroidism in children with cystinosis.

Eight children with cystinosis (3 with renal transplants, 2 on maintenance haemodialysis, 2 with chronic renal failure, and one with normal renal function) were studied for evidence of hypothyroidism, and compared with a control group of children with chronic renal failure due to other causes. Abnormal thyroid function was present in all the cystinotic patients: thyroxine (T4) low in 1, free thyroxine index (FTI) low in 2, thyroid-stimulating hormone (TSH) raised in 6; all had a supranormal TSH response to thyrotrophin-releasing hormone (TRH) stimulation, indicating impaired thyroid reserve compared with patients in the control group who had a depressed or normal TSH response. Increased growth velocity with thyroid supplementation occurred in only 2 patients, and the onset of puberty may have contributed to this improvement. Hypothyroidism is a common finding in cystinosis, and it is suggested that thyroxine treatment be started when the TSH concentration becomes raised.     

Lysosomal cystine transport in cystinosis variants and their parents

Children with nephropathic cystinosis store 50 to 100 times normal amounts of free cystine in many cells and display negligible lysosomal cystine transport in their leucocytes and cultured fibroblasts. A patient with intermediate (adolescent) cystinosis exhibited a similar deficiency of egress out of fibroblast lysosome-rich granular fractions. Another individual with benign (adult) cystinosis accumulated only 2.85 nmol 1/2 cystine/mg leucocyte protein, or 20-50% of the amount stored in nephropathic cystinosis leucocytes. His leucocyte granular fractions also displayed substantial residual cystine-carrying capacity, as determined by measurement of lysosomal cystine counter-transport. We conclude that the variant forms of cystinosis represent a continuum of lysosomal cystine storage, with the varied clinical presentation depending on the amount of residual cystine-carrying capacity, genetic predispositions, and differential tissue susceptibilities.     

Acquired structural genitourinary abnormalities contributing to deterioration of renal function in older patients with nephropathic cystinosis

The natural progression of nephropathic cystinosis to end stage renal disease can be delayed, sometimes by many years, by the reducing agent, cysteamine, which lowers intracellular cystine content to near normal. We report on two patients with nephropathic cystinosis who were treated with cysteamine and developed structural genitourinary abnormalities which may have contributed to an increase in the rate of decline of renal function. One patient, aged 11 years, was found to have massive megacystis and hydroureteronephrosis but no anatomic bladder outlet obstruction. His abnormality was presumed to be related to chronic high urine volumes leading to megacystis and physiologic ureteral obstruction. Vesicostomy stabilized renal function. The second patient, aged 11 1/2 years, was found to have bilateral renal cystic disease which presumably was acquired and may have been related to long-standing hypokalemia. Minor renal abnormalities were found by ultrasound in five additional cystinotic children. We concluded that older children with nephropathic cystinosis may be prone to acquire structural abnormalities of their kidneys or urinary tract.     

Early oral cysteamine therapy for nephropathic cystinosis

Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder in which intracellular cystine accumulates due to impaired transport out of lysosomes. The clinical manifestations include renal tubular Fanconi syndrome in the 1st year of life, with hypophosphatemic rickets, hypokalemia, polyuria, dehydration and acidosis, growth retardation, hypothyroidism, photophobia, renal glomerular deterioration by 10 years of age, and late complications such as myopathy, pancreatic insufficiency, and retinal blindnesss. The cystinosis gene, CTNS, codes for cystinosin, a 367 amino acid protein with seven transmembrane domains. More than 50 CTNSmutations have been identified, but approximately 50% of Northern European patients have a 57257-bp deletion which removes the first nine exons of CTNS. The mainstay of cystinosis therapy is oral cysteamine (Cystagon). This aminothiol can lower intracellular cystine content by 95%, and has proven efficacy in delaying renal glomerular deterioration, enhancing growth, preventing hypothyroidism, and lowering muscle cystine content. Its early and diligent use is critical; in one study, for every month of treatment prior to 3 years of age, 14 months' worth of later renal function were preserved. Several examples of individual patients treated early and having preserved renal function and normal growth are available. Newborn screening using a chip containing cDNA to detect common CTNSmutations may allow diagnosis and treatment in the first weeks of life. CONCLUSIONS: Early diagnosis and treatment of nephropathic cystinosis can change the course of this disease.     

A patient with cystinosis presenting transient features of Bartter syndrome

A 16-month-old boy was admitted to the clinic because of vomiting and growth failure. His weight and height measurements were under the fifth percentile. He had fair hair and skin, enlarged wrists and rachitic rosaries. The presence of metabolic alkalosis, hypokalemia, hypochloremia, and high renin and aldosterone levels were suggestive of Bartter syndrome. However, in view of the growth failure, fair hair and skin, proteinuria, polyuria and active rickets, cystinosis was considered. Bone marrow smear examination was normal, despite the existence of suspicious crystals in the cornea. Cystine crystals were seen in the conjunctiva biopsy and increased leukocyte cystine level was measured; therefore, definitive cystinosis diagnosis was made. Renal Fanconi syndrome with metabolic acidosis is prominent in cystinosis; however, in rare instances, if sodium-dependent trans-tubular transport defect is present, patients could have Bartter syndrome findings such as hypochloremic metabolic alkalosis. Our case is a good example demonstrating that metabolic alkalosis should not exclude cystinosis and the other signs and symptoms of the patient should be thoroughly evaluated.     

Endocrine function in thai children infected with human immunodeficiency virus

Most children infected by HIV show manifestations which mimic the clinical features of endocrine dysfunction, such as failure to thrive and hyperpigmentation. Our cross-sectional study was designed to assess the endocrine function of Thai children infected with HIV and to determine any relationship between disease severity, height and endocrine function. Thirty-six prepubertal children infected by HIV, 12 boys and 24 girls, aged 4-12 years (mean +/- SD 7 +/- 2 years), were tested for thyroid function (serum T4, T3, TSH and free T4), morning serum cortisol level, serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3). Disease severity was assessed using CD4+ T-lymphocyte percentage. Ten (28%) patients showed abnormal thyroid function. Five patients had euthyroid sick syndrome. Thyroid function tests indicated another five patients had a condition compatible with compensated hypothyroidism. Most patients had normal morning serum cortisol levels. Two-thirds and one-third of the patients showed low IGF-I and IGFBP-3 standard deviation scores (SDS), respectively. Twenty-six (72%) patients had CD4+ T-lymphocyte <15%, thus were classified as severely immune suppressed. A weak linear relationship was indicated between disease severity and endocrine function (r = -0.03 to 0.41). Statistical significance was found between CD4+ percentage and IGF-I SDS, IGFBP-3 SDS, serum T3 and free T4 (p-value = 0.03, 0.02, 0.02 and 0.01, respectively. Nearly half (44%) the patients were below the third percentile for height of Thai children. There was also a weak correlation between height SDS and endocrine function (r = -0.03 to 0.41). Statistical significance was observed between height SDS and IGF-I SDS, serum T3 and TSH (p-value = 0.02 and 0.01, respectively). We conclude that HIV-infected children with demonstrated growth failure and greater disease severity tend to have abnormal endocrine function, particularly disordered IGF-I levels.     

Evidence of hypothalamic-pituitary thyroid abnormalities in children with end-stage renal disease

Patients with end-stage renal disease may have abnormalities of growth and of gonadal and thyroid hormones, so we attempted to determine the mechanisms that may be involved in the altered thyroid function. We evaluated serum thyroid hormone levels, their changes immediately after hemodialysis, the serum thyrotropin (thyroid-stimulating hormone (TSH) response to thyrotropin releasing hormone, and the circadian pattern of serum TSH in nine children with end-stage renal disease who were between 7 1/2 years and 17 years 1 month of age. Seven patients had been receiving hemodialysis for a median of 3.3 years; the other two were receiving continuous ambulatory peritoneal dialysis. Four patients had low serum total thyroxine (T4) values, and all nine had low free T4 values. Mean concentrations of total T4, free T4, and total triiodothyronine (T3), which were significantly less than normal before hemodialysis, returned to normal levels immediately after dialysis. Postdialysis thyroid hormone increases did not correlate with the decrease in weight or the increase in hematocrit observed immediately after dialysis. All but one patient had basal TSH levels within the normal range. Three patients had a deficient TSH response to thyrotropin releasing hormone, and the TSH response was prolonged in all of them. The mean (+/- SD) nocturnal TSH surge was 50 +/- 68%. Five of the eight patients studied had a nocturnal TSH surge below the normal range (95% confidence limits 47% to 300%). Serum free T4 values correlated with the TSH nocturnal surge (r, 0.73; p less than 0.05). Our findings support the hypothesis that some patients with end-stage renal disease have central hypothyroidism.     

Raised serum TSH in hypothyroidism.

It is desirable to detect early hypothyroidism of the mildest degree even before conventional tests of thyroid function become abnormal. Serum TSH levels (normal: undetectable to 4 muU/ml) rise in patients with mild hypothyroidism long before serum T4 and T3 levels fall. In the patient described the serum TSH level was 310 muU/ml, while other tests of thyroid function gave normal results. After treatment with thyroxine, serum TSH returned to normal. It should now be accepted that patients with mild hypothyroidism have a raised serum TSH and that thyroid insufficiency can be confidently excluded if the serum TSH concentration is normal. It is thus important to assay serum TSH when suspicion of hypothyroidism is aroused.     

Growth and pubertal development in nephropathic cystinosis

In a retrospective investigation growth and pubertal development were evaluated in 30 patients with nephropathic cystinosis. Growth was investigated during the stage of chronic renal insufficiency as well as after successful kidney transplantation and growth rates were related to kidney function. Pubertal development was evaluated in 17 patients between 12 ans 25 years of age. Prepubertal growth rates were stable in a range between –2 and –3 height velocity SDS as long as glomerular filtration rate was above 20ml/min per 1.73m². A decrease in glomerular filtration rate below this threshold was followed by further decrease in height velocity. After kidney transplantation a significant catch-up growth was seen if immunosuppression was performed with cyclosporine A and lowdose prednisolone. This did not occur if conventional therapy with azathioprine and high-dose prednisolone was used. Onset of puberty was delayed in all patients. Gonadotropin and oestradiol levels in female patients showed normal fluctuations according to ovulatory cycles. In male patients after puberty there was an increase in gonadotropin levels above the normal range for adult men while testosterone levels remained in the low normal range. These results indicate that adult men with nephropathic cystinosis may develop hypergonadotropic hypogonadism.     

Thyroid hormone abnormalities at diagnosis of insulin-dependent diabetes mellitus in children

Comprehensive evaluation of thyroid hormone indices was performed in 58 children with insulin-dependent diabetes mellitus (IDDM) at the time of diagnosis and prior to insulin therapy. Two patients were found to have primary hypothyroidism, with markedly elevated TSH and very low T4, free T4, T3, and reverse T3 concentrations. The remaining 56 patients had the transient alterations in thyroid hormone indices that are characteristic of "euthyroid sick" or "low T3" syndrome. Mean TSH and reverse T3 values were significantly higher and the mean T3, T4, and free T4 levels were significantly lower than those observed in the control population. Ten of the diabetic patients had elevated TSH concentrations and normal or low free T4 values; eight had normal TSH levels and low T4 and free T4 values. The remainder of the group had thyroid indices compatible with abnormal peripheral metabolism of thyroid hormones. Elevated titers of antimicrosomal antibodies were found in 16% of the children with IDDM. We conclude that abnormal peripheral metabolism and altered hypothalamic-pituitary function are responsible for the transient changes in thyroid hormone indices in patients with untreated IDDM. The most reliable indicators of concomitant primary hypothyroidism in untreated IDDM are markedly elevated TSH and low reverse T3 values.     

Cysteamine in renal transplantation: A report of two patients with nephropathic cystinosis and the successful re‐initiation of cysteamine therapy during the immediate post‐transplant period

Nephropathic cystinosis is a rare disorder causing the accumulation of intracellular cystine crystals in tissues. The damage to the proximal tubules of the kidneys results in Fanconi syndrome, and patients with cystinosis experience the progression of chronic kidney disease, resulting in the need for kidney transplantation. Treatment of cystinosis with cysteamine has proven to be effective; however, it has many gastrointestinal side effects that are concerning for transplant specialists during the immediate post‐transplant period. Transplant specialists routinely discontinue cysteamine therapy for up to six weeks to ensure proper immunosuppressant absorption. This practice is worrisome because it communicates the acceptability of lapses of cysteamine treatment to patients. It may be better to re‐initiate cysteamine therapy shortly after transplantation while the patient is followed more closely by the transplant team. This report presents two pediatric patients with nephropathic cystinosis who successfully restarted cysteamine therapy in the immediate post‐transplant period without issue in regard to immunosuppression absorption or gastrointestinal side effects. These cases challenge current practice of discontinuing cysteamine therapy during kidney transplantation, and immediate re‐initiation of cysteamine therapy in cystinosis patients post‐transplant should be considered.     

The ocular anomalies in a cystinosis animal model mimic disease pathogenesis

Cystinosis is a lysosomal storage disorder characterized by abnormal accumulation of cystine, which forms crystals at high concentrations. The causative gene CTNS encodes cystinosin, the lysosomal cystine transporter. The eye is one of the first organs affected (corneal lesions and photophobia in the first and visual impairment in the second decade of life). We characterized the ocular anomalies of Ctns-/- mice to determine whether they mimic those of patients. The most dramatic cystine accumulation was seen in the iris, ciliary body, and cornea of Ctns-/- mice. Consistently, Ctns-/- mice had a low intraocular pressure (IOP) and seemed mildly photophobic. Retinal cystine levels were elevated but increased less dramatically with age. Consistently, the retina was intact and electroretinogram (ERG) profiles were normal in mice younger than 19 mo; beyond this age, retinal crystals and lesions appeared. Finally, the lens contained the lowest cystine levels and crystals were not seen. The temporospatial pattern of cystine accumulation in Ctns-/- mice parallels that of patients and validates the mice as a model for the ocular anomalies of cystinosis. This work is a prerequisite step to the testing of novel ocular cystine-depleting therapies.     

Cystinosis presenting with features suggesting Bartter syndrome. Case report and literature review

Features suggestive of Bartter syndrome (hypokalemia, hypochloremic metabolic alkalosis, and normal blood pressure despite hyperreninemia and hyperaldosteronism) were found in a 5-year-old black child with cystinosis and Fanconi syndrome. Review of his medical records revealed that these abnormalities had probably been present when he first became clinically ill at 2 years of age. Sodium and potassium chloride supplementation lead to improved growth and strength, partial correction of his electrolyte abnormalities, and a decrease in markedly elevated plasma renin activity. Literature review disclosed a similar presentation in four Caucasian children with cystinosis. Biochemical findings compatible with Bartter syndrome can occur together with evidence of generalized proximal renal tubular dysfunction (Fanconi syndrome) in nephropathic cystinosis.     

Longitudinal study on thyroid function in patients with thalassemia major

Primary hypothyroidism is one of the most frequent complications observed in patients suffering from thalassemia. We investigated thyroid function in a group of patients attending the Pediatric Department of Cardarelli Hospital in order to determine in how many patients thyroid function worsened during a 12 year-period of follow up. PATIENTS AND MEASUREMENTS: Fifty patients with beta-thalassemia major (27 females and 23 males), mean age 25.7+/-1.4 years, were re-evaluated according to the criteria of Faglia et al. Thyroid dysfunction was defined as follows: overt hypothyroidism (low FT4 and increased TSH levels >10 microU/ml); compensated hypothyroidism (normal FT4, TSH 5-10 microU/ml, and abnormal TRH test); subclinical hypothyroidism (normal FT4, basal TSH 0-5 microU/ml, abnormal TRH test). Correlation with hematological, biochemical and growth parameters was evaluated. RESULTS: Ten out of 50 patients evaluated in a previous study had moved to other centers, and four patients had died from cardiac problems. Thus, 36 patients completed a 12 year-period of follow-up. In 25% of the patients the degree of thyroid dysfunction worsened with different degrees of severity. The prevalence of overt hypothyroidism had risen to 13.9% from 8.4%. No cases of secondary hypothyroidism were observed, and anti-thyroglobulin and anti-thyroperoxidase (TPO) antibody titers were negative in all patients. Five (28%) out of 17 patients with normal thyroid function previously (one female, four male) showed an exaggerated TSH response to a TRH test, with normal serum levels of FT4, and they were classified as having subclinical hypothyroidism; while another patient died of cardiac complications. Four out of twelve patients with previous subclinical hypothyroidism showed worsening with a different degree of severity: two females changed to compensated hypothyroidism, and two males to overt hypothyroidism. Furthermore, two out of six patients with compensated hypothyroidism and one out of four patients with overt hypothyroidism died of cardiac failure. In all patients there was no correlation between serum ferritin levels, blood transfusion, pretransfusion Hb levels and worsening of thyroid function. Echographic data showed features of dishomogeneity of the parenchyma with different degrees of severity in accordance with the criteria of Sostre and Reyes. The highest score was observed in all patients with overt and compensated hypothyroidism. CONCLUSIONS: A slow worsening of thyroid function was observed in 25% of the studied patients and only two of them developed overt hypothyroidism. The echographic pattern seems to be strongly predictive of thyroid dysfunction.     

Endocrine deficit after fractionated total body irradiation.

Endocrine function was assessed in 31 children (17 boys) after fractionated total body irradiation used in the preparative regimen for bone marrow transplantation. Endocrine dysfunction was present in 25 children. Fifteen of 29 had growth hormone insufficiency 0.9-4.9 years after total body irradiation, yet only three of the 15 had received previous cranial irradiation. Five of 30 had thyroid dysfunction: two with a low thyroxine and raised thyroid stimulating hormone (TSH) concentration and three with a raised TSH and normal thyroxine concentration. Thus the incidence of thyroid dysfunction (16%) is much lower than that reported after single fraction total body irradiation (39-59%). In only two children were abnormalities of the hypothalamic-pituitary-adrenal axis demonstrated. The majority of pubertal children assessed (n = 15) showed evidence of gonadal damage. All the pubertal girls (n = 5) had ovarian failure, although there was evidence of recovery of ovarian function in one girl. All seven boys in late puberty showed evidence of damage to the germinal epithelium, and two of three in early puberty had raised follicle stimulating hormone concentrations. Despite the use of a fractionated total body irradiation regimen, endocrine morbidity is substantial and children undergoing such procedures will require long term endocrine review and management.     

Effect of indomethacin on clinical progress and renal function in cystinosis.

Three children with nephropathic cystinosis were treated with indomethacin 3 mg/kg a day for periods ranging from 9 to 18 months. The drug produced worthwhile clinical improvement in all, with marked beneficial effects on polyuria, polydipsia, and general wellbeing. Clearance studies performed under conditions of maximal water diuresis showed that proximal tubular sodium reabsorption was increased in all children, with consequent reduction in sodium delivery to the distal nephron leading to reduced free water clearance and distal tubular cation exchange. Plasma sodium and potassium concentrations became normal in all patients, with improvement in phosphate and bicarbonate concentrations in one. Renal function continued to deteriorate, but without obvious acceleration of the process by the drug. We were unable to demonstrate a beneficial effect on growth; nevertheless, indomethacin is a useful adjunct to the symptomatic treatment of children with severe nephropathic cystinosis.