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such situations IPPV has been used for combating Lundstrom, N.-R. (1974). Clinical applications of echocardiography in infants and children. Acta Paediatrica Scandinasevere oedema (Robin et al., 1973). In other reports vica, Suppl. 243. surgical ligation of the patent ductus has been Roberton, N. R. C. (1974). Prolonged continuous positive advocated (Gay et al., 1973). However, treatment airways pressure for pulmonary oedema due to persistent ductus arteriosus in the newborn. Archives of Disease in with CPAP for prolonged periods can be a most Childhood, 49, 585-587. efficient therapy as shown in our case. In our Robin, E., Cross, C. E., and Zelis, R. (1973). Pulmonary experience, as in Roberton's (1974), surgical treatedema. New England Journal of Medicine, 288, 292-304. ment can be avoided and IPPV is only necessary in Siassi, B., Emmanouilides, G. C., Cleveland, R. J., and Hirose, F. (1969). Patent ductus arteriosus complicating prolonged the most severe cases for a short time, followed by assisted ventilation in respiratory distress syndrome. CPAP. Journal ofPediatrics, 74, 11-19. Transpulmonary distending pressure with CPAP Silverman, N. H., Lewis, A. B., Heymann, M. A., and has become an established method for treatment of Rudolp, A. M. (1974). Echocardiographic assessment of ductus arteriosus shunt in premature infants. Circulation, RDS. CPAP via face chamber (Fc 100, Siemens50, 821-825. Elema) has been used for prolonged periods without hazards (Ahlstrom etal., 1976). The cardiopulmonary effects of an increased transpulmonary pressure GUDRUN E. BJORKHEM, NILs-RUNE LUNDSTR6M, include counteraction of alveolar collapse with and NILs W. SVENNINGSEN opening of atelectases, reducing intrapulmonary Department of Paediatrics, University Hospital, shunting, and increasing oxygenation. The resulting S-221 85 Lund, Sweden. increase in arterial oxygenation presumably initiates Correspondence to Dr. G. E. Bjorkhem. ductal constriction. In addition the applied pressure may have some effect on concomitant pulmonary oedema. Our observations show that changes in left atrial size, indicating changes in shunt flow even within a short period of time, can be followed closely by Cystinotic rickets treated with repeated echocardiographic examination. In this way vitamin D metabolites the duration of CPAP treatment for infants with Nephropathic cystinosis is a lethal inborn error of RDS plus PDA can be decided. metabolism characterized by the autosomal recessive inheritance of an unknown biochemical defect which Summary produces massive intracellular cystine accumulation. In a preterm infant with the respiratory distress The disorder presents in childhood with failure to syndrome complicated by patent ductus arteriosus, thrive, thirst, dehydration, stunting of growth, continuous positive airways pressure (CPAP) photophobia, and rickets. Most of these features treatment relieved the signs of cardiac decompensa- appear to be secondary to a widespread failure of tion associated with left-to-right shunt. Echocardio- renal tubular reabsorptive function, which produces graphy enabled the change in left atrial size, an glycosuria, phosphaturia, generalized aminoaciduria, indirect measure of the shunt, to be followed. In this renal tubular acidosis, and hypokalaemia (Schneider way the rapid effect of CPAP in reducing left-to-right and Seegmiller, 1972). The rickets may have several shunting could be monitored. This noninvasive possible causes which include acidosis, hypophostechnique could have many applications in neo- phataemia, and renal glomerular failure. Treatment of the bone disease usually involves correction of the natology. acidosis, together with administration of vitamin D References in large doses and of phosphate, separately or in combination. Ahistrom, H., Jonson, B., and Svenningsen, N. W. (1976). The rickets of cystinosis does not respond to Continuous positive airways pressure treatment by a face chamber in idiopathic respiratory distress syndrome. physiological doses of vitamin D and part of this Archives of Disease in Childhood, 51, 13-21. resistance may be due to reduced formation of the Gay, J. H., Daily, W. J. R., Meyer, B. H. P., Trump, D. S., active metabolite 1,25 dihydroxycholecalciferol Cloud, D. T., and Molthan, M. E. (1973). Ligation of the patent ductus arteriosus in premature infants. Report of 45 (1,25-DHCC) (Kodicek, 1974) in the diseased kidney. In short-term studies, Balsan et al. (1975) were cases. Journal ofPediatric Surgery, 8, 677-683. Kitterman, J. A., Edmunds, L. H., Jr., Gregory, G. A., unable to detect any biochemical change in 2 Heymann, M. A., Tooley, W. H., and Rudolph, A. M. cystinotic children given 2 ,ug 1,25-DHCC in daily (1972). Patent ductus arteriosus in premature infants. Incidence, relation to pulmonary disease and management. doses, but Gertner et al. (1976) demonstrated healing of rickets in 3 boys with cystinosis given 1 oc-hydroxyNew England Journal of Medicine, 287, 473-477.
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cholecalciferol (Ioc-HCC) in daily microgram doses for up to 11 months, in addition to their usual therapy. We here report an additional child with cystinotic rickets in whom improvement was associated with treatment with 1,25-DHCC and with the metabolically active analogue 1 oa-HCC. Case report
A 22-month-old girl was admitted in September 1974 with a one-week history of cough, cold, and respiratory difficulty. Motor development had been retarded from about 6 months of age. She had not grown significantly in height since the age of one year and had never walked independently. She had 2 normal sibs, aged 13 and 15; her parents were normal and not consanguineous. On examination she was a pale, dehydrated blonde child who was acidotic, with signs of pneumonia and a perianal abscess. Height and weight were below the 3rd centile. On admission serum bicarbonate was 2-0 mmol/l (2 mEq/l), potassium 2 -6 mmol/l (2 -6 mEq/l), and Hb 5 4 g/dl. There was proteinuria, glycosuria, and a generalized aminoaciduria. A blood culture grew E. coli. Cystine-like crystals were found in the bone marrow and cornea. There were x-ray changes of rickets (Fig. 2a).
1, 25, DHCC
The biochemical course after initial resuscitation is shown in Fig. 1, and the radiological changes in Fig. 2. Initially sodium bicarbonate (45 mEq/day) and potassium bicarbonate (15 mEq/day) corrected the acidosis, but she remained hypophosphataemic with an increasing alkaline phosphatase. Repeat x-rays in January 1975 (not illustrated) showed persistent rickets. In February 1975 neutral sodium phosphate solution giving approximately 0 33 g P per day in divided doses was added to her treatment. This increased the plasma phosphate and temporarily the alkaline phosphatase and was probably associated with some healing of the rickets. In early July 1975 wrist x-ray (Fig. 2b) showed patchy calcification in the region of the growth plate but there was still marked abnormality. Treatment was therefore started with oral 1,25-DHCC 1 ,tg daily. In the ensuing months the alkaline phosphatase fell to low normal levels, and the rickets healed rapidly (Fig. 2c, October 1975). There was also some increase in linear growth rate. Since supplies of 1 ,25-DHCC were limited, la-HCC was later substituted in the same dose. This dose was halved in November 1975 because of a rising plasma Ca, and was stopped in December 1975. Subsequently the plasma phosphate has fallen and the alkaline phosphatase has slowly increased though the wrists remain radiologically normal. The parathormone level in the blood
KHCC:0 NaHCO, ZZ/Z0
Fig. 1 Changes in plasma calcium, phosphate, alkaline phosphatase, and height in a child with cystinotic rickets treated from the age of 22 months. X-ray examinations (arrows) are illustrated in Fig. 2a-c.
i-. 0 E E
iE E E
S O N D J F M A M J 1975 1974
A S O N D J
F M A
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two occasions were 2 68 mmol/I and 2 8 mmol/l (10-7 and 11 -2 mg/100 ml). Plasma 25-hydroxycholecalciferol concentration was measured in July 1975 when it was 39 ng/ml, and in October 1975 when it was 30 ng/ml. These values are around the upper limit of normal for the time of the year (Preece et al., 1975).
Cystinotic rickets does not respond to physiological doses of vitamin D, or to small doses of 25-hydroxycholecalciferol (25-HCC) (Balsan and Garabedian, 1972), and it is reasonable to suppose that in this disease there is defective renal conversion of 25-HCC to its subsequent metabolites. In our patient the healing of the rickets during 1,25-DHCC therapy tends to support this idea. However, interpretation is confused by the concurrent phosphate treatment, which produced a considerable increase in the alkaline phosphatase associated with partial radiological healing. The fall in parathormone level may be due to Fig. 2 Radiological appearences of the left wrist. (a) Sept 1974, on admission. (b) July 1975, after treatment the slight rise in plasma Ca, or it may be a direct effect of 1,25-DHCC (Rasmussen et al., 1974). If we with bicarbonate (10 months) and phosphate (5 months). accept that physiological amounts of 1,25-DHCC or (c) October 1975, after additional treatment with 1,25-DHCC for 3 months. its metabolically active analogue 1o-HCC (Gertner et al., 1976) can cure cystinotic rickets, their further clinical evaluation is important. One possible advanmeasured in February 1975 was 4 06 ng/ml, which is tage of such metabolites over much larger doses of high for a normal plasma Ca (upper limit of normal, native vitamin D required to cure rickets in this 0-9 ng/mI), and in October 1975 (during treatment disorder is their shorter biological half life (Kanis with vitamin D metabolites) it had fallen to et al., 1977) which permits easier reversal of iatrogenic 0 4 ng/ml. The respective plasma Ca values on these hypercalcaemia.
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A 22-month-old girl with cystinotic rickets was given 1 fig 1 ,25-dihydroxycholecalciferol (1,25-DHCC) daily in addition to standard treatment. Her rickets healed and linear growth rate appeared to increase. It is suggested that the effect of 1,25-DHCC and its metabolically active analogues on cystinotic rickets should be further studied.
average in intelligence but not severely subnormal; the skin showed excessive brown pigmentation which was not racial-2 were of southern English descent and 2 Jewish. Pigmentation increased on exposure to light. One was an only child, each of the others had one healthy sib of normal size and colouring; the parents were healthy and not consanguineous. In each case pregnancy, birth, and neonatal state were normal; the babies were not small at birth, their weight being in the range 2950-3450 g. Other features are indicated in the Table.
We are grateful to Dr. R. H. Wilkinson for biochemical help, to Mr. A. J. Bron for the slit-lamp examinations, and to Dr. J. G. G. Ledingham for advice, and also to Leo Laboratories and Roche Table Features of 4 patients with short stature and Products Ltd. for supplies of vitamin D metabolites. pigmentation References Balsan, S., and Garabedian, M. (1972). 25-hydroxycholecalciferol. A comparative study in deficiency rickets and different types of resistant rickets. Journal of Clinical Investigation, 51, 749-759. Balsan, S., Garabedian, M., Sorgniard, R., Holick, M. F., and DeLuca, H. F. (1975). 1,25-hydroxy vitamin D3 and 1-hydroxyvitamin D3 in children: biologic and therapeutic effects in nutritional rickets and different types of vitamin D resistance. Pediatric Research, 9, 586-593. Gertner, J. M., Brenton, D. P., Dent, C. E., and Domenech, M. (1976). Treatment of the rickets of cystinosis with 1 o-hydroxy vitamin D3. XII European Symposium on Calcified Tissues (in press). Kanis, J. A., Heynen, G., Russell, R. G. G., Smith, R., and Walton, R. J. (1977). A therapeutic advantage of lahydroxylated compounds over vitamin D. Clinical Science and Molecular Medicine, 52, 29P. Kodicek, E. (1974). The story of vitamin D. From vitamin to hormone. Lancet, 1, 325-329. Preece, M. A., Tomlinson, S., Ribot, C. A., Pietrek, J., Horn, H. T., Davies, D. M., Ford, J. A., Dunnigan, M. G., and O'Riordan, J. L. H. (1975). Studies of vitamin D deficiency in man. Quarterly Journal of Medicine, 44, 575-589. Rasmussen, H., Bordier, P., Kurokawa, K., Nagata, N., and Ogato, E. (1974). Hormonal control of skeletal and mineral homeostasis. American Journal of Medicine, 56, 751-758. Schneider, J. A., and Seegmiller, J. E. (1972). Cystinosis and the Fanconi syndrome. The Metabolic Basis of Inherited Disease, 3rd ed., pp. 1581-1604. Ed. by J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson. McGraw-Hill, New York.
1 F Sex 143 Adult height (cm) + Relatively short limbs Small hands and feet + + Reduced bone age + Sparse scalp hair + High forehead ± Long cranium Small low ears + Epicanthus and antimongoloid slant + + Refractive error Weak lateral rectus + + Systolic murmur Mental dullness + ESN School 22 Menarche (years) Cerebral atrophy on AEG + ACTH level normal in blood ,, MSH , Growth hormone level after I
stimulation Chromosome analysis normal
M 145 + + + + + + + +
? ? 0 0 + ? + +
123 + + 0 + + + + + +
Normal ? t +
Normal ESN 16 ? + + + +
*Under 3rd centile at the age of 8 years. tAEG not done but x-rays showed a tubular bony spur arising from the anterior wall of the pituitary fossa. ESN = school for educationally subnormal; ACTH =adrenocorticotrophic hormone; MSH=melanocyte-stimulating hormone; AEG= lumbar pneumoencephalogram.
In 3 cases vomiting was severe in the early months and also in the fourth case at 3 years; fever was associated with vomiting in 3. Tonsillitis occurred P. ETCHES, D. PICKERING, and R. SMITH Department ofPaediatrics and Nuffield Department of often in 3, leading to tonsillectomy. In each head size was increased or was concordant with age rather than Medicine, Radcliffe Infirmary, Oxford OX2 6HE. bodily size at some stage. Dentition was normal. Correspondence to Dr. P. Etches. Available information suggests that when grown up these patients are rather hypomelic little people with brownish skins, cheerful, with useful social accomplishments and somewhat low intelligence. As an example, at the age of 26 in Case 1 the weight was Short stature with pigmentation of an average 16-year-old, the height of a 10-year-old, The course of 4 children who grew slowly has been with chest circumference suitable for 12 years, and followed for from 21 to 23 years; they were all below span and upper: lower segment ratio for 6 years.