Infantile nephropathic cystinosis presenting as ... - Springer Link

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THE INDIAN JOURNAL OF PEDIATRICS

DISCUSSION

Hernia around the umbilicus is common in this part of the world. Most are supraumbilical hernias and are usually symptomlcss. In a previous study it was found that most parents would not want surgical repair.Cosmetic desire is most frequcnt indication for surgery in the uncomplicated hernias. Surgery aims at correcting the defect and cstablishing a firm anterior abdominal wall, as is done for large ventral hernias in cases of gastroschisis and exomphalos. Hurler syndrome (Type I mucopolysaccharodosis) is inherited as an autosomal recessive condition.It has a poor prognosis as most of the cases die by the age of 10 years, frequently from myocardial failure? The case presented hcre of a severelymentally retarded child with grotesque and coarse fades is of interest, particularly in the African setting, that in spite of these severe handicaps and apparent poor prognosis, the parents opted for corrective surgery to improve the physical appearance of the child. In a giant hernia, after reduction of the

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hernia and closure of the sac a definitive repair of the defect has to be achieved. Increased intra-abdominal pressure which is likely to reduce lung compliance should be anticipated and the postoperative period should be closely observed for ventilatory insufficiency. I~R]ZNcEs

1. Askar OM. A new concept of the aetiology and surgicalrepair of paraumbilical and epigastric hernia. Ann Roy Co/Surg Engl 1978; 60 : 42.48. 2. Ajao OG, Tolar JE Jr, Richardson M, Gaventa WC. Umbilical hernia and surgical indication. Trop Doct 1979; 9 : 176177. 3. McKusickVA. Heritable disorders of connective ~sues. 4th Ed. St Louise CV Mosby. 1972 : 521-686. 4. Mayo WJ. Radical cure of umbilical 5.

hernia. JAm Med Assoc 1907; 48 : 18421844. Farris JM, Smith OK, Beattie AS. Umbilical hernia; eat inquiry into the principle of imbrication and a note on preservation of the umbRical dimple.Am J Surg 1959;,98 : 236-247.

Infantile Nephropathic Cystinosis Presenting as Incomplete Fanconi Syndrome and Refractory Rickets V. Samuel Rajadurai, PreeUShanbag, M.S. Seshadd*, Urna Khanduri**, T.A. Alexander*** and Malati A. Jadhav Departments of Child Health, *Medicine, **Clinical Pathologyand ***Ophthalmology, Christian Medical College Hospital, Vellore, TamilNadu Cystinosis is an inborn error of metabolism in which there is excessive intraceUu-

lar storage of cystine crystals in peripheral blood leukocytes, and in many tissues of

CLINICAL BRIEFS : INFANTILE NEPHROPATHIC CYSTINOSIS

the body especially reticulo-endothelial cells of bone marrow, liver, spleen, lymph nodes; thyroid, cornea and conjunctivae. The infantile nephropathic type has been the most thoroughly studied. Children with this form of cystinosis present in the first year of life with the renal tubular defects characteristic of Fanconi syndrome, and also have progressive renal glomerular damage which leads to the end-stage kidney failure usually before 10 years of age. It has recently been shown, using isolated lysosomes derived from leulcocytes, that a specific transport system found in normal individuals (presumably a genetically specific protein) which is responsible for the efflux of cystine from the lysozomes is absent or nonfunctional in persons with cystinosis.1 The disease is inherited as an autosomal recessive trait. Prenatal diagnosis is possible on the basis of increased content of non-protein cystine in cultured amniotic fluid cells by pulse labelling technique.~ After the original description by Lignac in 19243 several reports have appeared in western literature. But there have been only occasional reports in Indian literature.4,s,s-, C ~ r P~i,o r r

A 21-month-old girl was referred for investigation of excessive thirst, passing of increased quantities of urine and failure to thrive observed from the age of seven months. Elsewhere a diagnosis of Diabetes insipidus had been considered, presumably because she almost always had a dry tongue and her thirst could not be quenched in spite of iarge quantities of water and fruit juice offered to her hourly. During waking periods she drank about 100 ml of fluid half hourly, and her 24-hour fluid intake varied from 2000 to 2.500 ml. In

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addition there was increased frequency of micturition; she used to pass approximately 30 ml of urine every half hour. Thirst was excessive on a warm day and especially when she was exposed to sunlight. Ther, was no dysuria. She had failed to thrive ever since the onset of these symptoms at the age of seven months, and weight gain was barely 1 kg in subsequent 14 months. Further at the ages of 10, 11 and 16 months respectively, she became seriously ill with vomiting and dehydration requiring hospitalization and parenteral fluid therapy on each occasion. Family pedigree was significant. (Fig.l). Parents were consanguineous being uncleniece. There first born was also diagnosed to have diabetes insipidus. He too had thrived for the first 8 months. Then at 10 months he had developed vomiting and diarrhoea requiring hospitaliT~tion and parenteral fluid therapy. At the age of 12 months he was hospitaliTed a second time for rapid breathing and chest cold and had required fluids intravenously. When 18 months old he had again developed vomiting and rapid breathing and died in spite of the therapy. Three maternal cousins, a boy and two girls who presumably had diabetes insipidus had also died in early childhood. These 4 children had not been investigated at CMCH, Vellore Physical examination showed a wasted girl with mild pallor. Weight was 6.4 kg (56.6 per cent of expected weight of 11.35 kg). Length was 71 cm (85 per cent of expected 83.7 cm). Upper segment was 43 cm, lower segment was 28 cm. Upper segment: lower segment ratio was 1.53. Head and chest circumferences were 44 and 39.5 cm respectively. Anterior fontanelle measured 4 x 2.5 cm. Rachitic rosary was pres-

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Fig. 1. Pedigree showing horizontal transmission propositus brother and mother's paternal aunt's 3 children w~re affected ent. Widening of the mists and double malleoli were present. There was no frontal bossing or craniotabes. External ears were not low set. Skin turgor was normal. Tongue was moist. Respiratory rate was 28/min and breathing was not acidotic. Heart rate was 124/min and systolic blood pressure was 70 mm of Hg. The trachea was central. Apical impulse was felt in 3rd left intercostal space medial to the mid-clavicular llne. Percussion note was resonant and equal bilaterally. Breath sotmds were vesicular and there were no adventitious sounds. The upper border of liver was in the 5th right intercostal space in the midclavicular line. The initial clinical diagnosis was renal tubular acidosis with rickets, probably Fanconi syndrome. The results of laboratory investigations were consistent. Haemogram: packed cell

volume 35/dl, total WBC count 8400/mm_,3 differential count P 41, E 9, and L .50 per cent respectively. Urine sugar was negative, pH 7.5, and specific gravity 1.003. Arterial blood pH was 7.3, whilst simultaneous urine pH was 8. Serum calcium was 10.4 mg/dl, phosphorous 2.3 mg/dl, alkaline phosphatase 30 KKU/I, sodium 138 mEq/l, potassium 2.7 mEq/l, bicarbonate 19 mEq/l and creatinine 0.45 mg/dl. Total serum protein was 7.3 gm/dl with albumin 4.55 gm/dl; and SGOT 28 units/l, SGPT 11 units/1. Plasma aminogram showed normal pattern whereas histidine, serine, glycine and alanine were prominent in the urine. Serum copper was 100 ug % (Normal range 7-170 ~tg%), serum ceruloplasmin was 141 a/l (Normal range 62-140 aft), 24hour-urine copper was 76 ag/24hour (Normal range upto 100 j~g/24 hour). Thyroid function tests : total thyroxine 0"4) 11.9 ug


Fig. 2. Slit lamp examination showing corneal cvjstals

Fig. 3. Cvstine crystals in mononuclear macrophages of bone marrow

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THE INDIANJOURNALOF PEDIATRICS

% (Normal range 6-12 ag%), free thyroxine concentration 2.1 ng % (Normal range 0.8- 2.0 ng %). X.ray of wrist showed cupping, widening and fraying of the diaphyseal end of the radius and ulna. The diagnosis of Fanconi syndrome with renal tubular acidosis and refractory rickets was thus confirmed. Treatment consisted of Scholl solution (4 mEq alkali per kg/day); mixture potassium chloride 2 mEq/kg/day, and injection vitamin D 300,000 units IM, once a month. On this treatment there was dinica] improvement and 6 months later she had gained 1200 gm and increased ill height by 2 cm. However subsequently she failed to thrive despite regular therapy, instead she developed proximal muscle weakness of lower limbs, pain in the extremities and polyuria and polydipsia persisted. As the urinary bicarbonate excretion was 69 mEq/24 hours, the possibility of renal tubular acidosis with renal bicarbonate wasting was considered and the dose of Scholl solution was increased so as to provide 6 mEq/l of alkali/kg/day but this too was not beneficial. Biochemical investigations revealed persistent hypokalaemia (potassium of 3 mEq/l), severe hypophosphataemia (phosphorous 1.8 md/dl) and elevated alkaline phosphatase (513 ~/ 1). Roentgenogram of the wrist showed persistence of active rickets. The possibility of cystinesis was considered at age 27 months while contemplating the caus~ for refractory rickets. Silt-lamp e~mination showed corneal crystals and fundus examination revealed diffuse pigmentary disturbances in both eyes. (Fig. 2). Bone marrow preparation showed presence of characteristic square or rectangular refractile cystine crystals in mononuclear

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macrophages at bone marrow (Fig. 3):Cysfine crystals were not visualized in the peripheral leukocytes and urine. DISCUSSION

It is interesting that the patient under discussion presented as an incomplete type of Fa,nconi syndrome associated with vitamin D resistant tickets as one of the prominent features. Comanguinooug parentage and horizontal mode of tra~m;~sion as shown in the pedigree gave clue to the diagnosis of cysfinosis which was confirmed by silt-lamp examination of the cornea and demonstration of the characteristic crystals in the bone marrow. Incomplete or complete Fanconi syndrome should be investigated in depth to exclude secondary causes of which the foremost is cysfinosis. The possibility of cysfinosis should be considered whenever an infant or child presents with the triad of features v/z. polyuria, failure to thrive and rickets. Distal renal tubular acidosis, idiopathic Fanconi syndrome and secondary cause of Fanconi syndrome such as Wilson's disease, heavy metal poisoning, Low syndrome, galactosaemia, tyrosinaemia, hereditary fructose intolerance are the other differential diagnoses to be considered. Tf~ree major types of cysfinosis have been descn'bed - a severe and fatal infantile nephropathic form, a benign adult type and late onset adolescent type of intermediate severity.3

Children with nephropathie cystinmis appear normal at birth and during the first 3 to 6 months of life. The fn'st overt signs of the disease are usually produced by the renal tubular defect in water reabsorption resulting in .polyuria and polydipsia. In addition, by one year of age they usually show growth failure, rickets, irritability, renal

CLINICALBRIEFS : INFANTILENEPHROPATHICCYSTINOSIS

tubular abnormalities resulting in acidosis, anorexia and biochemical evidence of Fanconi syndrome such as increased excretion of glucose, amino adds, phosphate and potassium. Most of the symptomatology is thought to be related to profound hypokalaemia? Sionificant hypokalaemia in the early stages of disease may be hazardous to the patient. Some patients show recurrent episodes of acute prostration, weakness and cardiovascular collapse which may occur spontaneously or during intravenous infusion of glucose probably due to hypokalaemia. Failure to thrive is one of the most dominant features of the disease and affected children almost always remain below the third percentile in both height and weight throughout life. Vi!amin D resistant rickets may be a prominent features as in this patient. Certain distinctive clinical features r/z. cherubic fades, blond hair and fair complexion descn'bed in western literature were absent in this patient as also in one instance reported from India/ Some patients with cystinosis present with features of Bartter's syndrome and conversion to Fanconi syndrome may occur? Photophobia is a distinctive symptom and is common in the first few years of life. Slit-lamp examination discloses homogenously dispersed tinsel-like refractile opacities in the anterior two-thirds of the cornea, which are virtually pathognomonic of the disease. These corneal abnormalities which are not present at birth appear before the full clinical manifestation of nephropathic cystinosis is expressed. Fundus examination may show a patchy pigmentation with superimposed pigment clumps of irregular distribution in the temporal part of the peripheral retina. This

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retinopathy is pathognomonic of the nephropathic form and may precede the onset of other clinical syndromes by many months and may be the first clue to the diagnosis. Retinal lesions have been demonstrated in a five-week-old infant with nephropathic cystinosis as woh as in an affected aborted foetus? The biochemical features are those of F~nconi syndrome with renal tubular aciY. 9 doses, hypokalemia, hypophosphataemla, glycosuria and amino aciduria being prominent: Blood urea and serum creatinlne are normal early in the disease. X-rays of long bones show characteristic evidence of rickets. The diagnosis is confu'med by the demonstrafion of refractile corneal crystals seen on slit-lamp e~aminafion, and the presence of cystine crystals in the bone marrow, lymph nodes, conjunctival or rectal biopsy. Measurement of intracellular cystine levels in leukocytes or cultured skin fibroblasts generally yields values upto 100 times the normal. Characteristic cystine crystals may not be seen in the urine on microscopic examination and in peripheral leukocytes whereas they can be demonstrated by slit-lamp e~mlnation of the cornea or unstained bone marrow preparation. Some patients with cystinosis die in early life from acidosis, dehydration and hypokalemia, precipitated by a mild upper respiratory tract infection or gastroenteritis. Others develop chronic renal failure due to unremitting progression of glomerular damage within the first decade and endstage renal failure before puberty. Severe growth failure and hypothyroidism due to deposition of cystine crystals in the thyroid epithefium may accompany this stage,s There is no cure. Dietary restriction of cystine and methionine; treatment with

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penicillamine dithiothreitol (DTT) and reduction agents (vitamin E, ascrobic acid) have not proved beneficial. Cysteamine given for prolonged periods results in decrease in the cystine contents of leukocytes, plasma and urine, but does not improve the physiological derangements associated with cystinosis, notably, renal tubular function and growth velocity.3,7~ However Da Silva et al have suggested that if therapy could be started early in life, eysteamine might be effective in preventing the progressive renal damage? The symptomatic treatment in the early stages of nephropa[hic cystinosis consists of providing an adequate fluid intake, correcting the metabolic acidosis, potassium deficit, and healing the rickets with vitamin D and phosphorus supplementation. Rickets or osteopenia will respond to large doses of vitamin D (2000-4000 units kg/day). Serum calcium and 24-hour urinary calcium levels must be monitored closely to avoid v i t ~ i n D toxicity. Occasionally hypophosphataemia may be sew: and persistent despite vitamin D therapy, (as in our patient) necessitating oral supplementation with inorganic or neutral phosphorus at a dose of 1-3 gm per day, given in 4-5 equally spaced doses throughout the waking hours. The metabolic acidosis can be corrected with SchoU solution and the dose 2-15 mEq of alkali/kg/day may be adjusted to raise the serum bicarbonate to near normal levels of 18-20 mEq/l. Potassium supplements at a does of 2-3 mEq/kg/day or more may be necessary to prevent hypokalemia. Extra salt and water both day and night should be provided to counter excessive losses, especially in warm weather. Indomethacin has been reported to be helpful in improving the water and electrolyte

imbalance in C~tSthosis. 3 Vigorous intravenous fluid therapy, administration of potassium and correction of acidosis is often necessary when the patient develops diarrhea or vomiting. For patients with end-stage renal failure, haemodialysis and renal transplantation are recommended?0 However haemodialysis does not lower tissue cystine leveLs. Although cystine may accumulate in the transplanted kidney, the severe renal tubular disease has not recurred, presumably because cystine accumulation occurs only in the recipient's macrophages which have infiltrated the transplanted kidney? ACKNOWLEDGEMENT

We thank Mr. E. Srinivasan and Miss. A Elizabeth for their secretarial help in the preparation of this manuscript. RZFZP~NC~S 1.

2. 3.

Morrow G 1II, Auerbach VII. Defects-in metabolism of amino acids. In Behrman RE, Vaughan VC, eds. Nelson Textbook of Pediatrics. XII Edition. Philadelphia: WB Saunders Co., 1983 : 430. States B, Blazer B, Harris D, et al. Prenatal diagnosis of cystinosis.I Pediatr 1975; 87 : 558-562. Schneider .IA, Schulman JD. Cystinosis. In Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS, eds. The Metabolic Basis of Inherited Dis-

4.

5. 5a. 6.

ease. V Edition. New York : McGraw Hill, 1983; 1844-1862. Sundaravalli N, Ranganathan G, Balagopal Raju V. Cystinosis : A ease report. Indian Pediatr 1975; 12 : 355 - 357. Edibam B. Cystinosis : A case report. Indian Pediatr 1972; 9 : 117-118. Dinesh Gera, Mehta MJ, Shah BM. Cystinosis.IndianPediatr 1985; 22:535 - 537. Lucky AW, Howley PM, Megyesi K, et al.


7.

8.

Endocrine studies in cystinosis: Compensated primary hypothyroidism. 1 Pediatr 1977; 91 : 204-210. Howard G Worthen. Disorders of the renal tubules and renal interstitiura. In KelleyVC, Ed. Practice of Pediatrics. Vol 8, Chapter II. Philadelphia : Harper and Row. 1984; 1-$5. Yudkoff M, Foreman JW, Segal S. Effects of Cysteamine therapy in nephropa-

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thic cystinosis. N Engl I Med 1981; 304 : 141-145. . De Silva VA, Zurbrugg MD, Lavanchy P, et al. Long term treatment of infantile nephropathic cystinosis with cysteamine. NEngldMed 1985; 313 : 1460-1463. 10. Mahoney CP, StnXer GE, Hickman RO, eta/. Renal transplantation for childhood eystinosis. N Engll Med 1970; 283 : 397 402.

Von Willebrand's Disease in Identical Twins Prema Sivasankaran, H.S. Keshava Prasad and P. Nalini* Department of Pathology and Pediatncs, *Jawaharlal,Institute of Postgraduate Medical Education and Research, Pondicherry

Von Willebrand's disease is a rare genetic disorder with mild to moderate bleeding tendencies. The disease is inherited by at least three different mechanisms 3 the classic form inherited as an incompletely autosomal dominant trait. 2 The expressivity of the abnormality is highly variable. Usually, the patients present with features of cutaneous and mucosal bleeding but in the severe forms with low factor VIII levels, the presentation may resemble hemophilia A. 3 The pathogenesis of the disease is complex. Usually, the levels of factor VIII - related antigen are subnormal. 4' s Because of the abnoxmalities of factor VIII, the adhesion of flatelets to subendothelial collagen is impaired, and this explains the defective haemostasis characteristic of the disorder. REPORT OF CASE

Two male identical twins six years of

age, presented with two years history of easy bruisability and prolonged bleeding after trivial injuries and bleeding gums for six months. There was history of 3~ consanguinity in the parents. There was no family history of similar disorder. On examination, both the children were anemic and had mild b~uises on their legs. They were investigated. The results of the laboratory tests are given in Table 1. In view of the combination of a prolonged bleeding time and a plasma defect in the thromboplastin generation test, yon Willebrand's disease was suspected and platelet aggregation with ristocetin was carried out. Both the children showed subnormal ristocetin-induced aggregation. There was significant correction on adding normal platelet-poor plasma (to almost 60%), which confmned that tim abnormality was in the patient's plasma and not in the platelets. With these findings, a d iagno-