Cranial manifestations of hypophosphatasia in childhood nephrotic syndrome

into J. Oral Surg, 1984: 13: 249-255 (Key words: nephrotic syndrome - hypophosphatasiai

Cranial manifestations of hypophosphatasia in childhood nephrotic syndrome J. H. MEURMAN AND P. E. HAKALA Department of Oral Pathology, Institute of Dentistry, University of Helsinki, Helsinki, Finland

ABSTRACT - A 7-year-old boy was referred to the children's hospital because of gross oedema and tiredness. Massive proteinuria wasfound and the condition was diagnosed as a childhood nephrotic syndrome. Concomitantly, pathologically low levels of serum alkaline phosphatase were recorded, and this, together with generalized osteoporosis and premature synostosis of cranial sutures, led to a seconddiagnosis: hypophosphatasia. The patient's family historyfurther confirmed this conditionof a heritable defect of metabolism. Dental inspection revealed very carious teeth with characteristically enlarged pulpchambersin molars. Histological examination of an extracted tooth revealed an unusually wide zone of predentine with some other dentinal irregularities. No cement layer was found. The skeletalage and exfoliation of primaryteeth, however, werenormal, unlike most reported cases of hypophosphatasia. The patient's renal diseasewas treated mainly with corticosteroids. There is no treatment for hypophos-

phatasia. (Received for publication 1 June 1982, accepted 11 May 1983)

Nephrotic syndrome is a systemic disorder associated with heavy proteinuria, hypoalbuminemia, and generalized oedema. This renal disease is either of a congenital nature, idiopathic, or a manifestation of numerous systemic diseases such as connective tissue diseases or autoimmune forms of glomerular disease. The cause of the juvenile idiopathic nephrotic syndrome is not known. Its pathogenesis is probably due to immunological disorders and atopic children are more prone to this disease. Histologically the childhood nephrotic syndrome exhibits minimal change or nil dis-

ease in renal biopsy specimens. Prognosis is generally good, and the disease usually responds well to corticosteroid therapy. Later complications can often be attributed rather to treatment than to the disease-", Oral manifestations of childhood hypophosphatasia were recently reviewed by JEDRYCHOWSKI & DUPERON 9 • Usually, hypophosphatasia produces premature exfoliation of the primary dentition, the reason these patients may first approach the dentist. Other signs that lead to diagnosis of this systemic disorder are decreased serum alkaline phosphatase levels, increased urinary

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excretion of phosphoetanolamine and occasional elevation of serum phosphorus level. Abnormal mineralization of bones and dental tissues may occur. We present a case of a typical childhood nephrotic syndrome of unknown origin presenting concomitant hypophosphatasia. This was reflected, in particular, in the patient's craniofacial skeleton.

Case report Medical history and management The patient, a 7-year-old boy, was first referred to Helsinki University Central Hospital, Department of Pediatrics because of generalized oedema and ascites. The clinical and laboratory findings were diagnosed as nephrotic syndrome (Table 1). During hospital stay, recurrent low levels of serum alkaline phosphatase were recorded. This led the clinicians to suspect a concomitant bone disease. The patient was the third child of 4 pregnancies. His earlier medical history showed premature closing of cranial fontanelles, abnormal skull growth leading to craniostenosis, but otherwise normal somatic, motor, and psychological development. Both his parents had enjoyed good health, but his father's sister was said to have had a juvenile bone disease leading to deformed fin-

gers. The patient's cousin had very fragile bones and abnormal cranial growth. 2 weeks before admission to the hospital, the patient had been very tired, and he developed gross oedema, in particular of the face. A regimen of diuretics (furosemide and spironolactone) and corticosteroids (methylprednisolone) was started. The marked proteinuria vanished in 2 weeks, and the patient responded well to the treatment. Urography was normal. Renal biopsy was taken, and minimal change glomerulonephritis was diagnosed. Some membranic deposits and epithelial proliferation were observed in the biopsy specimen. As stated earlier, the levels of serum alkaline phosphatase remained low, 0.3-1 BL units (normal 2.3-8.4 Bessey-Lowry-Brock units). This, together with the family history and cranial abnormalities indicated a hereditary bone disease. The diagnosis of hypophosphatasia was further confirmed by radiographs that showed generalized osteoporosis, premature synostosis of frontal and sagittal sutures, multiple radiolucent impressions on the cranial skeleton (impressiones digitatae), and prominent outgrowth of frontal bones (Fig. 1). Otherwise, the patient's skeletal age was normal. Dental history and findings The patient's mother said that the boy had had more dental problems than had his sisters. The exfoliation of primary teeth, however, had been normal. At dental examination, the patient had

Table 1. Some laboratory findings during the patient's first stay in hospital Laboratory test ESR S-P j S-Ca S-afos S-cholesterol S-total protein S-creatine BUN U-PEA U-protein d-xylose absorption test FIGLU

Result and clinical norms

112 nun in 1 hr 7.2 mg/dl 4.9 mEq/l 0.3 BL/I 400 mg/dl 3.4 g/d) 0.75 mg/dl 12 mg/dl 1300 mg/dl 27.4%

(0-5) (4.0-7.0) (4.5-5.4) (2.3-8.4) (120-130) (6.0-8.3) (0.4--0.7) (10-20) (-)

(0) (20-33) «30 mg/dl)

ESR"'erythrocyte sedimentation rate; S-P j = serum inorganic phosphate; S-Ca=serum calcium; Safos '" serum alkaline phosphatase; BUN = blood urea nitrogen; U-PEA = urine phosphoethanolamine excretion; FlGLU =formiminoglutamate test.

NEPHROTIC SYNDROME AND HYPOPHOSPHATASIA

251

many carious teeth (DS 15). The eruption of permanent teeth appeared normal, and the status of mixed dentition corresponded with the patient's age. In orthopantomogram (Fig. 2), the first permanent molars appeared very carious, the

Fig. 2. Orthopantomograph showing abnormally wide pulpal chambers in the first permanent molars. The erupting premolars appear narrow in between the crown and the root. Carious cavities extend widely beneath enamel in dentin, in particular in the first permanent molars.

A

lesions seemed to extend widely beneath the enamel in dentin. The pulpal cavities appeared enlarged with long pulpal horns in the first permanent molars. The erupting premolars showed narrowing between the crown and the root. The skeletal structures appeared radiolucent. Temporo-mandibular joints were normal. Because of advanced caries in d. 53, the tooth was extracted and prepared for histopathological study. The tooth was decalcified in formic acid, sectioned, and stained with haematoxylin and eosin. Normal-appearing pulpal tissue was lined by an odontoblast cell layer. The predentine zone was wide and granular, dentinal tubules were wider than in normal teeth (Fig. 3). The pulp horn extended up to the incisal edge. No cement layer was found and occasional remnants of periodontal ligament seemed to adjoin directly to the root dentin (Fig. 4). Later course of the disease During a 4-year period after first admission to the hospital, the patient suffered 3 relapses of the nephrotic syndrome. After the second relapse he was treated with intermittent prednisone and azathioprine for 6 months. He was then in remission for about 1 year, developed marked proteinuria again, and was treated with prednisone. After that, the patient has been in remission and without medication. There is no treatment for hypophosphatasia.

B Fig. 1. Skull radiograph of the patient taken

during his first hospital stay. Generally osteoporotic bony structure causing the characteristic impressiones digitatae, and partial craniostenosis is seen. The skull form is abnormal. A. Lateral view, B. Antero-posterior view.

Discussion Our case is that of a typical childhood nephrotic syndrome. The patient responded well to corticosteroid therapy, although the

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MEURMAN AND HAKALA

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antimetabolite azathioprine was needed to cure the second relapse. The renal biopsy findings showed minimal change glomerulonephritis, which is the underlying renal disease among the great majority of these patients '". The nephrotic syndrome is a chronic renal disease and the dentist must understand the implications of a possible renal failure when treating the patient. Many oral manifestations of chronic renal disease have been listed, including decreased salivary flow, increased tooth mobility, and periodontal problems 8 . Particular radiographic changes have also been reported, such as the loss of lamina dura, absence of trabecular patterns, and altered jaw density". Such alterations, however, commonly indicate an end-stage renal disease with osteodystrophy-P'!", Above all, dental treatment of patients with nephrotic syndrome calls for consultation with the patients' physician. Precautions regarding the prescription of drugs must be taken and, in particular, if the patient's renal function is impaired, modification of the doses of many antibiotics and analgesics is essentiale". Because the cause of nephrotic syndrome is often suspected to be of an immunological

nature, the focal dental infections are of special concern. Immuno-complex pathogenesis of the renal lesions may be triggered by oral streptococcr'". This stresses the importance of oral hygiene to prevent the spread of infection from dental causes . Sometimes prophylactic antibiotics may be administered. This may even be mandatory if the patient is being treated with immunosuppressive drugs, as was done in the present case. In our patient, the aetiology of his renal disease remained obscure. The minimal change glomerulonephritis is frequently associated with allergic conditions. Such an association could not be confirmed here. However, the condition was cured after steroid-induced clinical remission which is the usual course of the nephrotic syndrome in childhood". Subsequently, the observed

NEPHROTIC SYNDROME AND HYPOPHOSPHATASIA

bone manifestations could not be caused by the patient's renal disease. That our patient had hypophosphatasia probably has nothing to do with the nephrotic syndrome. Hypophosphatasia is a heritable inborn error of metabolism. The disease is classified on the basis of age of onset as newborn, infant, childhood, and adult form 12. The newborn form is fatal, and the patients usually die within their first year of life. Infant form patients show a gradual onset of symptoms, which include failure to grow, premature cranial synostosis, and premature exfoliation of the primary teeth. Half the patients in the infantile group die in infancy when they have symptoms of vomiting, constipation, unexplained fever, and convulsions and irritability. The childhood form resembles rickets radiologically, and the course of this disease form tends to be mild and self-limiting. Adults with hypophosphatasia apparently are those who survived the juvenile form, and frequently give a history of renal stones, dentition difficulties, and childhood "rickets" 2. Hypophosphatasia is an autosomal recessive disorder where the primary defect is suggested to be in the enzyme ethanolaminephosphate phospho-Iyase '? The substance affected is phosphoethanolamine (PEA), and it is commonly excreted in excessive amounts in the urine. Increased urinary PEA is regarded as one of the biochemical hallmarks of the disease, the other being decreased levels of serum alkaline phosphatase. The metabolism of PEA, however, has not been related clearly to alkaline phosphatase - an enzyme primarily found in osteoblasts during mineralization. Thus, it may only be a coincidence that PEA usually correlates with serum alkaline phosphatase activity and that it has been used to predict the carrier state of hypophosphatasia 12. In our patient, PEA was never detected in his urine during the 4-year follow-up, despite the permanently low levels of alkaline phos-

253

phatase in serum (Table I). Furthermore, it may be of interest to note that there was no PEA excretion in urine of the patient's family members or relatives either. Yet the patient's 12-year-old brother showed diagnostically low alkaline phosphatase levels and, as stated earlier, the patient's cousin and his father's sister had bone anomalies. The cardinal skeletal and dental signs of hypophosphatasia are premature loss ofprimary dentition, general osteoporosis, and craniostenosis 2 ,6 . 1 1 , 1 3 , 14 , 1 5 , 1 9 . The two latter signs are well fulfilled on our case. The patient's dentition was in bad condition which suggests possible defects in mineralization. BEUMER et al. reported that, in hypophosphatasia, the teeth had wider predentin zones than normal, wide pulp chambers, a reduced number of odontoblasts, and abundant interglobular dentin. As seen in Fig. 3, these changes were not so distinct in our case, except the abnormally large pulp chambers that could also be seen in the orthopantomogram (Fig. 2). Many authors state that the reason why hypophosphatasia patients loose their primary dentition prematurely is because these teeth lack cementum 1,4,5,? ,21, Even though there was no history of premature loss of teeth, the lack of cementum was evident in the extracted tooth specimen of our patient (Fig. 4). Furthermore, we suggest that hypocementosis could also occur in premolars because of the distinct narrowing seen between their crown and root in the radiograph (Fig. 2). For other disorders whose oral manifestations resemble those of hypophosphatasia, the reader is advised to refer to the paper of 9 JEDRYCHOWSKI & DUPERON . In our patient, the malabsorption tests (d-xylose absorption test and FIGLU) were done for differential diagnostic reasons. As seen in the Table, these tests were negative. In conclusion, our patient, a 7-year-old boy presented childhood nephrotic syn-

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drome with characteristic clinical and laboratory findings, and concomitantly, pathologically low levels of serum alkaline phosphatase activity. This, together with radiological and family history studies, led us to suspect hypophosphatasia. Dental findings showing abnormally large pulp chambers in molar teeth, a poor dental condition with large carious cavities in general , and characteristic histological findings such as the lack of cementum confirmed the diagnosis. The nephrotic syndrome was treated mainly with steroid therapy. There is no treatment for hypophosphatasia.

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(eds.): Cecil Textbook of Medicine. W. B. Saunders Co. , Philadelphia, 1979: 15: 22252265. 3. BACH, R ., LANDECK, E., SEIPELT, H. & HrLGENFELDT, E.: Zahnentwicklung, Kariesfrequenz und Struktur des Alveolarfortsatzes bei Kindem mit chronischer Niereoinsuffiziens. Stomatal. DDR 1981 : 31: 408-413. 4. BEUMER, J., TROWBRIDGE, H. 0 ., SILVERMAN, S. & EISENBERG, E.: Childhood hypophosph at asia and the premature loss of teeth. Oral Surg, 1973: 35: 631-640. 5. BRIITArN, J. M., OLDENBURG, T. R. & BURKES, E. J.: Odontohypophosphatasia: report of two cases. J. Dent. Child. 1976: 43: 106-111. 6. BRUCKNER, R. J., RICKLES, N. H. & PORTER, D . R. : Hypophosphatasia with premature shedding of teeth and aplasia of cementum. Oral Surg . 1962: 15: 1351-1369 . 7. GIGLlOTn, R., HARRISON, H., REVELBY, R. A. & DRABKOWSKI, A. J.: Familial vitamin Drefractory rickets. J. Am . Dent. Assoc. 1971: 82: 383-387 . 8. HEARD, E., STAPLES, A. & CZERWINSKI, W. W .: The dental patient with renal disease: precautions and guidelines. J. Am . Dent. Assoc. 1978: 96: 792-796.

9. JEDRYCHOWSKI, 1. R . & DUPERON, D. : Childhood hypophosphatasia with oral manifestations. J. Oral Med. 1979: 34: 18-22. 10. KELLY, W. H ., MIRAHMADI, M. K ., SIMON, J. H . S. & GORMAN, J. T. : Radiographic changes of the jawbones in end stage renal disease. Oral Surg. 1980: 50: 372-381. 11. MCCANCE, R. A., FAIRWEATHER, D. Y. L, BARRETI, A. M. & MORRISON, A. B.: Genetic, clinical, biochemical , and pathological features of hypophosphatasia. Quat. J. Med. 1956: 25: 523-537. 12. POLAND, C., EVERSOLE, L. R., B1XLER, D. &

CHRISTIAN, J. C.: Histochemical observations of hypophosphatasia, J. Dent. Res. 1972: 51: 333- 338 . 13. RATIIBUN, J. C.: Hypophosphatasia. A new developmental anomaly. Am. J. Dis. Child. 1948: 75: 822-831. 14. RATHBUN, J . C.: H ypophosphatasia. Helv. Ped. Acta 1959: 14: 548-553 . 15. RITCHIE, G. L. : Hypophosphatasia. A meta-

bolic disease with important dental man ifestations. Arc. Dis. Childh, 1964: 39: 584-590. 16. ROBINSON, R . R.: The major rena l syndromes. In : BEESON, P. B., McDERMOIT, W. & WYNGAARDEN, J. B. (eds.): Cecil Textbook of M edicine. W. 8. Saunders Co. , Philadelphia, 1979: IS: 1331-1336. 17. SCRIVER, C. R.: Hyperaminoaciduria. In: BER~ON , P. 8. , McDERMOTT, W. & WYNGAARDEN, J. B. (eds.): Cecil Textbook of Medicine. W. B. Saunders Co. , Philadelphia, 1979: IS: 2015 -2021. 18. SPOLNIK, K. J., MAXWELL, D. R., PAITERSON, S. S., KLElT, S. A. & COCKERILL, E. M .: Dental radiographic manifestations of endstage renal disease. Dent. Radiograp . Photogr. 1981: 54: 21-31. 19. SOBEL, E. H., CLARK, L. C., Fox, R. P. & ROBINOW, M.: Rickets deficiency of alkaline phosphatase activity and premature loss of teeth in childhood. Pediatrics 1953: 11: 309322 . 20. SOWELL, S. 8. : Dental care for patients with renal failure and renal transplants. J. Am. Dent. Assoc. 1982: 104: 171. 21. WIHR, N. L. : Abnormal dentition in vitamin

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NEPHROTIC SYNDROME AND HYPOPHOSPHATASIA 23. WRONG, O. M.: Nephrotic syndrome. In: BEESON, P. B., McDERMOTT, W. & WYNGAARDEN, J. B. (eds.): Cecil Textbook of

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Address: J. H. M eurman

Department of Oral Pathology Institute of Dentistry University of Helsinki M'annerheimintie 172 SF-DD280 Helsinki 28 Finland

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