Case reports

Acute myelogenous leukaemia inHurler's syndrome

SUMMARY The occurrence of the Hurler syn-drome and acute myelogenous leukaemia in a 2year-old girl is described. This represents the firstpublished report of the concurrence of these twodiseases.

In this report we describe a patient with mucopoly-saccharidosis type I (Hurler's syndrome) (Bach et al.,1972; Stevenson et al., 1976), in whom acutemyelogenous leukaemia developed. The occurrence ofthese two rare diseases in the same person has notbeen previously documented.

Case report

A 6-month-old white girl was referred to the Univer-sity of Minnesota Health Sciences Center in Septem-ber 1974 because of a heart murmur. Past medicalhistory showed that the mother's pregnancy anddelivery and the patient's newborn period wereuncomplicated. At 1 month of age the child wastreated for otitis media and at 3 months of age had anepisode of severe diarrhoea which required admissionto hospital. At 5 months, she developed persistent oralthrush and a urinary tract infection which was suc-cessfully treated with antibiotics. The patient's heartmurmur was thought to be caused by a small ventri-cular septal defect which did not require immediateintervention.

At the age of 11 months, the patient was admittedto the University of Minnesota Hospitals in acute renalfailure caused by persistent diarrhoea and dehy-dration. Physical examination showed facial dys-morphia resembling that of the Hurler syndrome, anumbilical hernia, and hepatomegaly. Radiologicalexamination disclosed the bony changes character-istic of dysostosis multiplex. Blood counts, including aleucocyte differential count, were normal. Exa-mination of blood smears showed cytoplasmicinclusions in approximately 20% of the lymphocytes.These inclusions were usually coarse, sharplydelineated, and surrounded by small clear haloes.They stained darkly with Wright's-Giemsa stain andwere metachromatic when stained with toluidine blue.Urinary total acid mucopolysaccharide was 10.6mg/24 hr (normal: 0-6 mg/24 hr). Urinary excretionof dermatan sulphate was 6.6 mg/24 hr (normal: 0 to1.0 mg/24 hr) and excretion of heparan sulphate was

1.5 mg/24 hr (normal: 0 to 1.5 mg/24 hr). Thediagnosis of mucopolysaccharidosis type I-H wasmade by the demonstration of defective a-L-iduroni-

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Table a-L-iduronidase activity*

Sourm Leucocytes Cultured skin(nmol/18 hrper mgprotein) fibroblasts

Patient 10.5t 0-927-1t

25-9§Mother 67-7t1Father 78-3tNormal range 111-272 1450-3242

(m = 180-0) (m = 2213)

Assayed with phenyl-a-L-iduronide as substrate (Hafl and Neufeld,1973).t Activity in mixed leucocytes isolated by dextran sedimentation (Desnicket al., 1973).t Activity in peripheral blood granulocytes (Boyum, 1968) post-leukaemia.§ Activity in peripheral blood lymphocytes and monocytes (Boyum, 1968)post-leukaemia.

dase activity; the levels of enzymatic activity in leuco-cytes and cultured skin fibroblasts from the patientand her parents are shown in the Table. The patient'sa-L-iduronidase activities in both sources were muchdecreased. Both parents had intermediate levels ofenzymatic activity consistent with heterozygosity forthe Hurler gene.

During the ensuing 18 months, the patient hadrecurrent episodes of bilateral otitis media andrequired myringotomies with placement of P-E tubes;she had no other serious medical problems. At 27years of age, the patient was once again admitted tohospital, this time after a 6-week history of easybruising. In addition to the previously describedphenotypic manifestations, generalised ecchymosesand splenomegaly were observed on physical exa-mination. Blood studies revealed anaemia, thrombo-cytopenia, and a leucocytosis of 29 600/mm3 with41% myeloblasts. Approximately 20% of the blastsstained positive for peroxidase and occasional blastscontained Auer rods (Fig. la). Approximately 15% ofthe blood lymphocytes had cytoplasmic inclusions asdescribed above, characteristic of Hurler's syndrome(Fig. la). Ultrastructural examination of the lympho-cytes showed multiple single membrane boundvacuoles which were nearly empty (Fig. lb); pre-sumably these vacuoles were secondary lysosomeswhich were engorged with undegraded mucopoly-saccharide before processing for ultrastructuralstudies. The bone marrow showed hypercellularity,with 26% myeloblasts. A diagnosis of acute myelo-genous leukaemia was made. Histiocytes filled withcytoplasmic inclusions similar to those in the lympho-cytes were found in the marrow (Fig. 2).The patient died one week after admission. Nec-

ropsy showed massive retroperitoneal haemorrhageand haemorrhagic staphyloccocal pneumonia. Exten-sive leukaemic infiltration was present in the bonemarrow, liver, spleen, and lymph nodes. Hurler's cells

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Case reports

Fig. la (top) Blood smear showing a myeloblast with an Auer rod (arrow). A lymphocyte (upper.right) has multiple coarsedarkly staining inclusions surrounded by clear haloes characteristic ofHurler's syndrome. (Wright's-Giemsa. x 1000.)Fig. lb (bottom) Electron micrograph ofa lymphocyte with several single membrane bound vacuoles which appear nearlyempty after processingfor ultrastructural studies. (Uranyl acetate, lead citrate. x 13 000.)

were found in multiple organs including the liver,spleen, lymph nodes, brain, and mitral valve.

Discussion

Several genetic disorders havp been associated withan increased incidence of leukaemia. The most striking

example is Down's syndrome with a twentyfoldincrease in the development of acute leukaemia (Krivitand Good, 1957; Conen and Erkman, 1966). Aremarkably frequent occurrence of acute leukaemiahas also been reported in patients with Fanconi'sanaemia (Bloom et al., 1966; Swift and Hirschhorn,1966) and Bloom's syndrome (Sawitsky et al., 1966).

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Fig. 2 A bone marrow histiocyte contains numerous cytoplasmic inclusions similar to those in the lymphocytes. (Wright's-Giemsa. x 1000.)

In all of these conditions, however, either an abnormalchromosomal constitution (Conen and Erkman, 1966)or an increased susceptibility to in vitro chromosomebreakage (Sawitsky et al., 1966; Swift and Hirchhorn,1966) has been shown. No chromosome abnormali-ties or increased susceptibility to chromosomalbreakage in vitro have been identified in Hurler'ssyndrome.

Both Hurler's syndrome and acute myelogenousleukaemia were well documented in the presentpatient; both are rare diseases. The estimated fre-quency of Hurler's syndrome is approximately onecase per 40 000 (McKusick, 1972) to 100 000 births(Lowry and Renwick, 1971). The death rate for myelo-genous leukaemia in persons less than 20 years of ageis approximately 0.28 to 0-62 deaths per year per100 000 population (Stark and Oleinick, 1966). Thechance association of these two disorders in the samechild would be extremely rare, presumably accountingfor the fact that no previous descriptions of such anoccurrence have been reported in the medicalliterature.

This work was supported in part by grants C-174 and1-273 from the National Foundation-March of Dimesand a grant AM 15174 from the National Institute ofHealth. Dr Desnick is a recipient of a National Insti-tute of Health Research Career Development Award(AM 00042).

KARL T. K. CHEN, ROBERT W. MCKENNA, ANDROBERT J. DESNICK

Department ofLaboratory Medicine and Pathology,University ofMinnesota, Minneapolis, Minnesota55455; and the Division ofMedical Genetics, Mt.Sinai School ofMedicine, New York, N. Y. 10029,

U.SA.

References

Bach, G., Friedman, R., Weissman, B., and Neufeld, E. F. (1972).The defect in the Hurler and Scheie syndromes: deficiency ofa-L-iduronidase. Proceedings of the National Academy ofSciences ofthe United States ofAmerica, 69, 2048-2051.

Bloom, G. E., Warner, S., Gerald, P. S., and Diamond, L. K. (1966).Chromosome abnormalities in constitutional aplastic anemia.New England Journal ofMedicine, 274, 8-14.

Boyum, A. (1968). Isolation of mononuclear cells and granulocytesfrom human blood. Scandinavian Journal of Clinical andLaboratory Investigation, 96, Suppl., 77-89.

Conen, P. E., and Erkman, B. (1966). Combined mongolism andleukemia: report of eight cases with chromosome studies.American Journal ofDiseases ofChildren, 112,429-443.

Desnick, R. J., Allen, K. Y., Desnick, S. J., Bernlohr, R. W., andKrivit, W. (1973). Fabry's disease: enzymatic diagnosis of hemi-zygotes and heterozygotes. a-Galactosidase activities in plasma,serum, leukocytes, and urine. Journal ofLaboratory and ClinicalMedicine, 81, 157-171.

Hall, D. W., and Neufeld, E. F. (1973). a-L-iduronidase activity incultural skin fibroblasts and amniotic fluid cells. Archives ofBio-chemistry and Biophysics, 158, 817-821.

Krivit, W., and Good, R. A. (1957). Simultaneous occurrence ofmongolism and leukemia. American Journal of Diseases ofChildren, 94,289-293.

Lowry, R. B., and Renwick, D. H. G. (1971). Relative frequency ofthe Hurler and Hunter syndromes (letter). New England JournalofMedicine, 284, 221-222.

McKusick, V. A. (1972). Heritable Disorders ofConnective Tissue,4th ed., p. 546. C. V. Mosby, St. Louis.

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242Sawitsky, A., Bloom, D., and German, J. (1966). Chromosomal

breakage and acute leukemia in congenital telangiectaticerythema and stunted growth. Annals of Internal Medicine, 65,487-495.

Stark, C. R., and Oleinick, A. (1966). Urban or rural residence andhistologic type distribution in 21,000 childhood leukemia deathsin the United States 1950-59. Journal of the National CancerInstitute, 37, 369-379.

Stevenson, R. E., Howell, R. R., McKusick, V. A., Suskind, R.,Hanson, J. W., Elliott, D. E., and Neufeld, E. F. (1976). Theiduronidase-deficient mucopolysaccharidoses: clinical androentgenographic features. Pediatrics, 57, 111-122.

Swift, M. R., and Hirschhorn, K. (1966). Fanconi's anemia:inherited susceptibility to chromosome breakage in various tissue.Annals ofInternal Medicine, 65,496-503.

Requests for reprints to Dr Robert W. McKenna,Department of Laboratory Medicine and Pathology,Box 198, Mayo Memorial Building, Minneapolis,Minnesota 55455, U.S.A.

Meckel's syndrome (dysen-cephalia splanchno-cystica) intwo Pakistani sibs

SUMMARY A Pakistani couple, who were firstcousins once removed through their fathers, andwhose mothers were also related, had two live-

Case reports

born children, a boy and a girl. Both childrendied within 2 hours of birth with occipitalencephalocele, microcephaly, polycystic kidneys,and cystic distension of intrahepatic bile ducts.Both children had normal karyotypes. Theseabnormalities constitute Meckel's syndrome(dysencephalia splanchno-cystica); this is thefifth report of parental consanguinity, addingfurther support to the evidence for autosomalrecessive inheritance of the disorder.

Sibs with microcephaly, occipital encephalocele, andpolycystic kidneys were first reported by Meckel in1822. Both patients had, in addition, polydactyly andcleft palate. Numerous case reports in both this andthe last centuries have appeared, including a review byGruber (1934), who added one case of his ownobservation and proposed the name dysencephaliasplanchno-cystica. Opitz and Howe (1969) describeda further case and called the disorder Meckel'ssyndrome; they suggested that it was inherited in anautosomal recessive manner. Hsia et al. (1971)reported 7 patients including 2 pairs of concordantmonozygotic twins in 1 family and 3 sibs in another.Fried (1973) has drawn attention to the relatively highprevalence among oriental Jews. Sibs, born to con-sanguineous Pakistani parents, are presented here;they provide additional supporting evidence for auto-somal recessive inheritance.

Fig. 1 (a) First case (IV.14). (b) Second case (IV.I5).

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