Case reports

philtrum' and high serum potassium (Palmer et al.,1977).

The technical assistance of Miss E. Pandelia is grate-fully acknowledged.

G. B. CO6TE, S. PAPADAKOU-LAGOYANNI,AND S. SBYRAKIS

Institute ofChild Health and Paediatric Unit,Aghia Sophia Children's Hospital, Athens 617,

GreeceReferences

Breuning, M. H., Bijlsma, J. B., and de France, H. F. (1977). Partialtrisomy 6p due to familial translocation t(6;20)(p2 l;p 13). HumanGenetics, 38, 7-13.

Gouw, W. L., ten Kate, L. P., and Anders, G. J. P. A. (1973). A caseof 18q- in a family with a translocation t(6p+;18q-), identifiedby the Giemsa-banding technique. Humangenetik, 19,123-126.

Hunter, A. G. W., Ray, M., Wang, H. S., and Thompson, D. R.(1977). Phenotypic correlations in patients with ring chromo-some 22. Clinical Genetics, 12,239-249.

Kjessler, B. (1977). Repository of Chromosomal Variants andAnomalies in Man. Fourth Listing. Ed. by D. S. Borgaonkar.Division of Medical Genetics, Johns Hopkins Hospital, Balti-more.

Palmer, C. G., Hodes, M. E., Reed, T., and Kojetin, J. (1977). Fournew cases of ring 21 and 22 including familial transmission ofring 21. Journal ofMedical Genetics, 14, 54-60.

Requests for reprints to Dr G. B. Cote, Institute ofChild Health, Athens 617, Greece.

Osteosarcoma in a patient withHutchinson-Gilford progerial

SUMMARY A 13-year-old female with Hutch-inson-Gilford progeria, who developed an osteo-sarcoma of the right chest wall, is reported. Thisis the first reported association of a malignantneoplasm with this syndrome.

Sir Jonathan Hutchinson first described a patient with'congenital absence of hair and its appendages' in1886. A second patient was reported in 1895 byHutchinson. Gilford re-examined these patients and in1904 described the pathological changes of the diseaseand termed these clinical findings 'progeria'. Manypatients have been reported in the intervening 75 years(DeBusk, 1972). The present report is the firstexample of a malignancy diagnosed in a patient withprogeria.'Supported by a grant for a Genetics Study Center (PHS IOH 82 0004) andby a Mental Retardation Training Program no. 920 for the National Institutesof Health.

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Case report

A 13-year-old white female (Fig. 1) presented with adry cough and stabbing right anterior superior chestpain. She had a month long history of increasingfatigue. The early childhood history of this patient hasbeen previously reported, along with in vitro rep-licative studies of her fibroblasts, by Martin et al.(1970). The typical clinical features of progeria werenoted at approximately 2 years of age and were evenmore dramatic at the present admission. No pubertalsecondary sex changes had occurred. In spite of theloss of vision in one eye because of infectiouscomplications following strabismus surgery at age 21years the patient has been a 'straight A' student.

She was 103 cm tall with a weight of 13 kg. Theright chest was dull to percussion with decreasedbreath sounds and scattered rales. Chest x-ray (Fig.2a) revealed a large extra-pleural mass with loss ofintegrity of the 7th, 8th, and 9th ribs. A percutaneousbiopsy was performed with a histological diagnosis ofchondrosarcoma. No metastases were identified. Anen-bloc resection of a portion of the right chest walland ribs 5 to 9 was performed (Fig. 2b). The chest wallwas closed with Marlex, and considering the magni-tude of the procedure the patient had an uncom-plicated postoperative course with ventilatory supportfor only 24 hours. Grossly, the resected tumour wasnot encapsulated. It consisted of the major portion ofribs 5 to 9 and their accompanying muscles, except thelatissimus dorsi. The tumour mass was composed offibrous yellow-grey connective tissue with local cal-cifications. The margins of resection were free of

Fig. 1 Patient at 13 years; she is wearing a wig.

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tumour. Microscopically, the tumour was highly vari-able. A predominant feature was the presence of neo-plastic cartilage with focal calcification. Other regionsshowed highly vascular, atypical, loose connectivetissue. A few areas were more myxoid in character.The typical histology of osteosarcoma was charac-terised by pleomorphic cells with hyperchromaticnuclei and relatively sparse, spindle-shaped cytoplasm

(Fig. 3). Mitotic figures were frequent. A typicalosteoid matrix with its faintly eosinophilic, glassyappearance was seen lying between and surroundingthese malignant cells.

Positive right cervical nodes were identified 6months postoperatively. Chemotherapy with doxo-rubicin was begun. Surgical excision of recurrenttumour involving the diaphragm, lung, and chest wall

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Case reports

was performed. Additional local excision was per-formed 8 months later. Radiation therapy of 5000 radsto the thoracic spine was given. Pulmonary functionstudies, after completion of this therapy, identifiedmoderately severe restrictive changes without obstruc-tive change. An electrocardiogram was normal. Deathoccurred 16 months after diagnosis of pulmonaryfailure and pneumonia.At necropsy the typical features of Hutchinsoni-

Gilford progeria were identified. The right thoraciccavity had extensive adhesions and the right lung wasmarkedly fibrotic. No gross tumour was identified inthe right chest wall or lung. The left lung was diffuselydense and congested. The heart was enlarged and bothventricular walls were hypertrophied. The aortic valveand the coronary arteries showed moderately severecalcific atherosclerosis. The aorta was severely invol-ved with thickened atherosclerotic streaking andcalcific plaques. The liver, gallbladder, spleen,pancreas, kidneys, and gastrointestinal tract werenormal. No evidence of metastatic tumour was seen ina radiograph of the removed vertebral column (T3 toTi 1). The ovaries and uterus were small and prepuber-tal in appearance. The brain showed a normal gyralsurface pattern. No visible atherosclerosis was foundin the cerebral vessels or circle of Willis.

Microscopical sections of the left coronary arteryand aorta had typical changes of severe athero-sclerosis. The right lung showed marked atelectasiswith prominent radiation change. No microscopicalevidence of tumour was present. The left lung wasinvolved with acute organising pneumonia. In the skin,decreased numbers of hair follicles and sebaceousglands were observed. Microscopy of the liver, spleen,thymus, pancreas, kidney, ovary, uterus, gastro-intestinal tract, pituitary, thyroid, and adrenals wasnormal.

Discussion

Progeria is characterised by short stature, diminishedsubcutaneous tissue, craniofacial disproportion,micrognathia, beaked nose, alopecia, prominent scalpveins, thin dry skin, skeletal changes, and the generalappearance of extreme aging. The pathogenesis of thisprocess is unknown, but it has frequently beensuggested that progeria is an example of 'prematureaging'. Certainly these patients have the clinicalappearance of premature aging, but as has beensuggested by Spence and Herman (1973), histologicaland ultrastructural findings are not typical of the agingprocess, but rather of a degenerative process of meso-dermal tissue. Certain clinical features of the agingprocess, such as mental deterioration and malignancy,are notably absent in reported patients with progeria.

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The present patient is the first reported example ofmalignancy in a patient with Hutchinson-Gilfordprogeria. The frequent early death of progeria patientsfrom cardiovascular disease (median survival 13years) shortens their life span so drastically that thedevelopment of malignancy in these patients may notbe observed. Certainly the incidence of malignancy inthe general population is directly related to theincreasing age of the patient. Thus, it might beexpected that if progeria is actually an example ofpremature aging, malignancy would be seen earlierand more frequently in progeria patients. Malignancymight also occur more frequently in progeria, even if itis not a syndrome of premature aging, if predisposingfactors other than aging are present.

Patients with Werner's syndrome, perhaps a clearerexample of a syndrome of premature aging, have anincreased incidence of malignancy (Epstein et al.,1966; Bjornberg, 1976). Of patients with thisdiagnosis, 10 to 15% will develop malignancy. The ageof onset for a particular lesion is younger thanexpected for the same lesion in the general population.These patients develop tumours of a variety ofhistological types, and a single pathological entity doesnot predominate.

Recent investigation of progeria has centred aroundthe in vitro behaviour of fibroblasts from suchpatients: the replicative life span of these cells isdiminished (Martin et al., 1970; Rautenstrauch et al.,1977). This finding was previously confirmed in thepresent patient by Martin et al. (1970). Reducedactivity of heat stable enzymes has also been observed(Goldstein and Moerman, 1975). Perhaps moreimportant for the occurrence of malignancy are recentobservations regarding gamma radiation sensitivity(Epstein et al., 1973; Rainbow and Howes, 1977) andloss of cell surface antigens in cultured fibroblasts(Singal and Goldstein, 1973). Cells from patients withprogeria show reduced DNA repair after exposure togamma radiation (Epstein et al., 1973; Rainbow andHowes, 1977). Reduced ability to repair DNA damagecould lead to mutation and potentially neoplastictransformation. Such patients, as is the case withataxia telangiectasia (Taylor et al., 1975), mightrespond much more dramatically to radiation therapy.The prominent pulmonary radiation change in thepresent patient supports this suggestion. Singal andGoldstein (1973) have observed the failure of pro-geroid fibroblasts to express HLA surface antigens inculture. The lack of expression of cell surface antigenscould allow proliferation of neoplastic cells in vivowithout the action of normal immunological controlmechanisms. An increased predisposition to mutationfrom gamma radiation, or other mutagens, accom-panied by alteration in cell surface antigens maypredispose progeria patients to malignancy. As

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therapy for atherosclerosis and coronary arterydisease in these patients becomes more effective, moreprogeria patients may be identified with malignancy.

CHARLES R. KING, JOHN LEMMER,JoHN R. CAMPBELL,

AND ARNOLD R. ATKINS

Depart-ment ofObstetrics and Gynecology;Division ofMedical Genetics;Department ofPathology; andDivision ofPediatric Surgery,

University ofOregon Health Sciences Center,Portland, Oregon, USA

References

Bjornberg, A. (1976). Werner's syndrome and malignancy. ActaDermatologica, 56, 149-150.

DeBusk, F. L. (1972). The Hutchinson-Gilford progeria syndrome.Journal ofPediatrics, 80, 697-724.

Epstein, C. J., Martin, C. M., Schultz, A. L., and Motulsky, A. G.(1966). Werner's syndrome. Medicine, 45, 177-221.

Epstein, J., Williams, J. R., and Little, J. B. (1973). Deficient DNArepair in human progeroid cells. Proceedings of the NationalAcademy of Sciences of the United States ofAmerica, 70, 977-981.

Gilford, H. (1904). Progeria: a form of senilism. Practitioner, 73,188-203.

Goldstein, S., and Moerman, E. (1975). Heat-labile enzymes in skinfibroblasts from subjects with progeria. New England Journal ofMedicine. 292, 1305-1309.

Hutchinson, J. (1886). Congenital absence of hair and mammaryglands with atrophic condition of the skin and its appendages in aboy whose mother had been almost totally bald from alopeciaareata from the age of six. Transactions of the Medico-Chirurgical Society ofEdinburgh, 69, 473-477.

Hutchinson, J. (1895). (Title not available.) Archives of Surgery, 6,14-19.

Martin, G. M., Sprague, C. A., and Epstein, C. J. (1970).Replicative life-span of cultivated human cells. LaboratoryInvestigation, 23, 86-92.

Rainbow, A. J., and Howes, M. (1977). Decreased repair of gammaray damaged DNA in progeria. Biochemical and BiophysicalResearch Communications, 74,714-719.

Rautenstrauch, S. F., Drieg, T., Gay, S., and Muller, P. K. (1977).Progeria: a cell culture study and clinical report of familialincidence. European Journal ofPediatrics, 124, 101-111.

Singal, D. P., and Goldstein, S. (1973). Absence of detectable HL-Aantigens on cultured fibroblasts in progeria. Journal of ClinicalInvestigation, 52,2259-2263.

Spence, A. M., and Herman, M. M. (1973). Critical re-examinationof the premature aging concept in progeria: a light and electronmicroscopy study. Mechanisms of Ageing and Development,2,211-227.

Taylor, A. M. R., Harnden, D. G., Arlett, C. F., Harcourt, S. A.,Lehmann, A. R., Steven, S., and Bridges, B. A. (1975). Ataxiatelangiectasia: a human mutation with abnormal radiationsensitivity, Nature, 258,427-429.

Requests for reprints to Dr Charles R. King, Depart-ment of Obstetrics and Gynecology, University ofKansas Medical Center, 39th and Rainbow, KansasCity, Kansas 66103, USA.

Case reports

The Aase syndrome in a femaleinfant

SUMMARY This report describes a 2-month-oldfemale with the Aase syndrome, bringing to 8 thetotal number of cases of this disorder. Featuresinclude triphalangeal thumbs and congenitalhypoplastic anaemia. The occurrence of this dis-order in sibs born to unaffected parents and inboth sexes makes autosomal recessive inheritancethe most likely aetiology.

This report describes a female infant with tri-phalangeal thumbs and congenital erythroid hypo-plasia. Seven similar cases of this disorder, referred toas the Aase syndrome, have been described (Harvey,1966; Aase and Smith, 1969; Murphy and Lubin,1972; Jones and Thompson, 1973; Terheggen, 1974;van Weel-Sipman et al., 1977).

Case report

The patient was a 2-month-old Mexican female. Shewas born to a 20-year-old, gravida 1 woman after anuncomplicated 40 week gestation; birthweight was 2-9kg. Length and head circumference were 51 cm and35.5 cm, respectively. Paleness and progressivelethargy were noted at 6 weeks of age. She wasreferred at 2 months of age for evaluation of severeanaemia. Weight was 4-3 kg (25th centile for age),length was 54 cm (25th centile), and head circum-ference was 38 cm (50th centile). Positive physicalfindings included a grade 2/6 systolic ejection murmurat the lower left sternal border, and striking handabnormalities consisting of digitalised thumbs andhypoplastic thenar eminences (Fig. 1). Dermato-glyphs were normal except for a horizontal patternover the thenar areas.

Haematological evaluation showed: haemoglobin4.3 g/dl, haematocrit 14%, reticulocyte count 0.8%,white blood cell count 5-8 x 109/l with 33% neutro-phils, 7% bands, 39% lymphocytes, 16% mono-nuclear cells, and 5% eosinophils. Platelet count was600 x 109/l. Bone marrow showed a pure red cellaplasia with a myeloid to erythroid ratio of 75 to 1 andnormal numbers of megakaryocytes. Studies of cul-tured bone marrow showed a normal 46,XX karyo-type, with no evidence of chromosomal breakage suchas has been demonstrated in the Fanconi pan-cytopenia syndrome. Significant radiographic abnor-malities included a triphalangeal right thumb, hypo-plasia of the left thumb (Fig. 2), and a single bifidthoracic vertebra. Cardiac evaluation, including chest

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