Archives ofDisease in Childhood 1993; 68: 412-414

Cerebral aspergilloma in a child with autosomalrecessive chronic granulomatous disease

A F Dean, I Janota, A Thrasher, I Robertson, G Mieli-Vergani

AbstractA 2 year old girl presented with epilepsy 16months after being diagnosed as havingautosomal recessive chronic granulomatousdisease. Computed tomography showed acerebral mass which was surgicaily removedand proved histologicaily to be an asper-gilloma. This case illustrates the application ofmolecular diagnostic techniques to the diag-nosis of chronic granulomatous disease.The occurrence of, and unusual reaction to,cerebral aspergillus infection indicates theneed to consider this possibility in the differen-tial diagnosis of mass lesions in chronicgranulomatous disease. Furthermore, itis clear that autosomal recessive chronicgranulomatous disease cannot be consideredto be a clinically mild form that is exempt frommajor neurological complications.(Arch Dis Child 1993; 68: 412-414)

Department ofNeuropathology,Institute of Psychiatry,LondonA F DeanI Janota

Department of Medicine,University CollegeLondonA Thrasher

Department ofNeurosurgery, MaudsleyHospital, LondonI Robertson

Department of ChildHealth, King's CollegeHospital, LondonG Mieli-VerganiCorrespondence to:Dr A F Dean, Department ofNeuropathology, Institute ofPsychiatry, De CrespignyPark, Denmark Hill, LondonSE5 8AF.Accepted 28 October 1992

The chronic granulomatous diseases of child-hood are a heterogeneous group of inheriteddisorders arising from a defect in the superoxidegenerating system of phagocytic cells, theNADPH oxidase. Five components of thissystem have now been identified and comprisetwo subunits of a membrane bound cytochrome(cytochrome b-245) and three cytosolic factors.'Defects in any of these components results inchronic granulomatous disease. Approximatelytwo thirds of cases are due to defects in thecytochrome and are X linked, whereas one thirdare due to the absence of the 47 kilodaltoncytosolic protein, p47-phox, and have autosomalrecessive inheritance.' The clinical syndrome ischaracterised by extreme susceptibility to recur-rent infection with certain micro-organisms. Thetissues most often affected are the lymph nodes,skin, lungs, and liver; infection of the brain or itscoverings is rare.25The case reported here is the first documented

example ofan intracranial aspergilloma in a childwith chronic granulomatous disease.

Case historyA 2 year old black girl was admitted to hospitalfor the evaluation of epilepsy. She had been bornin the UK of parents native to Zaire. Theobstetric and neonatal history were normal andshe was thriving when, at 8 months of age,hepatosplenomegaly and cervical lymphadeno-pathy was detected at a health check up. Vene-puncture for blood tests caused an abscess todevelop from which Staphylococcus aureus and agroup B streptococcus were isolated. Viralhepatitis, tuberculosis, leishmaniasis, andstorage diseases were considered and excluded

and an HIV antibody test (Bhering) was negativeon three separate occasions. A diagnosis ofchronic granulomatous disease was made.The patient had four older siblings (two boys,

two girls), all of whom were well. No otherfamily history was available.The patient did not report for follow up for the

next year, but was then admitted to hospital afterhaving two focal seizures within one monthaffecting the right side of her body. On examina-tion she was afebrile and alert. There wasdecreased tone and brisk reflexes in the right armand leg, with both plantar responses downgoing.There was an equivocal sensory loss in the rightarm. Radiographic computed tomographyexamination showed a 3 cm lesion in theposterior frontal convexity of the left cerebralhemisphere that had homogeneously increasedsignal attenuation with respect to the brain,contained flecks of calcium, was surrounded byoedema, induced midline shift, and enhancedwith contrast (fig 1). There were no contiguousair sinuses.

Five days after admission her right pupilbegan to react sluggishly to light and the rightplantar response became upgoing. She was refer-red to neurosurgery and underwent a left fronto-parietal craniotomy and excision of the mass.At operation, there was a firm mass in the

frontoparietal convexity. Near the midline onthe top it had a site of dural attachment andperipherally a thin covering of brain; elsewhere,the mass could be dissected from the brain toleave a smooth surface. On incision some parts ofthe mass oozed caseous material. Almost all ofthe mass could be removed, leaving only a plaqueof fibrous tissue attached to the dura andsuperior saggital sinus.

Figure I Radiographic computed tomogram withoutcontrast of the cerebral mass (arrow).

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Cerebral aspergilloma in autosomal recessive chronic granulomatous disease

Figure 2 (A) Granulomashowing an epithelioidpalisade around a core ofpolymorphs and amorphousdebris (arrows) (haematoxylinand eosin stain x80). (B)Punctate basophilic bodies(arrow) within thecytoplasm ofmacrophagesand epithelioid cells(haematoxylin and eosinstain x320). (C)Granuloma with a core ofmultinucleated giant cells(haematoxylin and eosinstain x80). (D) Hyphaewithin a granuloma core(Grocott stain x320).

MethodsBIOCHEMICAL CHARACTERISATIONNeutrophils purified from peripheral blood weretested for the ability to produce superoxide usinga NBT slide test and cytochrome c reductionassay. Western blotting was carried out onpostnuclear supernatants prepared from sonic-ated neurophils using polyclonal antisera againstindividual components of the NADPH oxidase.i

HISTOPATHOLOGYSmears and a frozen section were prepared at thetime of operation. Subsequent paraffin sectionswere stained with haematoxylin and eosin, Ziehl-Nielsen, Grocott, Giemsa, and for reticulin.

BACTERIOLOGYMaterial obtained at operation was sent forculture of conventional bacteria, fungi, and acidfast bacilli.

PathologyBIOCHEMISTRYThe diagnosis of autosomal recessive chronicgranulomatous disease was made following anegative NBT slide test and absent superoxideproduction as measured by the reduction ofcytochrome c. Western blotting showed theabsence of the p47-phox cytosolic protein,indicating a probable autosomal recessive formof the disease.7

HISTOPATHOLOGYMacroscopically, the material received was pale,firm, and gritty to cut. Microscopically, smearsand the frozen section showed granulomata,

giant cells, and necrosis, possibly due to tubercu-losis. Subsequent paraffin sections showednumerous irregularly shaped granulomataranging in size up to 0 3 cm lying within denselyfibrous tissue that was infiltrated with manyplasma cells, some lymphocytes, and containedsparse small calcific concretions. In places thelesion was continuous with gliotic brain that wasalso stippled with calcium. Individual granulo-mata differed in appearance. Most consisted of apalisade of epithelioid histiocytes mingled withsome macrophages and multinucleated giantcells, arranged around a core (fig 2A). Punctate,basophilic, Grocott negative material could oftenbe seen in the macrophage element (fig 2B). Thecore usually consisted ofpolymorphs and macro-phages in varying proportions and stages ofdisintegration. Rare cores consisted entirely ofmultinucleated giant cells (fig 2C). Acutelybranching septate hyphae compatible withaspergillus species (fig 2D) were found in a fewgranulomata and in loose necrotic slough.

Other noteworthy features of the biopsysample were the lack of vascular involvement byfungi and the absence of eosinophils.

BACTERIOLOGYThere was no significant growth of conventionalbacteria nor fungi after three days in Sabouraud'smedium. Culture for acid fast bacilli wasnegative at eight weeks.

DiscussionChronic granulomatous disease was first des-cribed as a syndrome characterised by recurrentinfections and granuloma formation primarilyaffecting the skin, lung, and reticuloendothelialsystem.' The syndrome is now recognised to be

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414 Dean, Janota, Thrasher, Robertson, Mieli-Vergani

heterogeneous in mode of inheritance and on abiochemical basis, but all subtypes have a defectin the phagocyte oxidative activity that protectsagainst infection by certain groups of micro-organisms.9

In contrast with the rest of the body, infectionof the brain and meninges is less common.Johnston and Newman found 'meningitis andsepticaemia' in 17% ofpatients in their series, theagent invariably being bacterial.2 Overall fungalinfection occurs in 20% of patients with chronicgranulomatous disease, but intracranial infec-tion appears to be remarkably rare; examples ofchronic ventriculitis4 or epidural abscess' existonly as single reports. There is one reference to acerebral abscess in the brother of a proband, butno details are given.3

This report of an aspergilloma makesseveral clinical and pathological points. The firstis that, despite the autosomal recessive variety ofchronic granulomatous disease being consideredas clinically mild,2 9 this patient had a major andpotentially fatal infective complication at anearly age. More recent studies of prognosis inchronic granulomatous disease have, in fact, notfound any differences with respect to the mode ofinheritance.'0 Secondly, cerebral aspergillosis inchronic granulomatous disease may arise with-out there being an obvious primary focus offungal disease. In this patient the chest radio-graph was clear, there was no history of sinusitisor relation of the lesion to the sinuses, and theoverlying bone was normal. Indeed, the childwas remarkably well before presenting withepilepsy. In contrast, cerebral aspergillosisarising on a background of malignancy orimmunosuppression is invariably associatedwith evidence of disseminated fungal disease."Thirdly, the pattern of reaction to aspergillus isnoteworthy. When intracranial aspergillus infec-tion occurs in the context of haematologicalmalignancy or drug induced immunosuppres-sion, the pathology usually includes vascularinvasion with haemorrhagic infarction. In con-

trast, the reaction in non-immunosuppressedsubjects (for instance, related to chronicsinusitis) is granulomatous'2; and that is thepattern found here and in a previous reportof aspergillus epidural abscess5 occurring in apatient with chronic granulomatous disease. Theoverall 20% incidence of fungal infection inchronic granulomatous disease'3 clearly indicatesa predisposition to these organisms, but theproclivity to a granulomatous reaction ironicallyappears to offer some protection against moreinvasive disease.We are grateful to Drs Cox and Dawson for radiological interpreta-tion, Mr A Brady for his assistance with the illustrations and MrsM Chetty for the biochemical assays.

1 Segal AW. The electron transport chain of the microbicidaloxidase of phagocytic cells and its involvement in themolecular pathology of CGD. J Clin Invest 1989; 83: 1785-93.

2 Johnston RB, Newman SL. Chronic granulomatous disease.Pediatr Clin NorthAm 1977; 24: 365-76.

3 Mills EL, Rholl KS, Quie PG. X-linked inheritance in femaleswith chronic granulomatous disease. J Clin Invest 1980; 66:332-40.

4 Powers SK. Fenestration of intraventricular cysts using aflexible steerable endoscope and the argon laser. Neuro-surgery 1986; 18: 637-41.

5 Pollack IF, Dachling P, Schuit KE. Chronic granulomatousdisease with cranial fungal osteomyelitis and epiduralabscess. J Neurosurg 1987; 67: 132-6.

6 Casimir C, Chetty M, Bohler M-C, et al. Identification of thedefective NADPH-oxidase component of chronic granulo-matous disease: a study of 57 European families. EurJ7 ClinInvest 1992; 22: 403-6.

7 Volpp BD, NauseefWM, Clark RA. Two cytosolic neutrophiloxidase components absent in autosomal chronic granulo-matous disease. Science 1988; 242: 1295-7.

8 Berendes H, Bridges RA, Good RA. A fatal granulomatosis ofchildhood. The clinical study of a new syndrome. Minn Med1957; 40: 309-12.

9 Tauber AI, Borregaard N, Simons E, Wright J. Chronicgranulomatous disease: a syndrome of phagocyte oxidasedeficiencies. Medicine (Baltimore) 1983; 62: 286-309.

10 Finn A, Hadzik N, Morgan G, Strobel S, Levinsky RJ.Prognosis of chronic granulomatous disease. Arch Dis Child1990; 65: 942-5.

11 Young RC, Bennett JE, Vogel CL, Carbone PP, DeVita PP.Aspergillosis. The spectrum of disease in 98 patients.Medicine (Baltimore) 1970; 49: 147-73.

12 Linares G, McGarry PA, Baker RD. Solid solitary aspergilloticgranuloma of the brain: report of a case due to Aspergilluscandidus and a review of the literature. Neurology 1971; 21:177-84.

13 Cohen MS, Isturiz RE, Malech HL, et al. Fungal infection inchronic granulomatous disease. The importance of thephagocyte in defense against fungi. AmJ Med 1981; 71: 59-66.

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