American Journal of Medical Genetics Supplement 3:343-356 (1987) Berry Aneurysms, Cirrhosis, Pulmonary Emphysema, and Bilateral Symmetrical Cerebral Calcifications: A New Syndrome Ellen Kahn, James Markowitz, Lynn Duffy, Kenneth Kenigsberg, Jessica G. Davis, and Fredric Daum Departments of Laboratories (E.K.), Pediatrics (E.K., J.M., L.D., J. G.D., F.D.), and Surgery (K.K.), North Shore University Hospital, Manhasset, and Cornell University Medical College, New York, New York Familial idiopathic nonarteriosclerotic cerebral calcification (FINCC) constitutes a rare but pathologically well defined disorder. Thus far, central nervous system symptoms and signs have been the only recorded expression of this disease. Autosomal dominant and autosomal recessive inheritance have both been postulated as cause. We describe three sibs who had symmetrical cerebral calcifications, but three also had cirrhosis and pulmonary emphysema; two had congenital cerebral aneurysms. All were male and of short stature; they also had delayed development and seizures, and two had other neurologic deficits. One sib died at age 3 years of hepatic failure and portal hypertension. Ruptured cerebral aneurysms led to the death of the other two boys at ages 8 and 13 years. The cerebral calcifications symmetrically involved the basal ganglia and thalami, the dentate nucleus, and the cortical and subcortical areas of the cerebrum. The liver was studied by sequential biopsies in two of the children and in all three by autopsy. Fatty degeneration and portal fibrosis preceded a periportal and micronodular cirrhosis. Severe bilateral pulmonary emphysema was present in one sib at age 12 years, whereas all three had bullae and cysts at autopsy. Ruptured left middle cerebral artery aneurysms were demonstrated in two sibs, and one also had aneurysms of the anterior and posterior communicating arteries. We conclude that in this family FINCC is a complex pleiotropic mendelian mutation, either of autosomal or X-linked recessive nature, whose basic pathogenesis remains unknown but may involve a metabolic defect. This form of FINCC may be a previously undescribed syndrome or a form of FINCC in which extraneural manifestations were previously overlooked. Received for publication November 13, 1986; revision received January 6, 1987. Dedicated to Dr. Enid F. Gilbert for her friendship and inspiring work over 30 years in fetal genetic pathology and in experimental teratology. Address reprint requests to Dr. Ellen Kahn, Department of Laboratories, North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030. 0 1987 Alan R. Liss, Inc. Delayed walking Delayed walking Delayed walking + + + I 2 3" Short Short Short Somatic Development Superior Retarded Normal Mental Dysarthria, dysmetria, incoordination Dysarthria, dysmetria, incoordination ~ Neurologic deficit "Proband. Patients I and 2 were deceased at the time of the initial evaluation of this family. Motor Term Patient TABLE I. Clinical History + + + + + Hepatomegaly + Seizures 83/12 139/12 + 39/12 + + Death (years) Clubbing Ruptured cerebral aneurysm Ruptured cerebral aneurysm Sepsis Cause Berry Aneurysm-New Syndrome 345 Key words: congenital cerebral aneurysms, familial idiopathic nonarterioscleroticcerebral calcification, Fahr disease INTRODUCTION Familial idiopathic nonarteriosclerotic cerebral calcification (FINCC) constitutes a rare autosomal dominant or autosomal recessive disorder [Boller et al, 19771 with a well defined pathological pattern [Melchior et al, 1960; Lowenthal and Bruyn, 1968; Babbitt et al, 1969; Barwich, 1976; Constantinidis et al, 19781.Thus far, central nervous system signs and symptoms have been the only recorded clinical expression of this disease [Lowenthal and Bruyn, 1968; Babbitt et al, 1969; Moskowitz et al, 1971; Kousseff, 1980; Harati et al, 19841. We describe three brothers who, besides having symmetrical cerebral calcifications, also had hepatic and pulmonary disease; two had congenital cerebral aneurysms. We suggest that FINCC is a pleiotropic syndrome with diverse clinical manifestations. The extraneural components of FINCC have been eitherpreviously overlooked or incompletely expressed clinically. However, in this case, we may be dealing with a previously undescribed syndrome of FINCC with prominent extraneural manifestations. CLINICAL HISTORY (TABLE I) All three sibs were boys born at term; they were short. Height, weight, and head circumference of patients 1 and 3 were t 3 r d percentile. All three had seizures during infancy and delayed walking. Two had neurologic deficits including dysarthria, incoordination, and dysmetria; one child was mentally retarded. Clubbing of the digits (Fig. 1) and hepatomegaly were present in all three, and an increased anteroposterior chest diameter and radiologic signs of emphysema were evident in one boy. Patient 3 had an unusual Fig. 1. Patient 3. Bilateral clubbing of the digits. Fig. 2. Patient 3. Unusual facial appearance with hypertelorisrn, downward-slanting palpebral fissures, flat philtrum, and a vermillion border of the upper lip. 346 Kahn et al TABLE 11. General Autopsy Findings Patient 2 Patient 1 + Jaundice Ascites Peritonitis Splenomegaly Esophageal varices Patient 3 - ~ + - + + + ~ - ~ + + + + facial appearance (Fig. 2). Results of an extensive work-up for hypoparathyroidism, a,-antitrypsin deficiency, and other metabolic causes of liver diseases were unremarkable. Hepatic failure constituted the main clinical problem in patient 1, who had increased bruisability, epistaxis, gastrointestinal bleeding, ascites, and pancytopenia. Peritonitis and acute bronchopneumonia following a portocaval shunt led to his death associated with disseminated intravascular coagulation and sepsis at age 3 years. The clinical presentations of the other two boys were predominantly those of ruptured cerebral aneurysms with headache, vomiting, hemiparesis, and coma. These two children died of subarachnoid hemorrhage and encephalomalacia. Parents are not consanguineous; family history is otherwise unremarkable. Reproductive history shows that the parents first two pregnancies ended in early spontaneous abortion. Their third, sixth, and seventh pregnancies resulted in the birth of patients 1, 2, and 3. The surviving sibs, who were products of their fourth and fifth pregnancies are now 23 years (male) and 20 years (female) old. Both sibs and their parents are asymptomatic but have refused evaluation. PATHOLOGIC FINDINGS The most important pathologic findings relate to the central nervous system, liver, and lungs. The remaining pertinent findings noted at autopsy are summarized in Table 11. Central Nervous System Cerebral calcijications. The distribution of the calcifications is documented in Table 111. The presence of calcifications was demonstrated antemortem by computerized tomography scan (Fig. 3) and confirmed by postmortem xerography (Fig. 4) in patient 3. Microscopically, the calcifications appeared as both vascular and nonvascular deposits. Both types of accumulations were present throughout the brain, midbrain, and cerebellum. Vessel-related calcifications were more evident in the white matter and nonvascular deposits in the grey matter. These deposits were basophilic, and staining reactions identified the presence of iron and calcium. Cellular reaction or neuronal changes were not TABLE III. Central Nervous System Calcifications Cerebrum Patient 1 2 3 Basal ganglia + + + Cerebellum Thalamus Cortex ? + + + ? + White matter + + + Cortex White matter Dentate nucleus + + + + + + + + + Berry Aneurysm-New Syndrome 347 Fig. 3. Patient 3 at age 13 years. Computerized tomography depicting calcifications of basal ganglia (BG), thalamus (TH), and cerebellum (CE). C, caudate nucleus; P, putamen. associated with these calcifications. The vessel-related deposits consisted of small granular spheres along the capillary wall, isolated or confluent, fine or coarse, with or without preservation of the vascular lumen (Fig. 5A). Calcifications were also seen in the media and adventitia of arterioles and small arteries of the cerebrum (Fig. 5B) and leptomeninges. The nonvascular calcifications were larger, of different sizes and shapes, and frequently confluent (Fig. 5C), with a homogeneous or lamellated appearance. Cerebral aneurysms. Cerebral aneurysms were documented by angiography and by autopsy in patients 2 and 3. Aneurysms of the left middle cerebral artery had ruptured in both. Aneurysms of the right anterior and right posterior communicating arteries were noted by angiography and confirmed by autopsy in patient 3 (Fig. 6 ) . Microscopic examination showed changes usually associated with berry aneurysms: thickened or focally absent internal elastic membrane, thickened or attenuated vascular wall with disorganized smooth muscle, and intimal fibrosis (Fig. 7A,B). The rupture site was composed of a blood clot with repair surrounded by recent and old hemorrhage. An intact larger artery adjacent to the ruptured aneurysm had a wavy, thickcncd, hyalinized internal elastic membrane and patchy subintimal fibrosis. No calcifications were seen in these vessels. Arteries of similar size but in different locations were unremarkable. 348 Kahnetal Fig. 4. Patient 3 at age 13 years. Xerography. A Note bilateral calcifications of thalami (TH), basal ganglia (BG), and cerebral cortex (CC). B Involvement of cerebellar folia (CF) and dentate nucleus (DN). Fig. 5. Different microscopic patterns of cerebral calcifications. A Fine granular calcifications adjacent to capillaries (arrows). Hematoxylin and eosin, x200. B Calcifications of media and adventitia of small arteries (arrows). Hematoxylin and eosin, x 50. C Coarse interstitial calcifications (arrows). Hematoxylin and eosin x 200. 350 Kahn et a1 Fig. 6 . Patient 3. Circle of Willis with multiple berry aneurysms (arrows). The largest is ruptured and involves the left middle cerebral artery (arrowheads). Liver Liver changes (Table IV) were studied by sequential liver biopsies in two of the children and in all three by autopsy. Macro- and microvesicular fatty degeneration predominantly of periportal hepatocytes constituted the only and earliest lobular change at age 6 months (Fig. 8A). The portal spaces were expanded by fibrosis and contained a moderate mononuclear cell infiltration and hemosiderin-laden macrophages. Portal bridging was present. Cirrhosis was apparent by 39/12 years with persistence of the fatty degeneration and portal mononuclear infiltration. The cirrhosis was predominantly periportal and micronodular. Minimal portal infiltration persisted, whereas the fatty degeneration was no longer apparent at 13712 years (Fig. 8B,C). The rhodanine stain never demonstrated presence of any copper. a,-antitrypsin inclusions were not demonstrated by the D-PAS and immunoperoxidase stains. The interlobular bile ducts were intact. Peroxisomes were identified by electron microscopic examination. Lung Pulmonary emphysema with bleb and cyst formation was present in all patients. The emphysema was bilateral and more severe at the periphery (Fig. 9A,B). Cysts were focally associated with cholesterol granulomata and fibrosis, interpreted as a reaction to previous hemorrhage. Ruptured, richly vascularized interalveolar septae protruded into the cystically dilated air spaces. Berry Aneurysm-New Syndrome 351 Fig. 7 . Berry cerebral aneurysm. A Whole mount. Note aneurysmatic dilatation with thrombus (solid arrow) and intact vessel wall (open arrow). Elastic Van Gieson stain, x200. B Microscopic appearance characterized by intimal fibrosis and abnormal or absent internal elastic membrane (arrow). Elastic Van Gieson stain, x200. 352 Kahnet al TABLE IV. Hepatic Histology Age Patient 1 6 months 39/12 years 31712 years" Patient 2 8'/12years" Patient 3 8 months 13v2 years 1 3 %yearsa ~ Fatty degeneration + + + + + Cholestasis Hemosiderin Portal infiltration Portal fibrosis + + + + - + + + + + + + + + + + + + + - + + + - - - ~ ~ Portal ~ - Portal + - - - - - + ~ + Portal bridging Cirrhosis - + + 'Autopsy . DISCUSSION We describe three brothers with FINCC, hepatic cirrhosis, and pulmonary emphysema who died between age 3 and 13 years. In addition, berry aneurysms were present in two. The macro- and microscopic findings in the central nervous system are consistent with those of FINCC, also known as strio-pallido-dentate calcifications or Fahr disease [Copeland et al, 19771. In this entity, calcifications are present in the nucleus pallidus and dentate nucleus but may involve the entire basal ganglia, thalami, cortex, and subcortex of the cerebrum and cerebellum [Melchior et al, 1960; Lowenthal and Bruyn, 1968; Babbitt et al, 1969; Barwich, 1976; Constantinidis et al, 19781. Hypoparathyroidism is present in two-thirds of these patients, whereas in the remaining familial cases the pathogenesis remains unknown [Hastings-James, 1970; Moskowitz et al, 197I]. The cerebral calcifications in our patients are most consistent with those described in the familial idiopathic group. In these patients, the pathogenesis of the cerebral calcifications also remains obscure. Local factors [Lowenthal and Bruyn, 1968; SchCda, 1970; Seth and Roy, 1972; Aicardi and Goutibres, 19841 or more generalized metabolic defects [Dinkel, 19711 have been postulated. Growth retardation [Babbitt et al, 19691, seizures, mental deficit, and cerebral motor and cerebellar disorders [Moskowitz et al, 1971; Kousseff, 19801 usually became apparent after age 35 years but may be present in childhood [Moskowitz et al, 19711. Our three patients all had idiopathic cirrhosis, and two had splenomegaly and esophageal varices as signs of portal hypertension. Why liver failure developed only in patient 1 is unclear. Cirrhosis was preceded by fatty degeneration and was well established by age 3 years. Fatty degeneration and cirrhosis have been described in two of four relatives with FINCC [Cockel et al, 19731, but pulmonary emphysema and cerebral aneurysms were not mentioned. Patients 2 and 3 died of subarachnoid hemorrhage and encephalomalacia from ruptured berry aneurysms of the left middle cerebral artery. At autopsy, patient 3 had two additional aneurysms in the anterior and posterior communicating arteries. The microscopic pattern was similar to that described in patients with congenital aneurysms [Bolander et al, 1978; Rodin et al, 19821. These autosomal lesions are rare in children, and associated findings, such as those in our patients, have not been reported previously [Rodin et al, 19821. Fig. 8. Sequential hepatic changes of patient 3. A Liver biopsy at age 18 months. Moderate fatty degeneration with portal fibrosis. Hematoxylin and eosin, x200. B Liver biopsy at age 13 years. Perilobular fibrosis and inactive micronodular cirrhosis. Note absence of fatty degeneration. Trichrome stain, x 200. C Gross appearance of the liver at autopsy at age 13 years with a uniform, finely granular cut surface. 354 Kahnet al Fig. 9. Patient 3, pulmonary emphysema. A Grass appearance of the lungs at autopsy: bilateral pulmonary emphysema with cyst formation. B Whole mount of lung with emphysema and cysts of different sizes. Hematoxylin and eosin. Berry Aneurysm-New Syndrome 355 How does one interpret the combination of cerebral calcifications, cirrhosis, and emphysema in three brothers, with cerebral aneurysms in two of them? Review of the literature on FINCC shows other rare associations such as hydrotic ectodermal dysplasia [Copeland et al, 19771, phenylketonuria [Parker and Landing, 19771, steatorrhea and pseudoobstruction [Cockel et al, 19731, glaucoma [Kousseff, 19801, and cystic astrocytoma [ Morimota et al, 19841. These findings are probably merely coincidental; however, it is highly unlikely that cerebral calcifications, cirrhosis, and emphysema present in each of our three patients represent chance concurrence. Of interest in this context is a new syndrome in adults characterized by a peculiar phenotype, hyalinosis of small vessels, FINCC, and, in one patient, a cerebral aneurysm [Rambaud et al, 19861. We did not observe small vessel hyalinosis in our patients. Bilateral ganglia calcifications have also been described in association with osteopetrosis and renal tubular acidosis, an autosomal recessive syndrome due to carbonic anyhydrase I1 deficiency [Sly et al, 19851. The syndrome described by us evidently is due either to an autosomal or to an X-linked recessive mutation. Furthermore, our observations seem to indicate that FINCC is a causally nonspecific disorder that can occur as a component of several different syndromes. The relationship of cerebral aneurysms with cerebral calcifications, cirrhosis, and emphysema is intriguing. However, we lack an adequate biochemical basis to postulate a testable pathogenetic hypothesis. 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