American Journal of Medical Genetics 52:5845 (1994)

Autosomal Recessive Congenital Intrauterine Infection-Like Syndrome of Microcephaly, Intracranial Calcification, and CNS Disease

W. Reardon, A. Hockey, P. Silberstein, B. Kendall, T.I. Farag, M. Swash, R. Stevenson, and M. Baraitser Departments of Paediatric Genetics (W.R., M.B.) and Neuroradiology (B.K.), Hospitals for Sick Children, The London Hospital (M.S.), London, England; Princess Margaret Hospital for Children (A.H., P.S.), Perth, Western Australia; Greenwood Genetic Center (R.S.), Greenwood, South Carolina; and Kuwait Medical Genetics Centre (T.I.F.), Sulibikhat, Kuwait

We present data on 10 patients from 5 fami- lies with a condition of microcephaly, intra- cranial calcification, and a clinical course resembling congenital TORCH infection. Repeatedly, negative TORCH investigations are a prerequisite for the identification of this disorder and the value of disturbed liver function and thrombocytopenia as aids to diagnosis is emphasised. Several similar families with recurrence of the disease in sibships are identified in the literature and the genetic implications of our observations are considered. 0 1994 Wiley-Liss, Inc.

KEY WORDS: TORCH, intracranial calcifi- cation, microcephaly, auto- soma1 recessive

INTRODUCTION The causes of microcephaly with intracranial calcifi-

cation are multiple [Winter and Baraitser, 19931, in- corporating both environmental and neurometabolic aetiologies. In the past decade one or more distinct ge- netically determined conditions have emerged from this heterogeneous group [Baraitser et al., 1983; Ishitsu et al., 1985; Burn et al., 19861. These reports have documented sibships with microcephaly and in- tracranial calcification in whom extensive investigation has failed to identify an underlying metabolic diagnosis and the clinical picture closely parallels that of in- trauterine infection but the appropriate confirmatory tests are normal in all cases. In total, 6 such cases (4M, 2F) have been recorded. We report details of 10 further

Received for publication October 25, 1993; revision received February 25,1994.

Address reprint requests to Dr. W. Reardon, Department of Paediatric Genetics, Hospitals for Sick Children, Gt. Ormond St., London WClN 3JH, England.

0 1994 Wiley-Liss, Inc.

patients, 9 familial and 1 isolated, whose uniform pre- sentation is of microcephaly, neurological delay, and in- tracranial calcification. In the familial cases congenital infection was suspected after the birth of the first af- fected child, despite normal investigations. The birth of another affected patient, after several normal inter- vening pregnancies in two instances, led to a reap- praisal of this diagnostic assumption and extensive in- vestigations for a neurometabolic aetiology which have been universally negative. The radiological abnormali- ties in these patients, as well as the 6 previously recorded, are considered in relation to the literature survey which suggests that other cases, reported in dif- ferent guises, may share the condition(s) we describe.

CLINICAL REPORTS Family 1 (Fig. la)

These children were reportedly normal at birth but were not smiling by age 3 months. Sucking was poor from the beginning and developmental progress very limited. Seizures, occurring every few minutes, began at age 3 or 4 months. The nature of the seizures was variable, sometimes comprising myoclonic jerks with major, often focal, seizures being observed occasionally.

Examination is remarkable for the degree of hypoto- nia. Head circumferences are 41 cm (aged 4.5 years) in 11, (<3rd centile) and 42 cm in her brother 11,. The youngest child has not been seen, but is reported to be following an identical course. Linear growth is below the 5th centile in both cases seen. There are no minor anomalies or neurocutaneous defects. The ophthalmic examination showed no signs of choroidoretinitis. Ex- tensive investigations for a known neurometabolic cause have been normal. Liver function is normal, as are haematological indices. Culture and immunological tests for congenital infection have been repeatedly neg- ative. CT brain scan is reported to show marked cere- bellar and cerebral atrophy particularly involving the frontotemporal regions, but it has not been possible to review these scans as part of the current study. The re- port describes midbrain atrophy with dilated lateral

Congenital Intrauterine Infection-Like Syndrome 59

1

I

2

l a

2 1 3 2 1

1

Ic

2 3

I lb tl n

m 1 2 3

Id

I

1 2 3 '4 5 6 7

Fig. 1. a: Family 1. b Family 2. e: Family 3. d: Family 5.

and third ventricles. There is dense calcification of the basal ganglia, the thalami, both cerebellar hemi- spheres, and on either side of the midline behind the fourth ventricle. Although some periventricular calcifi- cation is seen, it does not resemble that found in toxo- plasmosis. The white matter density is lower than nor- mal, consistent with dysmyelination.

Family 2 (Fig. lb) IIIz was born at term, weighing 3.16 kg with a head

circumference of 32 cm (3rd centile). The pregnancy had been complicated by maternal chicken pox at 3 months gestation. At birth the baby was hydropic and required resuscitation and ventilation. Seizures com- menced almost immediately and required intravenous treatment for control. There were no cutaneous defects or minor anomalies. The liver was palpable (2-2.5 cm); platelet count and (285 x 109/L) and liver function were normal (bilirubin 49 mol/L). TORCH screen by culture and immunoglobulin analysis was normal. Antivari- cella virus antibodies, performed in view of the first trimester exposure, were almost undetectable. Skull films showed multiple small foci of intracranial calcifi- cation in the supratentorial white matter, both super- ficial and deep, and ultrasound confirmed echodense areas, particularly around the lateral ventricles, with

the cerebellum and midbrain being free of same. These findings were thought t o be consistent with intra- uterine infection.

The liver became enlarged over the next few days, the haemoglobin dropped, rcquiring transfusion, and the baby died. Autopsy showed intra-abdominal bleed- ing as the cause of death from a subcapsular haema- toma of the liver. The brain showed cerebellar hypopla- sia with extensive microcalcification of the brain stem and cerebral hemispheres. Despite negative tests for same, congenital intrauterine infection was thought to be the basis for the illness, and a low recurrence risk considered appropriate.

In the next pregnancy, microcephaly was noted ul- trasonically a t 23 weeks gestation. Later, fetal scalp oedema, ascites, and hydrops became apparent and the baby died in utero at 38 weeks. Microcephaly was con- firmed on delivery. The recurrence risk was modified to 25% for future pregnancies.

Family 3 (Fig. Ic) 114 was delivered at 36.5 weeks of gestation for a

footling presentation. Birth weight was 2.24 kg (25th centile). Ultrasound study one month prior to delivery showed microcephaly, IUGR, and intracranial calcifica- tion. OFC at birth was 27 cm ( ~ 3 r d centile). Hepato-

60 Reardon et al.

splenomegaly was noted, as was neonatal jaundice. Over the next few days a petechial rash developed and thrombocytopenia was documented (platelet count 50 x 109/L, normal range 150-400). TORCH titres were normal and several attempts to isolate CMV from urine, CSF, and throat swabs failed. Fundal examina- tion was normal. Reviewed at 2.5 months, the OFC was 31.5 cm (<3rd centile) and the major problem was seizures. The baby succumbed to E. coli meningitis and autopsy showed multiple ventricular septa1 defects in the heart. Neuropathological examination of the brain showed micro-polygyria of the cerebral cortex, with ex- tensive demyelination in the deep hemispheric white matter. Patchy dystrophic calcification was seen throughout the cerebral cortex and cerebellum. There was widespread white matter gliosis. Subependymal asterocyte proliferation had given rise to numerous ependymal nodules. The patchy calcification was also noted on sections of the pons and midbrain. No viral inclusions were identified.

The mother then had 2 normal boys and, before con- ceiving her 7th child, was commenced on thyroxine for hypothyroidism, on which medication she was main- tained throughout the pregnancy. Case 2 was born by caesarian section. He was limp with a poor cry and suck; OFC measured 32 cm at birth (2nd centile), and hepatomegaly and jaundice were noted. Liver transam- inases and bilirubin were elevated. Petechiae and pur- puric rash quickly developed (platelet count 35 X 109/L, Hb 17.5). Irritable, jittery behaviour over the next few days gave way to seizures. Brain CT scan showed mul- tiple foci of calcification in the supratentorial white matter, both superficial and deep. There were also some foci in the basal ganglia. There was low density in the white matter and the lateral ventricles were dilated with a cavum septum pellucidum (Fig. 2). The changes were consistent with toxoplasmosis. Fundal examina- tion was normal as were repeated TORCH titres and the baby’s IgM was normal. Numerous attempts to cul- ture a causative organism failed to identify any useful information.

He has survived to 14 months but is neurologically grossly abnormal with a DQ of about 20 and OFC of 42.5 cm (2nd centile). His fundi remain normal but he fixes only briefly and tends t o be inattentive. There are signs of bilateral spasticity affecting lower, more than upper, limbs and there is marked dystonia with some athetosis a t times. A repeat CT scan shows some in- crease in ventricular size and accumulation of fluid over frontal lobes, interhemispheric fissure, and in the basal cisterns; poor development of myelin; and in- crease in the degree of calcification, particularly around the white matter, but now also involving the cerebel- lar hemispheres (Fig. 3). The thrombocytopenia only lasted 6 weeks, the hepatomegaly has resolved, and the spleen is barely enlarged but he is prone to infection and grows slowly.

Family 4 (not shown) The first child of nonconsanguineous Indian parents,

he was born at 35 weeks following spontaneous onset of labour. Birth weight was 1.8kg (10th-25th centile). An-

tenatal scan at 30 weeks had noted IUGR as well as pericardial effusion, hepatomegaly, dilated 3rd and 4th ventricles, and the cerebellar vermis was not properly seen. Microcephaly and hepatosplenomegaly were noted at birth. Neonatal jaundice developed in the first few days (bilirubin 32 moVL) as did a petechial rash. Tonic clonic seizures required phenobarbital treatment. Thrombocytopenia (55 X 109/L) and elevated liver en- zymes (ALT 387 iUL, AST 903 iU/L, alkaline phos- phatase 405 iU/L) suggested a possible diagnosis of TORCH infection.

CT scan at age 4 days showed low density throughout the white matter. All ventricles and basal cisterns were enlarged. There was a small area of definite calcifica- tion in the head of the left caudate nucleus, consistent with toxoplasmosis.

Multiple cultures failed to show an infectious basis for his condition and his TORCH titres were never raised. Retinal examination was normal. Liver function tests continue to be elevated at 18 months of age and psychomotor development is significantly behind.

Family 5 (Fig. Id) 11, was born at 38 weeks of gestation with an OFC of

32 cm, length of 47 cm, and weight of 2.4 kg (all <3rd centile). At age 8 days he was found to have thrombo- cytopenia, manifested as bleeding from the umbilicus. The initial platelet count of 30,000/mm3 increased to 88,000/mm3 during the subsequent 2 weeks and to 198,000 by 5 months, without specific therapy.

Examination at day 8 showed growth retardation, possible micrognathia, and possibly low set ears. The liver and spleen were not enlarged. The corneae and retinae were normal. Skull films showed scattered cal- cification deposits in the periventricular area. Addi- tional laboratory findings included anaemia (Hdb 10.7 gm/dl) and leukopenia (WBC count 8,500/mm3). Pro- thrombin time, partial thromboplastin time, fibrinogen level, and serum transaminases were normal. Serum immunoglobulins in the infant and serological titres for rubella, cytomegalovirus, toxoplasma, and herpes virus were normal in the infant and mother. Examination of the urine for inclusion cells was negative as were nu- merous attempts to isolate cytomegalovirus from the urine.

The clinical course was of profound developmental failure, impaired vision, seizures, and skin mottling. An EEG at 5 months showed a pattern of hypsarryth- mia. The OFC remained more than 2 standard devia- tions below the mean but length and weight increased to normal centiles by age 6 months. The patient died at 10 months.

After 17 years and the birth of 3 normal girls, 115 was born after 36 weeks of gestation. Birth measurements of 30 cm OFC, length 48.5 cm, and weight of 2.1 kg were all below the 3rd centile. The pregnancy had been mon- itored by ultrasound because of slow fundal growth. De- creased amniotic fluid and slow cranial growth were noted during the antenatal examinations.

The initial examination showed no distinctive clini- cal manifestations, other than confirming the growth retardation. Ocular examination was normal and the

Congenital Intrauterine Infection-Like Syndrome 61

Fig. 2. CT scans of II:, family 3, aged 2 weeks. Axial scan a) through the subthalamic region, b, c) through the basal ganglia and thalami, d) near the upper border of the lateral ventricles. There are ex- tensive bilateral foci of calcification involving the thalami and subthalaniic nuclei, the caudate and lentiform nuclei, and both the superficial and deep white matter of the cerebral hemispheres including the genu ofthe corpus callosum. There are patchy regions of low density in the cerebral white matter. There is a minor degree of dilatation of the lateral ventricles.

liver and spleen were not enlarged. CT scan of the brain showed calcification, localised mainly to the periven- tricular region (Fig. 4). An EEG showed periodic slow- ing of cerebral activity and focal spike waves in both cerebral hemispheres. On day 3, he was noted to have a low platelet count (40,000/mm3), haemoglobin of 14 gm/dl, and leukocyte count of 7,400/mm3. Hyperbiliru- binaemia with a peak bilirubin of 14.6 mg/dl was treated with phototherapy. Serum transaminases were normal. Thrombocytopenia persisted throughout the first month of life with the lowest platelet count (15,000/mm3) recorded on day 6. Bone marrow aspirate

showed the presence of megakaryocytes and the ab- sence of viral inclusions. Serological studies for toxo- plasma and cytomegalovirus infections were normal as were repeated urine cultures for cytomegalovirus. Treatment consisted of platelet and immunoglobulin infusions. The patient had made no developmental progress. He had focal seizures involving the limbs and eyes and was startled easily. The glabella was slightly prominent and epicanthal folds were present. There was generalised skin mottling. Muscle tone was in- creased, deep tendon reflexes at the knees were in- creased, and plantar responses were upgoing.

62 Reardon et al.

Fig. 3. CT scans of II,, family 3, aged 8 months. Axial sections a) through the basal ganglia and b) through the bodies of the lateral ventricles. There has been considerable increase in the size of the ven- tricles and intracranial subarachnoid spaces indicating marked progression of atrophy since the earlier scan. Although the septum pellucidum is not visualised, it was positively identified on the original film.

At 9 months OFC, length and weight were well below the 3rd centile and development was severely im- paired. Platelet count was normal, as were other haematological parameters. High resolution chromoso- mal studies were normal, and lymphocyte cultures treated with diepoxybutane showed no evidence of in- creased chromosome breakage. Plasma amino acids were normal.

DISCUSSION Congenital infection of the newborn with toxo-

plasma, rubella, cytomegalovirus, herpes, and other TORCH agents can be an elusive diagnosis [Gotoff, 19921. Frequent clinical indicators which prompt this diagnostic possibility are IUGR (Intra Uterine Growth Retardation), non-specific abnormalities of haematolog- ical indices, hepatosplenomegaly, choroidoretinitis, and hydrops. Central nervous system abnormalities are common, microcephaly being more characteristic of cytomegalovirus exposure and intracranial calcifica- tion more of toxoplasmosis, although both these find- ings are seen in between 10-20% of patients with either infection [Gotoff, 19921. Clinical course and outcome are highly variable. Against this diverse clinical back- ground, it is not surprising that the common concern in all the families we describe was that of a congenital infection which was undetected in the firstborn affected child. However, extensive investigation for such a cause was normal in all instances. The recurrence of the con- dition in siblings in Families 1, 2, 3, and 5 supports the conclusion that autosomal recessive condition(s) ex- ist which may clinically mimic congenital TORCH infection.

Such an observation has been the subject of several previous reports [Baraitser et al., 1983; Ishitsu et al., 1985; Burn et al., 19861. In 1983 Baraitser et al. re- ported brothers with microcephaly and intracranial calcification, spasticity, and seizures from the ages of 2 and 4 weeks, respectively. The calcification was pre- dominantly cerebellar and brain stem in distribution in case 1 and thalamic in case 2. Toxoplasmosis was thought to be the most likely diagnosis after case 1 was born, although confirmatory tests were all negative, but a genetic aetiology was inferred with the birth of the second affected child (Table I).

Likewise Ishitsu et al. [I9851 reported a pair of Japanese brothers with microcephaly, severe spastic quadriplegia, and diffuse calcification of the cerebral white matter. The cerebral hemispheres were atro- phied, but the cerebellum was normal radiologically. Confirmatory tests for toxoplasma were normal in chil- dren and mother. Haematological indices were normal (Table I).

Burn et al. [1986] later reported a pair of sisters, off- spring of a consanguineous mating, whose condition was characterised by microcephaly, hepatomegaly, pe- techial rash, and extensive periventricular rash in both children. There was a fatal outcome in both, and patho- logical examination of the brain showed cortical dis- organisation with polymicrogyria and multiple other abnormalities. Following a presumptive diagnosis of congenital infection after the birth of the first child, a low recurrence risk had been counselled (Table I).

As well as the diversity in clinical findings among the patients already reported and in the further cohort we now describe (Tables I, 11), there is marked variability

Congenital Intrauterine Infection-Like Syndrome 63

Fig. 4. CT scan of 11,, aged 1 week, demonstrating extensive periventricular calcification.

in the distribution of the intracranial calcification. Roentgenograms and/or CT scan were available from families 2-5 and these have been reviewed. While the findings did not resemble those seen in the original re- port [Baraitscr et al., 19831, families 2-5 radiologically are entirely consistent with intrauterine infection, par- ticularly with toxoplasmosis, and are in keeping with the radiological observations in the other reports of af- fected sibships [Ishitsu et al., 1985; Burn et al., 19861.

Interestingly, all these families [2-5 of the present re- port, and Burn et al., 19861 appear quite similar clini- cally with thrombocytopenia ? petechiae ? hepato- splenomegaly, in addition to the microcephaly, seizures, and abnormal intracranial radiologic findings. Haema- tological abnormalities or visceromegaly were not pres- ent in Baraitser’s original sibling pair, nor in the Japanese report. Neither does family 1 show these signs, and the radiologic findings in these infants, while nonspecific, appear to be distinct from families 2-5, who appear clinically and radiologically close to the phenotype described by Burn et al. [19861.

The phenomenon of nonarteriosclerotic idiopathic in- tracranial calcification has been recognised since the mid-nineteenth century [Melchior e t al., 19601. Reports of familial cases date from 1929 [Geyelin and Penfield, 19291. Collectively, the term Fahr’s disease has some- times been applied to such cases, although the Fahr re- port concerned an adult in the sixth decade with calci- fication of the corpus striatum, globus pallidus and dentate nucleus [Fahr, 19301. Melchior drew attention to the heterogeneous nature of this categorisation and recognised “genetic conditions occurring early in in- fancy” within this broad clinical group [Melchior et al., 19601. One condition within this group which bears many similarities to that described here is the Aicardi- Goutieres syndrome, characteriscd by progressive en- cephalopathy, basal ganglia calcification, elevated CSF protein, and CSF lymphocytosis [Aicardi and Goutieres, 19841. The onset occurs during the first year of life, often after an initial period of normal develop- ment, with a normal head circumference at birth. The course is characterised by a deteriorating neurological picture, characterised by spastic dystonia. CSF lym- phocytosis is commonly found but might not be manda- tory. Our patient group appears different - head cir- cumference was small from birth in all cases. Not only were the characteristic CSF findings positively ex- cluded in families 3 and 4 of this report, but the abnor-

TABLE I. Summary of Previous Reports

Baraitser et al. 119831 Ishitsu et al. [19851

Case 1 Case 2 Case 1 Case 2 Case 1 Case 2

Burn et al. [19861

Microcephaly + + + + + + Spasticity + + + + SeizuresfiEG abn + + + + ? ?

- -

Calcification Cerebral white Cerebral white Periventricular matter matter Basal ganglia

Cerebellum Thalamus Thalami Cerebellum

Brain stem Cerebellum Calcified Normal” Normal“ ? Calcified Hepatomegaly - -

Abnormal LE’Ts ? ? Petechial rash - -

Thrombocytopcnia ? ? Optic fundi Normal ? Normal Normal ? ? Sex M M M M F F Consanguinity No No No No Yes Yes Other Cerebral -

-

? ? + + + +

? ? + + +

- - L

- -

Cerebral Cerebral Died 30 days Died 50 days atrophy atrophy atrophy

Radiologically.

64 Reardon et al.

TABLE 11. Summary of Present Reaort

Family 1 Family 2 Family 3 Family 4 Familv 5 Microcephaly Spasticity SeizuredEEC abnormal Calcification

Cerebellum Hepatomegaly Abnormal LFTs Petechial rash Thrombocytopenia Optic fundi Sex Consanguinity Other

+ + +

Basal ganglia Thalami

Cerebellum Atrophy

-

Normal lM, 1F

No Cerebral atrophy

t -

+ Cerebral

hemispheres Brain stem Hypoplastic

+ ~

-

-

? 2F

Yes Died 1 week

+ + +

Cerebral white matter

Basal ganglia Calcified +

+ + +

Normal 2M No

Died 3 months

+ + +

Caudate nucleus

Normal + + + +

Normal 1M No

Cerebral atrophy

+ + +

Cerebral white matter

Basal ganglia Normal

-

-

+ Normal

2M No

Died 10 months

malities of liver size and function, as well as the throm- bocytopenia to which we allude, do not appear to be part of the Aicardi-Goutieres spectrum. Moreover, most patients with this latter autosomal recessive condition have been blind-a handicap not encountered in any of our surviving cases (families 3-5).

Other authors have sought t o identify a separate, but similar condition [Razavi-Encha et al., 19881 on the ba- sis of absence of CSF lymphocytosis and the distribu- tion of the intracranial calcification- this being more prominent in the basal ganglia than in the Aicardi- Goutieres patients. Clear delineation of this entity is hampered by the lack of a specific confirmatory test and it is still possible that it is genetically identical to Aicardi-Goutieres syndrome. Cerebellar hypoplasia is an inconstant finding but haematological indices are normal, as are liver size and function. MRI scanning has confirmed extensive involvement of cerebral white matter with diffuse delay in myelination [Bolthauser et al., 19891.

Based on our observations, we propose that there is at least one further genetically determined condition, apart from the Aicardi-Goutieres syndrome, charac- terised by microcephaly from birth, seizures, periven- tricular calcification, 2 hepatosplenomegaly 2 platelet dysfunction, and purpura which clinically mimics TORCH infection. This condition incorporates the Burn et al. [1986] cases as well as families 2-5 of this series. Six of the 9 cases identified died before the age of one year. Reinvestigation of the oldest survivor (117, family 3) shows apparent progress in the neurological disease as evidenced by the more extensive CT brain scan changes, involving white matter also. The main distin- guishing manifestations of the condition we describe are the abnormal haematological and liver indices and their clinical sequelae. It is important t o observe the two affected cases in family 3 were separated by two normal outcome pregnancies, as were the two affected cases in family 5 separated by 3 normal outcome preg- nancies, thus reducing the likelihood that the illness in these brother pairs was due t o undetected TORCH in- fection. The available evidence, with affected sisters in a consanguineous mating [Burn et al., 19861, as well as

recurrence in male siblings (Families 3 and 5) and fe- male siblings (Family 21, suggests autosomal recessive inheritance. There may also be a further genetically de- termined condition, with broadly similar features, but lacking the haematological abnormalities and mani- festing a more malignant seizure disorder of earlier on- set, which is represented in this series by family 1, whose clinical course and intracranial calcification dis- tribution appears more reminiscent of the Baraitser et al. [19831 and Ishitsu et al. 119851 reports.

The difficulties in attempting to characterise further this emerging syndrome are emphasised by reference to reports of 3 other cases not previously considered in the context of this disorder. Hoyeraal et al. [1970] described brothers with microcephaly, cerebellar hypo- plasia, thrombocykopcnia, and spasticity. Although in- tracranial calcification is not remarked upon, the clini- cal course, fatal outcome, and pathological observations in the brain were in keeping with the report of Burn et al. 119861. A further male case, offspring of a consan- guineous union, has also been reported [Hreidarsson et al., 19881, in whom periventricular calcifications were observed, as well as all the changes noted by Hoyeraal et al. [ 19701 of microcephaly, cerebellar hypoplasia, thrombocytopenia, and psychomotor retardation. It is likely that these 3 cases are further examples of the condition described by Burn et al. [19861 and repre- sented by Families 2-5 in our series.

No specific diagnostic test for this condition exists yet. Neither is it immediately apparent as to how the phenotypic spectrum may be refined further so as t o aid recognition in single or atypical cases. Consequently, counselling must be cmpiric in nature but take cogni- sance of the five sibship recurrences which we under- line [Burn et al., 1986; Hoyeraal et al., 1970; our study families 2, 3, and 51.

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