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Case Reports

Indian Pediatrics 2002; 39:866-869  

Congenital Intrauterine Infection like Syndrome of Microcephaly, Intracranial Calcification and CNS Disease


D. Mishra
V.K. Gupta
D. Nandan
D. Behal

From the Neonatal Division, Department of Pediatrics, Dr. Ram Manohar Lohia Hospital, New Delhi 110 001, India.

Correspondence to: Dr. D. Mishra, 163, Sahyog Apartments, Mayur Vihar, Phase-I, New Delhi 110 091, India.

E-mail: dr_dmishra@rediffmail.com

Manuscript received: May 19, 2001;

Initial review completed: May 31, 2001;

Revision accepted: April 10, 2002.


Intracranial calcification and micro-cephaly at birth is commonly a consequence of congenital infection of newborn with either Toxoplasma or CMV, although, Rubella and Herpes simplex have also occasionally been implicated. Similar findings have also been reported in Cockayne syndrome, Aicardi - Goutiere syndrome, Miller - Dieker syndrome, COFS syndrome and Fahr disease(1,2). Since 1970, there have been reports of one or more distinct genetically determined conditions with microcephaly and intracranical calcification at birth(1-7). The clinical picture closely parallels that of

intrauterine infection but confirmatory tests are normal in all cases. We report a male infant with similar features but with certain additional findings and a fatal course. Although one Indian family has previously been reported(4), this is the first report of this condition from India.

Case Report

A male infant was born to non-consanguineous parents, at 35 weeks of gestation following spontaneous onset of labor. The mother had a normal pregnancy and childbirth three year back. The elder sib (female) was clinically normal. Both the parents were non-reactive for HIV by ELISA and, STS (VDRL). Maternal TORCH titres at 32 weeks were negative. Antenatal scan at 33 week had shown IUGR and gross ventriculomegaly. There was immediate cry and respiration at birth with Apgar score of 8, 8 and 10 at 1, 5 and 10 minutes after birth, respectively. There were no minor anomalies, neurocutaneous defects or dysmorphic features. Birth weight of the child was 1540 g with a head circumference of 26 cm (both less than 10th centile) and crown-heel length of 42.5 cm (less than the 25th centile). Placental examination did not reveal any abnormality.

Microcephaly, hepatosplenomegaly and bilateral congenital cataract were present at birth. A petechial rash developed within the first few hours postpartum and jaundice appeared in the first 12 hours, and continued rising despite phototherapy (serum bilirubin 6.9 mg/dL at 20 hour of age). On day one total leukocyte count was 5000 per cubic mm and platelet count 24000 per cubic mm. Serum electrolytes, calcium, magnesium, phosphorus, blood glucose, and plasma lactate and pyruvate were within the normal range. Coagulation profile, sepsis screen, and skeletal survey were unremarkable, except for intracranial calcification. Coomb’s test was negative and non-specific total IgM was 0.14 g/L on day 2. Liver function test were abnormal on the first day (AST: 140 U/L, ALT: 112 U/L, alkaline phosphates: 147 U/L). CSF examination and urinary and plasma aminoacidogram were within the normal limits. There was an increase in petechiae associated with a fall in platelet count (9000 per cubic mm) on day 3 and serum bilirubnin remained elevated (10.2 mg/dL with conjugated fraction 4.8 mg/dL). There were no seizures during the hospital stay, feeding behaviour was normal, and neurological examination was unremarkable.

CT scan head showed non-obstructive hydrocephalus and extensive periventricular calcifications. Corpus callosum was not visualized on the CT scan. USG abdomen and CT abdomen revealed hepatosplenomegaly. Histopathological examination of liver biopsy did not reveal inclusion bodies and was suggestive of neonatal hepatitis. Bone marrow demonstrated a marked decrease in megakaryocytes although the RBC and WBC series were normal. Acid-fast stain of bone marrow and liver biopsy specimen was negative. ELISA for IgM antibodies against TORCH group of agents (Toxoplasma, Rubella, Cytomegalovirus and Herpes virus), at the age of 1 day and 6 days (Eurogenetics NV, Belgium), and 30 days (Abott, USA) in the baby, and maternal titers in the third trimester and 6 days postpartum (Eurogenetics NV, Belgium) were negative and did not show a rise in titer. ELISA (IgM for A60 antigen) for tuberculosis was negative in the baby and the mother. CSF, blood and urine cultures on day 6 and blood and urine cultures at 1 month of age were negative for CMV, and Toxoplasma could also not be isolated.

The baby was discharged from the neonatal unit at 9 days of age, on parental request. His hematological parameters (Day 9: TLC: 5900 per cubic mm, platelet count: 38,000 per cubic mm, hematocrit: 27% and; day 30: TLC: 5600 per cubic mm, platelet count: 41000 per cubic mm, hematocrit: 21%) and liver function tests (Day 9: bilirubin: 12 mg/dL, direct: 8.6 mg/dL, ALT=180 U/L; Day 30: bilirubin: 15 mg/dL, direct: 12.1 mg/dL, ALT: 200 U/L, SAP: 243 U/L) were deranged at the time of discharge and follow-up visit at 30 days of age. The baby died at 41 days of age without coming for medical attention and permission for autopsy was refused. The exact cause of death could not be ascertained.


Intrauterine infection due to TORCH group and syphilis present a diagnostic dilemma as their clinical features overlap and may initially be indistinguishable. Due to the varied clinical course reported for congenital intrauterine infections, and consistent clinical findings, a diagnosis of congenital CMV infection was entertained initially for our patient but was excluded by the negative results of repeated immunovirologic studies and the failure to recover viral inclusions in urine culture and to isolate Toxoplasma organisms. Cockayne syndrome, Aicardi-Goutiere syndrome, Miller Dieker Syndrome, COFS Syndrome and Fahr disease, which are the other conditions with microcephaly and intracranial calcification, were excluded on the basis of the clinical features and investigations(1,2).

An autosomal recessive condition which is clinically similar to congenital TORCH infections was first described by Baraitser et al(1), and has been referred by various names in the literature viz. Congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification and CNS disease; Baraitser – Rearden syndrome, and Pseudo - TORCH syndrome(8). Subsequently, 11 more families with this syndrome have been reported with a marked clinical and neuro-radiological variability among them; however, microcephaly from birth, intracranial calcification and cerebral atrophy are uniformly present(1,2, 4-8). Other clinical findings reported are hepatomegaly, neonatal hyperbilirubinemia, cerebellar abnormalities, spasticity, seizures, EEG abnormalities and thrombocytopenia. On review of the available case reports, it appears that our case is a further example of the condition described by Burn et al(2). Vivarelli et al, have recently delineated a specific clinical profile of this condition(8).

Another condition with similar features has also been described and named eponymously as Hoyeraal - Hriedarsson syndrome (3). The differentiating features from Pseudo-TORCH syndrome are progressive pancytopenia and dispropor-tionate cerebellar hypoplasia(9). Dale et al, have recently reported two siblings with hypocomplementemia and systemic lupus erythematosus (SLE), in addition to features similar to the congenital intrauterine infection-like syndrome(10). They have further suggested that complement levels and autoantibody profile should be a part of the workup in such cases, particularly when there are progressive dermatological complications. As our patient did not have any dermatological involvement, these investigations were not carried out.

Our case therefore seems to belong to the pseudo - TORCH syndrome in view of the presence of congenital microcephaly with intracranial calcification, and negative results from serum, urine and CSF studies for similar illnesses. Of the 17 cases reported, 9 died within first year of life. Hepatosplenomegaly, hematological abnormalities, agenesis of the corpus callosum, and hepatocellular changes similar to the present case have been reported previously(2,4,6-8). No specific diagnostic test for this condition has yet been described and diagnosis remains essentially clinical. The occurrence in consanguineous marriages(2,4,6,8) and sibship recurrence of either sex(1,4,6-8) indicates an autosomal recessive mode of inheritance. Eventhough an attempt has recently been made(8), the phenotype has not yet been clearly elucidated so as to help in recognizing single cases/first case in a non-consanguineous marriage.


We are thankful to Dr. Jotna Sokhey, Director, National Institute of Communicable Diseases, Sham Nath Marg, New Delhi, for help in carrying out the immunovirologic studies of the neonate. The authors are also thankful to Dr. T.P. Yadav, Senior Pediatrician, Dr. R.M.L. Hospital, New Delhi, for constructive discussion and critical review of the manuscript.

Contributors: DM drafted the article under VKG’s supervision. All the authors were involved in the management and work up of the patient. DN and DB helped in the literature review. VKG will be the guarantor of the report.

Funding: None.

Competing interests: None stated.


Key Messages

• In addition to congenital intrauterine infections, there is a further autosomal recessive condition with microcephaly and intracranial calcification at birth.

• Diagnosis of pseudo-TORCH syndrome requires presence of suggestive clinical findings but negative immunovirologic studies for congenital TORCH-group of agents.








1. Baraitser M, Brett EM, Piesowicz AT. Microcephaly and intracranial calcification in two brothers. J Med Genet 1983; 20: 210-212.

2. Burn J, Wickramasinghe HT, Harding B, Baraitser M. A syndrome with intracranical calcification and microcephaly in two sibs resembling intrauterine infection. Clin Genet 1986; 30: 112-116.

3. Aalfs CM, van den Berg H, Barth PG, Hennekam RCM. The Hoyeraal-Hreidarsson syndrome; the fourth case of a separate entity with progressive pancytopenia, cerebellar hypoplasia and prenatal growth retardation. Eur J Pediatr 1995; 54: 304-308.

4. Reardon W, Hockey A, Silberstein P, Kendall B, Farag TI, Swash M, et al. Autosomal recessive congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification, and CNS disease. Am J Med Genet 1994; 52: 58-65.

5. Ishitsu T, Chikazawa S, Matsuda I. Two siblings with microcephaly associated with calcification of cerebral white matter. Jpn J Hum Genet 1985; 30: 213-217.

6. Monatsiri K, Salem N, Korbi S, Snoussi N. Microcephaly and Intracranical calcification: two new cases (letter). Clin Genet 1997; 51: 142-143.

7. al-Dabbous R, Sabry MA, Farah S, al-Awadi SA, Simeonov S, Farag TI. The autosomal recessive congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification, and CNS disease: report of another Bedouin family (Abstract). Clin Dysmorphol 1998; 7: 127-130.

8. Vivarelli R, Grosso S, Cioni M, Galluzzi P, Monti L, Morgese G et al. Pseudo-TORCH syndrome or Baraitser-Reardon syndrome: diagnostic criteria. Brain Dev 2001; 23: 18-23.

9. Aalfs CM, Hennekam RCM. Differences between the Hoyeraal-Hreidarsson syndrome and autosomal recessive congenital intrauterine infection-like syndrome (letter). Am J Med Genet 1995; 58: 385.

10. Dale RC, Ping Tang S, Heckmatt JZ, Tatnall MF. Familial systemic lupus erythematosus and congenital infection - like syndrome. Neuropediatrics 2000; 31: 155-158.



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