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
May 19, 2001;
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
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.
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.
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.
Competing interests: None stated.
• 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