How to cite this article: Sarah A, Mehwish N, Laraib M, Sina A, Sadiq M, et al . Warburg Micro Syndrome- An Unusual Presentation with Brief Review
0015 of Literature. Acad J Ped Neonatol. 2020; 9(3): 555816. DOI: 10.19080/AJPN.2020.09.555816
Six months old child brought to our attention for developmental delay. Child came to our hospital for measles, on detailed history and
examination, developmental delay noted at 6 months of age. He was operated for cataract at 4 months of age. At this time other anomalies
including microcephaly, micro cornea, micro ophthalmia, anterior turning of ears, bilateral retractile testis, micro phallus was noted. X-ray
lumbosacral spine showed spina bifida occulta. No family history of any genetic disorder. MRI revealed partial agenesis of corpus callosum, all of
the mentioned findings are suggestive of a genetic disorder. Baby was therefore diagnosed as Warburg micro syndrome. It is therefore necessary
to look for other syndromes too other than congenital rubella, which closely mimics Warburg syndrome, if a child presents with bilateral cataract
Warburg micro syndrome is a rare autosomal recessive
disorder characterized by microcephaly, micro cornea, congenital
cataract, developmental delay, hypogonadism, structural brain
anomalies, large and asymmetric ears, low anterior hairline,
hypotonia, absent speech, and overlapping toe . In Pakistani
family Warburg micro syndrome was first described in 1993
by Warburg . This syndrome is characterized by mutation
of four genes: RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20.
Among the above mentioned four genes, the most common
mutation observed in Warburg micro syndrome are RAB3GAP1
and RAB3GAP2. Megarbane et al. (1999) reported four children
(one male and three females) from a Shiite Muslim family from
southern Lebanon . This case report documents a baby of Sunni
Muslim community, diagnosis of which was initially missed by a
private hospital. When seen by our tertiary care hospital, history
and detailed examination led to the diagnosis of a genetic disorder,
Warburg micro syndrome.
Six months old child brought to our attention for developmental
delay. Child had both motor and intellectual developmental delay.
Social smile attained at 3 months of life, recognized mother at
4 months of age. Neck holding was not achieved at that time (6
months). He was the first born, only son of two healthy cousins.
Parents are Sunni and Pakistani. Family history was unremarkable
for genetic disorders. Mother had fever in 8 months of gestation
but no history of rash, burning micturition or any other complains.
Child was delivered via Caesarean section due to non-progression
of labour. Birth weight was 2.5kg and APGAR 8 at 1 minute and
9 at 5 minutes. Length at birth was 50cm (50th centile) and FOC
33cm (10th centile). Child had bilateral cataract at birth. Rubella
serology of both mother and baby were negative. Cataract was
operated at 4 months of age with minimal improvement in
vision. The child used to wear spectacles and was unable to see
without it. On examination at 6months his weight was 4kg, FOC
was 37cm (below 2nd centile) and length 64cm. He had poor
postural control. Child had microcephaly, child was wearing
spectacles and responded poorly without it, hearing was normal,
microphthalmia, microcornea, bulbous nose, broad nasal bridge,
prominent ears, thin lips, long philtrum, prominent chin, micro
penis (1.5cm), bilateral retractile testis, two pits in sacral region,
and delayed milestones. No organomegaly. In view of bilateral
cataract and microcephaly, he had been evaluated for congenital rubella syndrome. Rubella serology was negative. Echo was also
normal. Xray lumbosacral spine revealed spina bifida occulta.
MRI brain detected diffuse cerebral atrophy with widening of
sulci. Both lateral ventricles were widely separated with bull horn
appearance, high riding third ventricle and interdigitation of gyri.
Splenium of corpus callosum partially visualized. Partial agenesis of
corpus callosum. Martsolf syndrome which mimics this syndrome
has less severe ocular and neurologic symptoms. Genetic testing
could not be done due to limited resources. However, typical
clinical findings and the available investigations are suggestive of
Warburg micro syndrome. Child is one year old now, neck holding
still not achieved. Child has started making cheerful voices. Child
often develops urine retention and on applying wet cloth passes
urine. Passes urine 5-6 times a day with interrupted stream.
Ultrasound identified right kidney hydronephrosis.
Warburg micro syndrome is very rare, its exact incidence is
not known . Most of the cases have been observed in Muslim
families, in males and in consanguineously married parents .
Our patient also belongs to Sunni Muslim community. And is the
only son of related parents. Warburg was the first who described
this syndrome in 1993 in three affected children, two siblings
and a cousin from an inherent Pakistani family. However, there
was no history of similar illness in the family. These children
include microcephaly, hypogenitalism, cryptorchidism, borderline
microphthalmia, micro cornea, congenital cataracts, optic nerve
atrophy, and retinal dystrophy, these children have mental
retardation and hypertrichosis, beaked nose with prominent
nasal root, short philtrum, and prominent ears . This baby
also had microcephaly, microphthalmia, microcornea, congenital
cataract and prominent ears. Warburg given it the term micro
syndrome because of these combination of features . Nassogne
reported a male child having polymicrogyria and progressive
motor neuropathy diagnosed as Warburg micro syndrome but
having no seizures and hypogenitalism . MRI of this baby
showed partial agenesis of corpus callosum. Our patient also had
no history of seizure. Ains worth highlighted that despite of early
cataract treatment findings like microphthalmos, lens opacity
and non-dilating atonic pupils, decreased vision due to cortical
impairment occur. They proposed that congenital cataract with
mental retardation is a common cause of this syndrome . Our
patient was operated for congenital cataract at four months of
age. Despite cataract extraction visual perception of this child was
poor. Therefore, child used to wear spectacles.
From the different case reports the combination of information
regarding micro syndrome includes mental retardation,
microcephaly, congenital cataract, micro cornea, microphthalmia,
agenesis/hypoplasia of corpus callosum, and hypogenitalism.
Hypo gonadotrophic hypogonadism leads to cryptorchidism,
micropenis, labioscrotal fusion, and hypo plastic scrotum.
Additional systemic manifestations included axial hypotonia with
evolving limb spasticity, and occasional seizures . The reported
case also had partial agenesis of corpus callosum, micropenis and
bilateral retractile testis. Our patient also had two pits in the sacral
region. Lumbosacral x ray spine showed spina bifida occulta.
Patient had also developed urine retention and poor urinary strea.
Ultrasound showed right kidney hydronephrosis and acoustic mass.
The diagnosis of this syndrome is based on clinical grounds, but
there are certain syndromes similar to Warburg syndrome, these
are CAMFAK syndrome (cataract, arthrogryposis, microcephaly,
failure to thrive, and kyphoscoliosis) , CAMAK syndrome
(cataract, arthrogryposis, microcephaly, and kyphoscoliosis) ,
COFS syndrome (brain atrophy with calcification, cataracts, micro
cornea, joint contractures, and growth failure) , COCKAYNE
syndrome (neurodegenerative disorder characterized by low
birth weight, growth failure, brain demyelination with calcium
deposits, cutaneous photosensitivity, cataract, and sensorineural
hearing loss) . Martsolf syndrome is very similar to Warburg
but it has less severe defects of ocular and neurodevelopment.
RAB3GAP1 mutations occur in Warburg micro while RAB3GAP2
mutation occur in Martsolf syndrome . The reported patient
had severe neurodevelopmental delay. Child used glasses because
of poor vision without it.
The above-mentioned case is presented to highlight the
importance of identification of micro syndrome in a patient
who was first brought to medical attention for bilateral cataract
only and was worked up in the view of congenital rubella only.
Detailed examination can identify disorders. However, spina bifida
occulta is an unusual finding in Warburg syndrome. Or is it a new