Autopsy Findings
Externally, ambiguous genitalia (Figure 1A) and low set ears
were noticeable. Ambiguous genitalia in the index case was
diagnosed as evidenced by the presence of microphallus,
hypospadias, bifid scrotum and bilaterally impalpable
gonads. No other external congenital malformation was
seen.
The testes were located intra-abdominally (Figure 1B). The corpus callosum was completely absent (Figure 1C). All other organs in thoracic and intra-abdominal cavity were in their normal anatomical position. Cortical thickness was increased (8-9 mm) (Figure 1D). Testes were confirmed histologically (Figure 2A,B). All other organs were histologically appropriate for the developmental age. No ovary was identified microscopically. A final diagnosis of X-linked lissencephaly, absent corpus callosum with ambiguous genitalia (XLAG syndrome) was therefore offered
In our case, the corpus callosum was completely absent and the cerebral cortex was abnormally thick (8-9 mm) with partial loss of sulci in both the anterior and posterior cortex. There were also ambiguous genitalia, low set ears, patent ductus arteriosus, foramen ovale and intra-abdominal testes. Testes were confirmed histologically. A few authors have described hypothalamic dysfunction with deficient control of body temperature[1,5], but body temperature control was normal in our patient and no hypothalamic dysfunction was noted (Table I). Absent corpus callosum can be associated with abnormalities such as agenesis of vermis cerebelli, hydrocephalus, polymicrogyria, cerebellar hypoplasia, and lissencephaly. Many cases of absent corpus callosum have syndromic association with Fetal akinesia syndrome, XLAG syndrome, Dandy-Walker Malformation, Trisomy 13,18,21 and Thanatophoric dysplasia[11,12].
Table I: Cases of XLAG syndrome reported in the literature
Seizures occur frequently in this syndrome. Tonic, multifocal myoclonic and generalized tonic-clonic seizures have been reported[4,5]. Uyanik et al. have described a case with marked fetal movements suggestive of prenatal seizure[5]. In the index case, the baby had episodes of multifocal clonic seizure with facial twitching which started within half an hour of birth and increased in intensity gradually. Overall prognosis in XLAG syndrome is poor with a maximum reported survival of 4 years (Table I). Though the sample was sent for karyotyping, satisfactory test results could not be obtained due to poor quality of the sample. However, the clinical and autopsy findings were enough to help us reach a diagnosis.
Antenatal history of mother revealed absent folic acid intake in our case. The association of absent folic acid intake in the mother and occurrence of this syndrome has not been previously reported. There is therefore a need for further investigation to know whether there is any relationship between absent folic acid intake and the occurrence of this disorder with developmental malformation of central nervous system.
In conclusion, the XLAG syndrome is an extremely rare congenital malformation of male newborns with ambiguous genitalia and loss of corpus callosum with hypothalamic dysfunction. This needs to be identified during prenatal radiological work up as the longest reported survival is only 4 years after birth. Proper counseling of the couple with karyotyping and genetic tests is imperative to decide upon future pregnancy.
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