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2019, Volume 35, Number 2, Page(s) 162-165
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DOI: 10.5146/tjpath.2017.01391 |
Ambiguous Genitalia Associated with an Extremely Rare Syndrome: A Case Report of XLAG Syndrome and Review of the Literature |
Brijnandan GUPTA1, Prashant RAMTEKE1, V K PAUL2, Tarun KUMAR1, Prasenjit DAS1 |
1Department of Pathology, All India Institute of Medical Science, NEW DELHI, INDIA
2Department of Pediatrics, All India Institute of Medical Science, NEW DELHI, INDIA |
Keywords: Lissencephaly, Corpus callosum, Ambiguous genitalia, Epilepsy, Syndrome |
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X-linked lissencephaly, absent corpus callosum, and epilepsy of neonatal onset with ambiguous genitalia comprises the XLAG syndrome and
only 15 cases have been reported in literature. Due to its rarity, the exact clinical course and outcome are not known. Exact associations of this
disease are also elusive. Hereby we are reporting this extremely rare entity and we searched the English literature extensively to get consolidated
knowledge regarding this entity that would help the readers. Pre-natal radiological work-up can detect these malformations, which should be
followed by medical termination, counseling and karyotyping. Till date the longest survival noted was 4 years only. |
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The syndrome of X-linked lissencephaly, absent corpus
callosum, epilepsy of neonatal onset with ambiguous
genitalia (XLAG syndrome) was first described by Dobyns
et al. in 1999, who reported a lissencephaly with a posteriorto-
anterior gradient, i.e. a posterior agyria and anterior
pachygyria 1. This rare genetic disease occurs due to
mutation of the ARX homeobox gene (Xp 22.13). This gene
is situated around the ventricles, neocortex, hippocampus
and can also be seen in the pancreas and testes 2.
Lissencephaly in this syndrome results from abnormal
neuronal migration 3. Small, dysplastic basal ganglia
with ventricular cysts have been described in association
with this syndrome 4. Till date only 15 cases have been
reported in published English literature 1,4-10. Herein
we report one such extremely rare case we encountered
during autopsy. |
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Abstract
Introduction
Case Presentation
Disscussion
References
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A preterm neonate, appropriate for date, was born by
spontaneous vaginal delivery to a 20-year-old primigravida
mother at 35+3 weeks of gestation. No history of
consanguineous marriage was present. The baby did not
cry after birth and was born limp and blue with APGAR
Score 5 and 8 at 1 minute and 5 minutes, respectively. The
birth weight of the neonate was 1882 grams and occipitofrontal
circumference (OFC) was 32cm. On examination,
the baby had ambiguous genitalia with non-palpable testes in the external genitalia. The baby had a first episode of
convulsion within half an hour of birth with facial twitching
requiring phenobarbitone followed by multiple episodes of
convulsions. USG brain on day 1 showed absent corpus
callosum with the underdeveloped gyri at the cortical
surface (lissencephaly). Chest X-ray showed bilateral clear
lungs. X-ray abdomen showed dilated bowel loops. The baby
had recurrent episodes of apnoea from 36 hours, requiring
initiation of nasal Intermittent Mandatory Ventilation
(IMV). The blood pressure, blood glucose level, sodium
and calcium levels were within normal limits. Congenital
adrenal hyperplasia was ruled out on the basis of the result
of biochemical examination. On the third day, the baby
had multiple episodes of apnoea requiring bag and mask
ventilation with the development of metabolic acidosis. The
baby died on the fourth day of life due to respiratory failure
and central nervous system malformation. A complete
autopsy was performed. The blood sample was also sent for
karyotyping but this could not be accomplished due to cell
degeneration.
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.
Click Here to Zoom |
Figure 1: A) Gross photograph show a fetus, where the abdomen was opened by a midline thoraco-abdominal incision showing
ambiguous external genitalia (arrow). B) Intra-abdominal bilateral testes (arrows). C) Brain examination showed absence of corpus
callosum (arrows). D) A coronal slice of the brain show increased cortical thickness and under developed sulci and gyri. The distinction
between cortex (C) and white matter (M) has been represented by a schematic line. |
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
Click Here to Zoom |
Figure 2: A) Seminiferous tubules (arrow) with Sertoli cells (H&E; x40). B) Epididymis (arrow) was also identified (H&E; x100). |
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Abstract
Introduction
Case Presentation
Disscussion
References
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Gestational ultrasound and MRI are often diagnostic for
the XLAG syndrome. The MRI findings are agyria with
an increased thickness of the cerebral cortex, with three
abnormal layers, including gray and white matters (6-7 mm) and complete agenesis of the corpus callosum. In
comparison to the XLAG syndrome (cortex consists of
three layers), in X-linked isolated lissencephaly sequence
(XLIS) the cortex consists of four layers and the white
matter is thinned out. MRI brain of asymptomatic mothers
of affected babies may demonstrate partial or complete
absence of corpus callosum 5.
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 temperature1,5, 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 dysplasia11,12.
Seizures occur frequently in this syndrome. Tonic, multifocal
myoclonic and generalized tonic-clonic seizures have been
reported4,5. Uyanik et al. have described a case with
marked fetal movements suggestive of prenatal seizure5.
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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Abstract
Introduction
Case Presentation
Discussion
References
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1) Dobyns WB, Berry-Kravis E, Havernick NJ, Holden KR,
Viskochil D. X-linked lissencephaly with absent corpus callosum
and ambiguous genitalia. Am J Med Genet. 1999;86:331-7.
2) Miura H, Yanazawa M, Kato K, Kitamura K. Expression of a
novel aristaless related homeobox gene ‘Arx’ in the vertebrate
telencephalon, diencephalon and floor plate. Mech Dev.
1997;65:99-109.
3) Neuronal migration disorders and cortical dysplasia. In:
Norman MG, McGillivray BC, Kalousek DK, Hill A, Poskitt KJ,
editors. Congenital malformations of the brain. Pathological,
embryological, clinical, radiological and genetic aspects. Oxford:
Oxford University Press;1995:223-77.
4) Bonneau D, Toutain A, Laquerrière A, Marret S, Saugier-Veber
P, Barthez MA, Radi S, Biran-Mucignat V, Rodriguez D, Gélot
A. X-linked lissencephaly with absent corpus callosum and
ambiguous genitalia (XLAG): Clinical, magnetic resonance
imaging, and neuropathological findings. Ann Neurol.
2002;51:340-9.
5) Uyanik G, Aigner L, Martin P, Gross C, Neumann D, Marschner-
Schäfer H, Hehr U, Winkler J. ARX mutations in X-linked
lissencephaly with abnormal genitalia. Neurology. 2003;61:232-5.
6) Spinosa MJ, Liberalesso PB, Vieira SC, Olmos AS, Löhr A Jr.
Lissencephaly, abnormal genitalia and refractory epilepsy: Case
report of XLAG syndrome. Arq Neuropsiquiatr. 2006;64:1023-6.
7) Jagła M, Kruczek P, Kwinta P. Association between X-linked
lissencephaly with ambiguous genitalia syndrome and
lenticulostriate vasculopathy in neonate. J Clin Ultrasound.
2008;36:387-90.
8) Okazaki S, Ohsawa M, Kuki I, Kawawaki H, Koriyama T, Ri
S, Ichiba H, Hai E, Inoue T, Nakamura H, Goto Y, Tomiwa K,
Yamano T, Kitamura K, Itoh M. Aristaless-related homeobox
gene disruption leads to abnormal distribution of GABAergic
interneurons in human neocortex: Evidence based on a case of
X-linked lissencephaly with abnormal genitalia (XLAG). Acta
Neuropathol. 2008;116:453-62.
9) Özdemir ÖM, Cağlar M, Koçyiğit A, Dündar NO, Sangün
Ö, Dündar B. Primary hypogonadism in a case with XLAG
syndrome. J Pediatr Endocrinol Metab. 2012;25:1161-3.
10) Motlagh AJ, Zahedpasha Y, Ahmadpourkacho M. X-Linked
Lissencephaly with absent corpus callosum and ambiguous
genitalia: A case report. Iranian Journal of Neonatology
2016;7:75-9.
11) Berg MJ, Schifitto G, Powers JM, Martinez-Capolino C,
Fong CT, Myers GJ, Epstein LG, Walsh CA. X-linked female
band heterotopia-male lissencephaly syndrome. Neurology.
1998;50:1143-6.
12) Kitova TT, Kitov B, Milkov D, Gaigi S. Postnatally diagnosed
agenesis of corpus callosum in fetuses. Fetal Pediatr Pathol.
2014;33:239-43. |
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Abstract
Introduction
Case Presentation
Discussion
References
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