Keywords
hydranencephaly -
LAMB1
- α-dystroglycanopathy - whole genome sequencing
Bi-allelic variants in the LAMB1 gene have been reported to cause a neurodevelopmental disorder characterized by psychomotor
delays, seizures, ocular anomalies, lissencephaly, and hydrocephalus (lissencephaly-5/LIS5,
OMIM #615191).[1]
[2] Mutations in this gene lead to malformations of cortical development due to aberrant
connection between the pial basement membrane and glial cells. We report a case of
hydranencephaly representing a more severe manifestation compared with previously
known phenotype of LAMB1.
Case Report
A 32-year-old G9 Yemeni female was referred to our institution for prenatal genetic
counseling following an antenatal ultrasonography (US) concerning for hydranencephaly
and polyhydramnios. Obstetric history was significant for spontaneous loss of three
previous fetuses. Physical features of the fetuses and etiology for miscarriages were
not ascertained. Of note, these were the products of a consanguineous union, as the
patient and her husband were double first cousins. The present pregnancy was otherwise
uncomplicated. Repeat US re-demonstrated hydranencephaly with a thin rim of falx cerebri
in addition to identifying a ventricular septal defect (VSD) and visualization of
a single ocular lens ([Fig. 1]). Chromosomal microarray analysis on amniocytes revealed loss of heterozygosity
in more than 20% of the genome, however, did not show any clinically significant deletions
or duplications. A dystroglycanopathy gene panel and sequencing of L1CAM gene were ordered given the combination of brain and ocular malformations, but the
results were nondiagnostic. Testing for congenital infections including toxoplasmosis,
rubella, cytomegalovirus was negative. A fetal MRI was performed shortly before delivery
which was consistent with the previously visualized anomalies. A male infant was delivered
at 34 weeks and 2 days of gestational age via caesarean section due to cephalopelvic
disproportion. The head circumference at birth was 48 cm which was greater than 99th
percentile and third standard deviation for gestational age. He had poor respiratory
drive at birth and needed intubation. The baby was noted to have low set, posteriorly
rotated ears, brachydactyly, a sacral dimple, and cryptorchidism in addition to the
antenatally diagnosed severe cortical malformations. A VSD with patent ductus arteriosus
was noted on echocardiography. Ophthalmologic evaluation showed irregular oval-shaped
pupils which were nonreactive. Baby was noted to have brief irregular episodes of
upper and lower extremity jerking which was characterized as benign myoclonus. Post-natal
course was also complicated by indirect hyperbilirubinemia. The baby could not be
weaned off ventilator and given severe brain malformations which were deemed incompatible
with life, life support was withdrawn. Whole genome sequencing analysis identified
a homozygous variant in the LAMB1 gene [c.4859T > C, p.Ile1620Thr]. This variant is a missense change that has not
been reported in population databases including Thousand Genomes and gnomAD and is
predicted to be damaging based on SIFT algorithm. The parents received appropriate
genetic counseling in our clinic.
Fig. 1 Antenatal ultrasound showing gross absence of cortical matter with the exception
of thin flax cerebri and replacement of cranial vault with cerebrospinal fluid.
Discussion
Hydranencephaly is a condition characterized by the absence of cortical mass with
cerebrospinal fluid filling the intracranial space. The etiology and pathogenesis
of hydranencephaly is not entirely delineated.[3] It is conventionally recognized to be secondary to vasculopathy or intrauterine
infections, and there are only a handful of reports regarding single gene causes of
hydranencephaly. Vascular incidents in the form of malformation of internal carotid
and other intracranial arteries lead to either arrest in brain development or destruction
of already formed brain tissue.[4] Congenital infections such as toxoplasmosis or rubella and teratogenic exposure
such as cocaine or valproic acid have also been implicated.[5] Syndromic or monogenic causes of hydranencephaly are not well known but there have
been reports associated with mutations in the COL4A1 gene and the PI3K-Akt3-mTOR pathway.[6]
[7] We report a case of homozygous single nucleotide variants in LAMB1 gene being causative of hydranencephaly in conjunction with mild cardiac and ocular
defects. LAMB1 mutations as a cause of cortical malformations were first reported in 2013, and at
the time of writing there were six individuals (three families) described ([Table 1]). Clinical features in these patients unanimously included moderate-severe developmental
delay, seizures, hydrocephalus, and a variety of ocular abnormalities ranging from
optic atrophy to lens opacification.[1]
[2] The pathognomonic neuroimaging findings were cobblestone lissencephaly and hydrocephalus,
but also included other anatomic peculiarities such as cerebellar hypoplasia, temporal
lobe cysts, and white matter abnormalities.[1]
[2] Although there was significant clinical overlap in our patient, the previous cases
were diagnosed later in childhood or in adolescence, and MRI findings were less dramatic.
Therefore, our proband possibly represents the most severe phenotype due to LAMB1 reported to date. The sibship reported by Tonduti et al lived up to at least third
decade of lives but with progressively worsening neurological symptoms. For our patient,
the possibility of multiple autosomal recessive conditions was raised given extensive
loss of heterozygosity, however, whole genome sequencing did not reveal pathogenic
or likely pathogenic variants in any genes associated with the phenotype. LAMB1 codes for subunit β 1 of laminin, is a crucial component of the basal laminae, and
helps to regulate the differentiation and migration of neuronal cells.[1]
LAMB1-associated malformative encephalopathy should be considered as a differential diagnosis
for muscle–eye–brain disease (α-dystroglycanopathies) and COL4A1-related porencephaly. This is propounded by shared clinical features (severe cortical
malformation and eye abnormalities) as well as our understanding of the molecular
mechanisms.
Table 1
Phenotypic spectrum of LAMB1-related neurodevelopmental disorder
|
Radmanesh et al (n = 3)
|
Tonduti et al (n = 2)
|
Present case
|
|
Psychomotor delays
|
3/3
|
2/2
|
N/A
|
|
Seizures and infantile spasms
|
0/3
|
2/3
|
?
|
|
Ocular abnormalities
|
0/3
|
Optic atrophy, lens opacities
|
Irregular nonreactive pupils
|
|
Age at the time of reporting
|
?
|
34 y
|
Passed away in first month of life
|
|
Brain anomalies
|
Cobblestone lissencephaly, hydrocephalus
|
Agyria/lissencephaly, hydrocephalus, white matter abnormalities
|
Hydranencephaly with thin falx cerebri
|
Conclusion
This report contributes to the scarce number of known monogenic causes of hydranencephaly
while expanding the phenotypic spectrum of LAMB1-related neurological disorder. It also adds to the list of differential diagnoses
that must be considered in a patient presenting with a conjunction of brain and eye
abnormalities.
