European Journal of Medical Genetics 56 (2013) 36e38

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European Journal of Medical Genetics

journal homepage: http://www.elsevier.com/locate/ejmg

Short clinical report

Association of severe autosomal recessive osteopetrosis and structural brain

abnormalities: A case report and review of the literature
Zornitza Stark a, *, Alessandra Pangrazio b, c, George McGillivray a, A. Michelle Fink d, e
a
Victorian Clinical Genetics Service, and Murdoch Children’s Research Institute, Melbourne, Australia
b
CNR-IRGB, Milan Unit, Milan, Italy
c
Humanitas Clinical and Research Center, Rozzano (MI), Italy
d
Department of Radiology, University of Melbourne, Melbourne, Australia
e
Medical Imaging Department, Royal Children’s Hospital, Melbourne, Australia

a r t i c l e i n f o a b s t r a c t

Article history: We describe a fetus with severe osteopetrosis diagnosed on post-mortem radiographs following
Received 10 July 2012 termination of pregnancy at 29 weeks for major brain malformations detected on ultrasound. SNP
Accepted 1 October 2012 microarray confirmed loss of heterozygosity in 5% of the genome, consistent with parental consanguinity.
Available online 17 October 2012
Sequencing of the genes known to cause severe recessive osteopetrosis, TCIRG1, CLCN7, OSTM1 and
SNX10, was negative. Brain malformations are not typically considered part of the phenotypic spectrum
Keywords:
of osteopetrosis. We review the literature, and propose that this may represent a novel autosomal
Osteopetrosis
recessive variant of osteopetrosis.
Recessive
Brain anomaly
Ó 2012 Elsevier Masson SAS. All rights reserved.

1. Introduction
Osteopetrosis (“marble bone disease”) is a descriptive term that
refers to a group of rare, heritable disorders of the skeleton char-
acterized by increased bone density on radiographs. The increase in
bone density results from abnormalities in osteoclast differentia-
tion and function and mutations in at least 10 genes have been
identified as causative in humans, accounting for 70% of cases [1].
Osteopetrosis is clinically heterogenous, ranging in severity from
asymptomatic to fatal in infancy. Although primarily considered
a bone disease, osteopetrosis impacts on other organs and tissues,
notably the hematopoietic and nervous systems. Structural brain
abnormalities are not usually considered to be part of the pheno-
typic spectrum.
2. Clinical report
We describe a fetus with osteopetrosis diagnosed on post-
mortem radiographs following termination of pregnancy at 29
weeks for major brain malformations detected on ultrasound. This
was the second child to consanguineous parents of Middle Eastern
* Corresponding author. Victorian Clinical Genetics Service, 4th floor, Murdoch
Children’s Research Institute, Flemington Road, Parkville VIC3052, Australia.
Tel.: þ61 3 8341 6368; fax: þ61 3 8341 6390.
E-mail address: zornitza.stark@ghsv.org.au (Z. Stark).
origin, who had one healthy child. The brain abnormalities were
detected on a routine morphology scan at 20 weeks gestation. Fetal
MRI at 25 weeks gestation (Fig. 1) demonstrated macrocrania,
agenesis of the corpus callosum, a giant communicating inter-
hemispheric cyst, hypoplastic falx, thin cerebral mantle and ven-
triculomegaly. The posterior fossa and cerebellum were extremely
small. The vermis was present and of normal size. The tectum was
bulky. The brainstem was thinned with absence of the normal
pontine belly and a narrow isthmus. The aqueduct and fourth
ventricle could not be identified. The findings were suggestive of
malformations secondary to failure of formation of the aqueduct
and fourth ventricle, possibly related to early embryonic defect in
ventro-dorsal patterning [2].
The infant was delivered at 29 weeks gestation following feto-
cide and induction of labor. The fetal growth parameters were on
the 50th centile, except for head circumference which was close to
the 95th centile. External examination showed hypertelorism,
micrognathia, fixed flexion of the fingers, clinodactyly bilaterally,
and severe talipes equinovarus. A post-mortem skeletal survey
demonstrated increased bone density in keeping with a diagnosis
of infantile osteopetrosis (Fig. 2).
Genetic evaluation included standard chromosome analysis
which showed a 46, XX karyotype. SNP microarray (Illumina
HumanCtyoSNP-12 v2.1, 0.20 Mb resolution) did not detect any
clinically significant genomic imbalances, but showed long stretches
of homozygosity representing 5% of the genome, consistent with

1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmg.2012.10.001
 Z. Stark et al. / European Journal of Medical Genetics 56 (2013) 36e38 37

Fig. 1. T2 weighted MRI of the fetal brain: (a) coronal image demonstrating agenesis of the corpus callosum, large interhemispheric cyst (C), ventriculomegaly and extreme
midbrain (*) and cerebellar (arrow) hypoplasia; (b) midsagittal image demonstrating marked brainstem anomaly with thin midbrain and pons, bulky tectal plate (arrow) and
relatively normal vermis, but absence of any visible aqueduct or fourth ventricle; (c) axial image demonstrating the extreme cerebellar and pontine hypoplasia with no visible fourth
ventricle (arrow); (d) axial image demonstrating marked midbrain and cerebral peduncular hypoplasia (white arrows) and ventriculomegaly (V) with thinning of the cerebral
mantle.

parental consanguinity. Molecular investigation included the
TCIRG1, CLCN7 and OSTM1 genes, as well as the recently identified
SNX10 gene [3] but did not identify any pathological mutations. The
other known ARO genes were excluded based on clinical findings.
3. Discussion
The most commonly observed neurological manifestations of
osteopetrosis are secondary to obstruction of the foramina through
which the cranial nerves, spinal cord and major blood vessels
transverse the skull, resulting in blindness, hearing loss, facial palsy
and hydrocephalus [4e6]. These neurological complications can be
particularly severe in classical autosomal recessive osteopetrosis
caused by TCIRG1 mutations. Distinct from these compressive
phenomena, some patients with autosomal recessive osteopetrosis
variants (neuropathic ARO) display primary seizures in the setting
of normal calcium levels, developmental delay, hypotonia, retinal
atrophy with absent evoked visual potentials and sensorineural
deafness [7]. This is due to primary neurodegeneration not
dissimilar to neuronal ceroid-lipofuschinosis, a lysosomal storage
disorder [6]. Reported brain MRI findings include significantly
delayed myelination, diffuse progressive cortical and subcortical
atrophy, and bilateral atrial subependymal heterotopias [7].
Neuropathic ARO is caused by recessive mutations in the CLCN7 and
OSTM1 genes [8e12].
Structural brain malformations are typically not considered to be
a part of the clinical spectrum of osteopetrosis. There are however
three previous reports of autosomal recessive osteopetrosis occur-
ring in association with structural brain malformations [13e15]. The
first report is that of two siblings born to non-consanguineous
parents who were diagnosed with neuroaxonal dystrophy and
osteopetrosis. Neuropathological examination of the first sibling
revealed cerebral atrophy, ventricular dilatation, absence of the
corpus callosum and a small hippocampus, whereas the second
sibling had partial agenesis of the corpus callosum [13]. The second
report was of an infant born to a consanguineous couple, who in
addition to the classical skeletal findings of ARO had macrocephaly,
hypertelorism, agenesis of the corpus callosum, hydrocephalus and
Dandy-Walker malformation [14]. The infant died at 2 months of
age. The couple had one other child who had osteopetrosis and
seizures, and died in infancy without any brain imaging being
performed. None of these individuals underwent molecular testing;
however testing of the parents of the siblings described by Ben
Hamouda et al. [14] did not detect mutations in the TCIRG1, CLCN7
and OSTM1 genes (AP, unpublished data). A milder brain phenotype
(loss of the corpus callosum and atrophy of the anterior visual
pathway out of proportion for the optic nerve canal narrowing) has
been reported in an infant with homozygous mutations in
the TCIRG1 gene who underwent successful hematopoietic stem
cell transplant [15]. However, structural brain anomalies have not

Fig. 2. Post-mortem radiographs at 29 weeks gestation: (a) AP view of the body and limbs demonstrating the abnormal increased bone density with sclerosis of the medullary
cavities of the long bones and metaphyseal irregularities. Postural deformities of the limbs; (b) lateral view of the skull demonstrating macrocrania, micrognathia and abnormal
density of the facial skeleton and skull base.
38 Z. Stark et al. / European Journal of Medical Genetics 56 (2013) 36e38
been reported in a large series of ARO patients with TCIRG1 muta-
tions [16].
Given the severity of the brain abnormalities in our patient and
the siblings reported by Ben Hamouda et al., and the absence of
mutations in the genes known to cause severe ARO in these two
families, we postulate that these cases represent a novel, albeit rare
ARO variant. The genetic etiology of approximately 30% of osteo-
petrosis cases is presently unknown, and these cases raise the
intriguing possibility of a link between the pathways governing
brain and osteoclast development. Structural brain abnormalities
are an under-recognized feature of other disorders which primarily
affect bone development, such as Apert syndrome caused by FGFR2
mutations and thanatophoric dysplasia caused by FGFR3 mutations.
Whereas some types of osteopetrosis are caused by aberrations in
the gene products involved in the osteoclast’s acidification
machinery (TCIRG1, CLCN7, OSTM1 and carbonic anhydrase type II),
other types are caused by mutations in genes coding for compo-
nents of the signalling pathways involved in osteoclast differenti-
ation (RANK and RANKL). The TGFb and WNT signalling pathways
have been implicated in both osteoclast function [17e21] and
embryonic brain development [22,23], and components of these
pathways would form natural candidates for future studies if more
mutation negative ARO patients with brain anomalies are reported.
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