osteopathia striata with cranial sclerosis and developmental delay in a male with a mosaic deletion...
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CLINICAL REPORT
Osteopathia Striata With Cranial Sclerosis andDevelopmental Delay in aMaleWith aMosaic Deletionin Chromosome Region Xq11.2S�ebastien Ch�enier,1 Abdul Noor,1 Lucie Dupuis,2 Dimitri J Stavropoulos,1,3
and Roberto Mendoza-Londono2*1The Hospital for Sick Children, Department of Paediatric Laboratory Medicine, Toronto, Ontario, Canada2The Hospital for Sick Children, Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto,
Ontario, Canada3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
Manuscript Received: 6 June 2012; Manuscript Accepted: 24 July 2012
Osteopathia striata with cranial sclerosis (OSCS) is an X-linked
disease caused by mutations involving WTX (FAM123B), a
tumor suppressor protein with dual functions. OSCS typically
affects females whereas males generally have fetal or neonatal
lethality. Surviving affected males have characteristic facial
dysmorphisms, skeletal features such asmacrocephaly and short
stature, neurodevelopmental disabilities and a high prevalence
of neuromuscular anomalies. On imaging, hemizygous males
display marked cranial and peripheral skeletal sclerosis without
the metaphyseal striations that are seen in women with OSCS.
Observations of striation inmalesmay be indicative of a somatic
mosaic mutation in WTX. To date only two cases of surviving
males haves been confirmed with mosaic point mutations in
WTX.We report on the first case of amale with amosaic deletion
of the entire WTX gene. We show that a mosaic deletion in a
hemizygous male patient can cause a mild phenotype of OSCS,
including facial and skull base bone striations, nasal stenosis,
conductive hearing loss, global developmental delay, and mild
facial dysmorphology without short stature or macrocephaly.
� 2011 Wiley Periodicals, Inc.
Key words: osteopatia striata; cranial sclerosis; developmental
delay; WTX; FAM123B
INTRODUCTION
Osteopathia striata with cranial sclerosis (OSCS; OMIM #300373)
is an X-linked disease caused by mutations involving WTX (also
known as FAM123B). All reported male and female OSCS patients
have truncatingmutations or deletions ofWTX. Clinical features in
affected females include macrocephaly, cranial nerve palsies, facial
dymorphisms (frontal bossing, hypertelorism, wide nasal bridge,
low-set ears), cleft or high plate, dental problems, and occasionally
developmental delay and intellectual disability [Currarino and
Friedman, 1986; Koudstaal et al., 2008; Jenkins et al., 2009; Perdu
et al., 2010]. On imaging, females show sclerosis of the skull and
longitudinal striations of dense sclerotic bone in the metaphyses of
long bones suggestive of differential X chromosome inactivation of
osteoblasts [Rott et al., 2003]. Hemizygous males generally have a
distinct and a more severe phenotype than heterozygous females
with OSCS. In addition to facial dysmorphisms and hyperostosis,
affected males described to date exhibit multiple severe malforma-
tions such as cardiac defects (ventricular septal defects, patent
ductus arteriosus, pulmonary atresia, or valve stenosis), gastro-
intestinal anomalies (omphalocele, intestinal malrotation, and
Hirschsprung disease), kidney malformations (multicystic kidneys
and multiple nephrogenic rests), or musculoskeletal abnormalities
(lumbar lordosis, syndactyly, camptodactyly, contractures, joint
luxation, fibula agenesis or bowed tibia, radius, ulna, and dupli-
cation of distal phalanges) [Currarino and Friedman, 1986;
Pellegrino et al., 1997; Rott et al., 2003; Jenkins et al., 2009; Perdu
et al., 2010; Holman et al., 2011].
S�ebastien Ch�enier and Abdul Noor contributed equally to this report.
The authors have no conflicts of interest to declare.
*Correspondence to:
Roberto Mendoza-Londono, Division of Clinical and Metabolic Genetics,
The Hospital for Sick Children and University of Toronto, 555 University
Avenue, Toronto, ON, Canada M5G 1X8.
E-mail: [email protected]
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 00 Month 2012
DOI 10.1002/ajmg.a.35619
How to Cite this Article:Ch�enier S, Noor A, Dupuis L, StavropoulosDJ, Mendoza-Londono R. 2012. Osteopathia
striata with cranial sclerosis and
developmental delay in a male with a mosaic
deletion in chromosome region Xq11.2.
Am J Med Genet Part A.
� 2012 Wiley Periodicals, Inc. 1
WTX has two isoforms, the full length WTXS1 and the shorter
isoform WTXS2. WTXS1 contains a binding domain for phospho-
lopids binding (PtdIns(4,5)P2), an acidic domain (AD), three APC
binding domains (APCBD1–3), a binding domain for b-cateninand for WT1 (Wilms tumor 1 protein). The WTXS2 isoform
excludes amino acids 50–326 containing the PtdIns(4,5)P2 and
part of the first APC binding domain. OSCS is associated with fetal
or neonatal lethality inmost affectedmales, particularly if theWTX
mutation is located 50 to the acidic domain (AC) [Jenkins et al.,
2009; Perdu et al., 2010, 2011; Holman et al., 2011]. In fact, among
the reported male cases with a non-mosaic mutation in that
region, 75% (6/8) with a mutation between the phospholipids
(PtdIns(4,5)P2) binding and the AC domain were severely affected.
All mutations located 30 to the AC have been associated withmildly
affected surviving males [Perdu et al., 2010, 2011]. Mildly affected
males share the characteristic facial dysmorphisms found in
severely affected males in addition to short sature, macrocephaly,
hearing impairment, neurodevelopmental disabilities, and a high
prevalence of neuromuscular anomalies such as ventriculomegaly,
malformation of the corpus callosum, joint contractures, and a
nemaline rod myopathy [Holman et al., 2011; Perdu et al., 2011].
Radiographic findings in males that are hemizygous for the
causative mutation display more marked cranial and peripheral
skeletal sclerosis without the metaphyseal striations seen in women
FIG. 1. Radiological findings in the patient at 2months (a,c,e) and4years of age (b,d,f). The cranial base showssclerosis (a,b). The pelvis andproximal
femurs show striations that became more noticeable by 4 years of age (c,d). The distal femurs and proximal tibias showed trabeculations as a
neonate (e), which became very accentuated by 4 years of age (f).
2 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
withOSCS.Observations of striation inmalesmaybe indicative of a
somatic mosaic mutation in WTX and should be considered in
sporadic male cases [Behninger and Rott, 2000]. Only two cases
have been confirmedwithmosaic pointmutations inWTX [Joseph
et al., 2010; Holman et al., 2011]. Until now, no living male with a
complete WTX gene deletion, mosaic, or non-mosaic, has been
reported.
Here, we report on the first case of a male with OSCS and a
�1.5Mb mosaic deletion which includes the entireWTX gene, the
OMIM gene ARHGEF9 and three other RefSeq genes (SPIN4,
KIAA0424, andLOC92249).Wedemonstrate that amosaic deletion
in a male patient may result in a milder phenotype of OSCS
when compared to the clinical features seen in some affected
females.
CLINICAL REPORT
Ourpatientwas thefirst andonly child born tononconsanguineous
parents after anuneventful pregnancy.Hewasborn at full termwith
a birthweight of 4,213 g (97th centile), birth length of 56 cm(>97th
centile), and head circumference of 36 cm (slightly below the 97th
centile). Postnatal adaptation was complicated by mild respiratory
distress and decreased oxygen saturation requiring vigorous suc-
tioning. At 3 days of life, a sinus CT scan was ordered because of the
inability to pass a #6 French nasogastic tube through both nares.
Imaging showed nasal stenosis of the mid portion of the nasal
cavity, rightmodiolus hypoplasia, and sclerosis of the skull. Skeletal
radiographs revealed increased density of the skull base and facial
skeleton aswell as longitudinal striations in themetaphyseal regions
of the long bones (Fig. 1). Conservative treatment, including nasal
steroid drops, provided symptomatic relief of breathing issues.
The patientwas re-evaluated at 4 years of age because of concerns
of moderate global developmental delay. His developmental mile-
stones were globally delayed. He achieved head control at almost 1
year of age, he sat up at 11/2, crawled after age 2 and walked by 21/2years old. At 4 years of age hewas still having problemswith balance
and had a wide gait. His vocabulary was limited to 40 words and a
few simple sentences.Hismedical history was positive for recurrent
ear infections and serous otitis media associated with conductive
hearing loss, which improved with tympanostomy tubes. He had
left eye strabismus. On clinical examination his weight was 17.6 kg
(75th centile), height was 103 cm (50th centile), and head circum-
ference 51.6 cm (50th centile). He had a square face, broad and
prominent forehead with a high anterior hair line implantation.
The nose was broad and tubular. In addition he had bilateral
epicanthal folds, high palate, small teeth with a gap between the
maxillary central incisors and normally placed but over folded ears
(Fig. 2).He did not have scoliosis or contractures but hadmild joint
hyperextensibility.
Investigations performed for the assessment of his global devel-
opmental delay and dysmorphisms included: G banding karyo-
type; fragile X testing; metabolic screen including carnitine
levels, acylcarnitine profile, plasma amino acids and urine organic
acids; brain CT, and abdominal ultrasound, all of which were
normal.
MATERIALS AND METHODS
DNA extracted from peripheral blood was used to perform com-
parative genomic hybridization array (aCGH) analysis on a custom
designed 4� 180K oligonucleotide microarray platform (Oxford
Gene Technology (OGT), Oxford, UK). Microarray experiments
were performed according to the manufacturer’s instructions.
Briefly, DNA from the proband and pooled same-sex reference
DNA (Promega, Madison, WI) were labeled with Cy3-dCTP and
Cy5-dCTP, respectively and were hybridized to the array slide
FIG. 2. Clinical findings on the patient at 4 years of age. a: Frontal view reveals squared head shape, high anterior hairline, hypertelorism, bushy
eyebrows with medial flare and wide spaced teeth. b: Lateral view shows normal ear implantation.
CHENIER ET AL. 3
according to the manufacturer’s protocol (OGT). The arrays were
scanned using the Agilent G2505Bmicroarray scanner. Data analysis
was performed using the Agilent Feature Extraction software
(10.7.11) and CytoSure Interpret Software version 3.4.3 (OGT).
FISH analysis using the spectrum green labeled RP11-93I16 bacte-
rial artificial chromosome (BAC) probe from TCAG (The Centre
for Applied Genomics, Toronto, Canada) was performed on cul-
tured lymphocytes using standard protocols.
RESULTS
The aCGH analysis of the proband’s DNA identified a �1.5Mb
(chrX: 61,848,425–63,346,191, hg18) mosaic deletion in chromo-
some regionXq11.2 (Fig. 3). The adjacent oligonucleotideprobes at
positions 61,698,573 and 63,372,661 showed normal copy number.
The log 2 ratios of probes within the deleted region were suggestive
of a mosaic deletion (mean log 2 ratio¼�0.70593). The deleted
region encompasses five known RefSeq genes SPIN4, LOC92249,
MIR1468, ARHGEF9, and FAM123B (WTX). Among these genes,
ARHGEF9 and FAM123B are OMIM genes, which are known to
cause X-linked early infantile encephalopathy-8 (OMIM 300607)
and osteopathia striata with cranial sclerosis (OMIM 300373),
respectively.
FISH analysis of interphasic cells (N¼ 200) and metaphases
(N¼ 12) using the RP11-93I16 BAC probe confirmed the presence
of mosaic deletion in the proband. The deletion was identified in
38% (76/200) of interphasic cells and 25% (4/12) of metaphases
(Fig. 3). FISH analysis of maternal chromosomes showed no
deletion, consistent with a de novo origin of this deletion.
DISCUSSION
WTX is a tumor suppressor protein with dual functions. WTX can
suppress canonical Wnt signaling by promoting b-catenin degra-
dation [Major et al., 2007] or uponWnt stimulation, it may act as a
scaffold protein promoting LRP6 phosphorylation and therefore
FIG. 3. Cytogenetic findings in the patient. a: Array CGHProbe coverage andgeneswithin the deleted region are shown. b: FISHanalysis using theRP11-
93I16 (green) probe shows cells with (red arrow) and without (green arrow) deletion, thus, confirming the presence ofmosaic deletion at this locus.
4 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
activation of Wnt signaling [Tanneberger et al., 2011]. Although
WTX has been found mutated in different types of cancer such as
Wilms tumor [Hammond et al., 2011], acute myeloid leukemia
[Mao et al., 2011], or colorectal cancer [Bosley et al., 2011],
germline mutations or mosaicism in OSCS patients do not seem
to predispose to tumorigenesis [Jenkins et al., 2009; Joseph et al.,
2010; Perdu et al., 2010]. TheWtx knockoutmouse shows neonatal
lethality, somatic overgrowth and malformation of bone, fat,
kidney, heart and spleen, suggesting a critical developmental role
of WTX in tissues derived from mesenchymal progenitor cells
[Moisan et al., 2011]. The importance of WTX during embryo-
genesis is also clearly demonstrated by the multiple structural
malformations found in patients diagnosed with OSCS, especially
in hemizygous males where it is often lethal [Jenkins et al., 2009;
Perdu et al., 2011].
The recent description ofmildly affected survivingmales showed
that their clinical presentation is broad but more severe than
affected females [Holman et al., 2011; Perdu et al., 2011]. Only
two other males with aWTXmosaic mutation have been described
so far in the literature [Joseph et al., 2010; Holman et al., 2011]. The
clinical features ofmales with a somaticmosaicmutation involving
WTX are presented in Table I. Here we show that a mosaic whole
gene deletion in a male patient, which reduces the amount of
functional protein can be associated with a phenotype similar to
that seen in affected females. Our case is the first reportedmale with
a mild OSCS phenotype without macrocephaly or short stature.
Like heterozygote females, our patient presents characteristic facial
dysmorphisism,mild conductive hearing loss, cranial sclerosis, and
longitudinal striations in the metaphyseal regions of the pelvis and
long bones. This latter observation in our patient supports the
hypothesis that the generation of bone longitudinal striations in
males or females with OSCS can be explained by the variability of
bone formation rate. This variability would be observed even in the
presence of a mosaic distribution of osteoblasts or osteoclast, with
and without a truncated protein or complete absence of WTX
signaling.
Our patient has moderate global developmental delay, which is
rarely observed in female patients with OSCS. Even if develop-
mental delay and intellectual disability have been previously
reported in males with WTX mutations resulting in mild OSCS
[Perdu et al., 2011], in our patient, we can not exclude the con-
tribution of other genes located within the deleted region or
disruption of regulatory sequences of neighboring genes. Notably,
the ARHGEF9 gene maps within the deleted region in our patient
and mutations of this gene have been associated with intellectual
disabilities and seizures [Harvey et al., 2004; Marco et al., 2008;
TABLE I. Clinical Features of Males With a Somatic Mosaic Mutation Involving WTX Gene
Features Joseph et al. [2010] Holman et al. [2011] Present studyMutation c.1108G>T p.E370X c.1072C>T p.R358X Contiguous gene deletion
involving WTXInherited or de novo NR De novo De novoAge at publication 37 years old 23 years old 4 years oldGrowth parameters
Head circumference >97th centile >97th centile 50th centileHeight NR NR 50th centileWeight NR NR 75th centile
NeurologyID or DD Mild ID Mild ID Moderate global DDSeizures NR NR NoneDeafness Bilateral reduced hearing Conductive hearing
impairmentConductive hearing
impairmentDysmorphisms
Forehead Broad Broad BroadEyes NR Epicanthus EpicanthusEye separation Hypertelorism Hypertelorism HypertelorismNasal bridge Flat Flat FlatMouth and Palate Cleft lip and palate Normal High palate
SkeletalSclerosis of the skull Present Present PresentMetaphyseal striations Present Present PresentScoliosis NR Present NoneContractures Ankylosis of the
temporomandibular jointsNone None
Joint hypermobility NR NR NoneOther Clubfeet Left club foot; obstructive
and restrictive lung diseaseLeft eye strabismus;
mid nasal cavity stenosis
NR, not recorded; ID, intellectual disability; DD, developmental delay.
CHENIER ET AL. 5
Kalscheuer et al., 2009; Lesca et al., 2011; Shimojima et al., 2011;
Holmanet al., 2012].Previous studieshave shown thepivotal roleof
ARHGEF9 in the formation of postsynaptic glycine and g-amino-
butyric acid receptor clusters. The phenotype of males with hap-
loinsufficiency for this gene supports its role in cognitive
development [Jedlicka et al., 2009; Papadopoulos et al., 2007; Lesca
et al., 2011; Shimojima et al., 2011]. Interestingly, it has been
recently suggested that the deletion of ARHGEF9might contribute
to the intellectual disabilities or the developmental delay seen in
females with OSCS harboring a deletion of WTX and neighboring
genes [Holman et al., 2012]. Unlike most cases with ARHGEF9
mutations, our patient does not have seizures [Harvey et al., 2004;
Marco et al., 2008; Kalscheuer et al., 2009; Lesca et al., 2011;
Shimojima et al., 2011; Holman et al., 2012]. This might be due
to the normal expression of this gene in a significant proportion of
his cells. Besides ARHGEF9 and WTX, our patient’s deletion also
involves two non-coding RefSeq genes, LOC92249, MIR1468, and
one protein coding RefSeq gene SPIN4. However, the function and
clinical significance of these genes is not yet known.
In conclusion, this case provides further evidence of the role of
WTX in OSCS. The diagnosis of OSCS should be considered in
maleswith skeletal sclerosis, especiallywith sclerosis of the skull and
longitudinal striations of dense sclerotic bone in the metaphyses of
longbones, even if it is not accompaniedbymacrocephaly andother
typical characteristics. Although, this report expands the clinical
spectrum ofOSCS inmale patients, the contribution of other genes
within deletion region cannot not be excluded. Furthermore, this
report also highlights the need to test for mosaic WTX deletions in
male patients with clinical features ofOSCS, particularly, in cases in
which no WTX sequence mutations are identified.
ACKNOWLEDGMENTS
Theauthorswish to thank thepatient and family for participating in
this study.
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