williams-beuren syndrome associated with caudal regression syndrome and coagulopathy—a case report
TRANSCRIPT
Williams-Beuren syndrome associated with caudal
regression syndrome and coagulopathy—a case report
Georg Singera,*, Johannes Schalamona, Herwig Ainoedhofera, Erwin Petekb,Peter M. Kroiselb, Michael E. Hollwartha
aDepartment of Pediatric Surgery, Medical University of Graz, 8036 Graz, AustriabInstitute of Medical Biology and Human Genetics, Medical University of Graz, 8010 Graz, Austria
AbstractWilliams-Beuren syndrome is a genetic disorder caused by a heterozygous deletion at 7q11.23.
The present report describes a female patient with Williams-Beuren syndrome combined with caudal
regression syndrome and two forms of coagulopathy. Besides the typical developmental abnormalities
such as mental and growth retardation, a distinctive facial appearance, and cardiovascular anomalies,
our patient showed fusion of fourth and fifth lumbar vertebra and a sacrococcygeal agenesis. Blood
coagulation tests revealed a deficiency of coagulation factor XI and XII. Magnetic resonance imaging
angiography showed multiple vascular stenoses mainly in the abdominal aorta and its major branches as
a consequence of the insufficient elastin gene. Previous reports identified a deletion of HLXB9 as a
possible genetic cause of the caudal regression syndrome, which could not be identified in the present
case. This unusual combination of the above-mentioned genetic disorders has not been published so far.
D 2005 Elsevier Inc. All rights reserved.
Williams-Beuren syndrome (WBS) is a genetic disorder
that mainly occurs sporadically with an estimated frequency
of 1:13.700 to 1:25.000 [1]. It represents a lesion affecting
the connective tissue and the central nervous system. The
WBS phenotype typically includes a distinctive facial
appearance, neurodevelopmental abnormalities, growth re-
tardation, and cardiovascular anomalies mostly in the form
of supravalvular aortic stenosis (SVAS) [2,3]. The molecular
cause is a heterozygous deletion of contiguous genes at
7q11.23 [4]. Although the haploinsufficiency of the elastin
gene (ELN) is known to be the cause of the vascular
stenoses [5], LIM-kinase 1 hemizygosity may contribute to
the specific cognitive profile [6]. The other characteristics of
WBS have not been specified by genes.
Caudal regression syndrome (CRS) is a rare congenital
disturbance showing lower vertebral agenesis mostly
combined with gastrointestinal and genitourinary anomalies
[7]. The only known gene showing a correlation to CRS is
HLXB9 [8], which has been mapped to 7q36.
We herein report the clinical and molecular genetic
findings of a patient with WBS combined with CRS and two
forms of coagulopathy (factor XI deficiency and factor XII
deficiency). To the best of our knowledge, this unusual
association has not been published so far.
1. Clinical report
1.1. Family history
The presented patient is the first child (female) of a
healthy mother (29 years of age) and father (35 years of age)
0022-3468/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.jpedsurg.2005.07.048
T Corresponding author. Tel.: +43 316 385 3762; fax: +43 316 385 3775.
E-mail address: [email protected] (G. Singer).
Index words:Williams-Beuren
syndrome;
Sacral agenesis;
Coagulation disorder
Journal of Pediatric Surgery (2005) 40, E47–E50
www.elsevier.com/locate/jpedsurg
without a family history of malformations or coagulation
problems. In the 29th gestational week, a maternal
gestational diabetes was diagnosed and managed by dietary
therapy only. Coagulation tests to the parents excluded a
coagulopathy, and because of the lack of symptoms, x-ray
studies to ascertain minor parental caudal regression defects
have not been performed.
1.2. At birth
The patient was born in the 40th week of gestation per
cesarean section after an otherwise uneventful pregnancy.
Urinary dribble and paresis of the lower limbs with high-
graded clubfoots were recognized after birth. Plain radio-
graphs of the spine showed fusion of the fourth and fifth
lumbar vertebra and a sacrococcygeal agenesis. In combi-
nation with the bladder dysfunction and an apparent anal
stenosis, a CRS was diagnosed.
1.3. Evolution
A high-grade vesicoureteral reflux necessitated an anti-
refluxplasty as described by Cohen [9] at the age of 11 years.
The small-capacity bladder resulting from the bladder
dysfunction required a bladder augmentation at the age
of 20 years.
During her development, a typical face showing a wide
mouth with fleshy lips, a flat nasal bridge, a small mandible,
prominent cheeks, and dental anomalies became obvious.
The child disclosed developmental delay, distractibility, and
deficient fine motor skills. In addition, growth retardation
below the third percentile was diagnosed. Cardiac ultra-
sound revealed an SVAS. To confirm the suspected
diagnosis of WBS, a molecular genetic analysis was
performed with special attention to the simultaneous
existing CRS. The analysis resulted in the typical deletion
of all examined WBS loci in 7q11.23, whereas the deletion
of HLXB9 on both chromosomes 7 could not be proven.
A systemic arterial hypertension required an antihyper-
tensive therapy since the age of 23 years. Coagulation tests
were performed to investigate a prolonged activated partial
thromboplastin time showing a deficiency of coagulation
factor XI and XII (35% and 37%, respectively).
Repeated episodes of severe abdominal pain suspicious
for postoperative adhesions indicated surgical exploration.
Laparoscopy and a division of several adhesions between
the bladder augmentation, the frontal abdominal wall, and
single loops of the small intestine were performed.
However, this intervention did not obtain pain relief.
Subsequently, an abdominal magnetic resonance imaging
(MRI) showed a diffuse narrowing of the abdominal aorta
and its major branches with severe affection of the renal
arteries, the truncus celiacus, and the superior mesenteric
artery (Fig. 1).
1.4. Situation at present
With the occasional use of analgesics (nonsteroidal
antirheumatics), pain control can be achieved at the
moment. The patient finished a transitional school and is
employed in a workshop for persons with disability. At the
time of this report, she is 29 years of age and is reexamined
by MRI angiography periodically to evaluate a possible
surgical intervention.
2. Discussion
The patient described in this report combines 4 uncom-
mon genetic disorders, a CRS, a WBS, a Rosenthal syn-
drome (factor XI deficiency), and a factor XII deficiency.
Caudal regression syndrome is a rare congenital lesion
of the lower vertebral column. The spectrum ranges from
agenesis of the coccyx to the absence of sacral, lumbar,
or even thoracic vertebrae. Additional symptoms are
anorectal and genitourinary anomalies. The causes of this
syndrome are poorly understood, but in about 16%, it is
associated with maternal diabetes [10]. Martinez-Frias et al
[11] showed a possible association of CRS and gesta-
tional diabetes in an epidemiological analysis. Dias and
Walker suspect a faulty gastrulation in the form of an
abnormal development of the notocord to be the main
cause of CRS [12]. In several patients, a terminal deletion
of the long arm of chromosome 7 (q36-qter) that
produces a haploinsufficiency of the HLXB9 gene has
been reported to be associated with sacral agenesis
[13,14]. In the Currarino triad (imperforate anus or anal
stenosis, genitourinary malformations, and sacral cleft
with anterior meningocele or teratoma), heterozygous
point mutations in HLXB9 have been described, but not
in the clear CRS [15,16]. In contrast to these reports, we
could neither find the deletion of 7q36-qter nor identify
the deletion of the homeobox gene HLXB9 in the
reported patient by performing fluorescence in situ
hybridization with an HLXB9-specific bacterial artificialFig. 1 Multiple arterial stenoses (MRI angiography).
G. Singer et al.E48
chromosome clone. However, the diagnosis of CRS was
determined by the clinical findings and the preexisting
maternal gestational diabetes.
Leading symptoms for diagnosis were the typical face
combined with mental and growth retardation. The thereby
suspected diagnosis of a WBS was confirmed by molecular
genetic findings. The molecular genetic deletion causing
WBS is located on the long arm of chromosome 7 (7q11.23)
including the gene for elastin, the major arterial wall protein
[5]. The arteriopathy caused by elastin deficiency leads to
thickening of the arterial walls resulting in diffuse arterial
stenoses. The vascular alterations are present in about 50%
to 79% of affected individuals including SVAS, aortic
coarctation, pulmonary stenosis, and stenoses of various
systemic arteries [17]. These vascular stenoses of renal
arteries are thought to be the cause of the higher incidence
of hypertension in patients with WBS [18]. In other cases,
there is no correlation between the severity of vascular
involvement and high blood pressure [19].
Matching with these facts, an MRI examination of our
patient showed vascular lesions with narrowing of truncus
celiacus, superior mesenteric artery, and renal arteries. In
addition, an SVAS and hypertension were diagnosed.
Possible options for treatment are balloon dilatation and
surgical repair of the affected vascular segments. Despite
initial hemodynamic improvement, the long-term results of
balloon dilatation of stenotic arteries in WBS are poor [20].
Surgical repair may be a potential approach in this difficult
group of patients. Because of the mild symptoms of the
reported patient and the sufficient mesenteric and renal
collaterals, surgical angioplasty has been postponed for the
time being.
Recent reports showed promising results about the use of
matrix metalloproteinase inhibitors preventing the degrada-
tion of elastic fibers with subsequent reduction of the
development of neointima formation. This new approachmay
be a future therapeutic option in patients with WBS [21].
Factor XI takes part in the coagulation process by
activating factor IX through proteolysis [22]. The human
gene for this factor is located on chromosome 4 (4q35) [23].
In severely affected individuals, factor XI deficiency
(Rosenthal syndrome, hemophilia C) leads to a variable
bleeding tendency ranging from none to excessive bleeding
after surgery [24]. Factor XII deficiency (Hageman trait) is
rarely found to be associated with bleeding, and its
physiological function is still under discussion [25]. Royle
et al [26] located the gene for factor XII on chromosome
5 (q33-qter). Despite the existence of these two defects of
the coagulation cascade, we could not notice any increased
tendency for bleeding in the present patient yet.
To our knowledge, no other patient has been described
before with this unusual coexistence of genetic disorders.
Still, Ounap et al described a patient with a hemivertebra
(L5) in a report about familial WBS [27]. Furthermore, one
of the patients with WBS examined by Pankau et al [1] had
a bony anomaly in the lower spine in the form of a double
fissure in the upper sacrum. Future studies may focus on the
identification of gene locations other than the HLXB9 with
relation to CRS.
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