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: georg.singer@meduni-graz.at (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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