AJ Griffith

Ali Al Kaissi

APM Van den Elzen

CA Francomano

CJ Williams

D Marshall

Franz Grill

GB Stickler

IH Maumenee

Klaus Klaushofer

M Baraitser

M Holder-Espinasse

MM Cohen Jr

RJ Shprintzen

RM Winter

Rudolf Ganger

S Ayme

TE Kelly

English

PubMed

Springer - Publisher Connector

BioMed CentralCases Journal
ssOpen AcceCase Report
Significant ophthalmoarthropathy associated with ectodermal 
dysplasia in a child with Marshall-Stickler overlap: a case report
Ali Al Kaissi*1,2, Rudolf Ganger2, Klaus Klaushofer1 and Franz Grill2
Address: 1Ludwig Boltzmann Institute of Osteology, at the Hanusch Hospital of WGKK and, AUVA Trauma Centre Meidling, 4th Medical 
Department, Hanusch Hospital, Vienna, Austria and 2Orthopaedic Hospital of Speising, Paediatric Department, Vienna, Austria
Email: Ali Al Kaissi* - ali.alkaissi@osteologie.at; Rudolf Ganger - rudolf.ganger@oss.at; Klaus Klaushofer - klaus.klaushofer@osteologie.at; 
Franz Grill - franz.grill@oss.at
* Corresponding author    
Abstract
Background: The Marshall-Stickler phenotype is an autosomal dominant trait comprising ocular
abnormalities, sensorineural hearing loss, craniofacial anomalies, and anhidrotic ectodermal
dysplasia.
Case presentation: A 5-year-old boy from non-consanguineous family in Austria was born with
features of Pierre-Robin association (cleft palate, micrognathia, and glossoptosis). Radiological
examination at birth revealed coronal clefts of the vertebrae, platyspondyly, and flaring of the
metaphyses of the long bones (features suggestive of the Weissenbacher-Zweymuller syndrome).
Significant features of ectodermal dysplasia such as sparse hair, defective dentition, dysplastic nails,
and deficient sweating associated with bouts of unexplained hyperthermia were present. These
features not shared by Stickler syndrome, Wagner syndrome, or Weissenbacher – Zweymuller
syndrome, all of which are conditions often confused with Marshall syndrome.
Conclusion: There is continuing debate over the clinical overlap and differential diagnosis of
Marshall and Stickler syndromes. We compared similar disorders, such as Weissenbacher-
Zweymuller, and Wagner syndromes, and conclude that our present patient manifests Marshall-
Stickler overlap. Focussing on subtle facial and ectodermal features may detract from recognising
the serious outcome of congenital vitreous/myopia anomaly. Retinal detachment with subsequent
blindness is a major risk in our current patient.
Background
The nosologic relationship of the Stickler and Marshall
syndromes and the nosologic relationship of the Marshall
and Wagner syndromes have been much mooted [1-6]
Ayme and Preus [7] Suggested that the facies differ.
Patients with the Marshall syndrome have a flat or
retracted midface whereas those with the Stickler syn-
drome have a flat malar, which is often erroneously
described as a flat midface. Baraitser [8] suggests that
Stickler syndrome is identical to Marshall syndrome,
although this is still disputed by Ayme and Preus. Mar-
shall syndrome patients have a significant short stature,
thick calvaria, abnormal frontal sinuses, and intracranial
calcifications. The eyeballs appear large, possibly because
of a shallow orbit. Marshall [3] emphasized the ectoder-
mal abnormalities, including defects in sweating and den-
tal structures in the family he reported. Ectodermal
Published: 24 October 2008
Cases Journal 2008, 1:270 doi:10.1186/1757-1626-1-270
Received: 7 August 2008
Accepted: 24 October 2008
This article is available from: http://www.casesjournal.com/content/1/1/270
© 2008 Al Kaissi et al; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 4
(page number not for citation purposes)
Cases Journal 2008, 1:270 http://www.casesjournal.com/content/1/1/270dysplasia and ocular hypertelorism, features not shared by
Stickler syndrome, Wagner syndrome, or Weissenbacher –
Zweymuller syndrome, all of which are conditions often
confused with Marshall syndrome [1-6].
Case presentation
A 5-year-old boy was referred to the department of paedi-
atric orthopaedics because of large/prominent and pain-
ful joints. The child was a product of full term uneventful
gestation. At birth his weight, length and OFC were
around the 10 Th percentile. Features of Pierre-Robin
association have been identified. A median cleft palate,
micrognathia, and glossoptosis were the main prominent
features. The mother was a 29-year-old gravida 1 abortus
0 married to a 33-year-old unrelated man. Both were
healthy and their family history was unremarkable. We
performed complete physical examination for the parents,
which include full oro-facial, musculo-skeletal, ophthal-
mologic, and audiologic assessments. No relevant features
have been detected.
Nasopharyngeal cannulation has been arranged to over-
come his respiratory obstruction. This cannula, which
itself acts as an airway, primarily acts as a sort of "splint"
which makes further airways on either side of the tube
between the tongue and the throat wall, thus assisting the
infant in breathing and preventing the tongue from falling
back down into the throat, which would cause the infant
to asphyxiate. This treatment was carried out for 6
months, at a time the jaw showed sufficient growth. His
cleft palate has been repaired at the age of 8 months. His
glossoptosis and micrognathia did not require surgical
intervention, as they had improved, but his mandibular
arch remains significantly smaller than average. Sen-
sorineural heraing loss has been detected at the age of 3
years. Bilateral hearing aids and a speech and language
therapist and audiologist have been assigned later on to
assist the child's speech retardation. His subsequnet
course of motor development has been of significant
retardation. Early joint stiffness associated with painful
bouts of early osteoarthritis were additional burden and
involved the weight bearing joints(hip, knee and ankle
joints). Early lumbar spondylosis associated with early
osteoarthritis of the neck and the back were present. Walk-
ing has been achieved lately albeit with difficulty because
of the enlarged/stiff joints, superimposed by his defective
vision. He had a history of frequent bouts of unexplained
hyperthermia. Examination showed growth deficiency of
-4 SD. Craniofacially, there was brachycephaly, sparse
skull hair, a retracted mid face, faint eyeborws, sparse eye
lashes, ocular hypertelorism (the eyeballs appear large)
and hypodontia was evident. The skin is dry and the nip-
ples are hypoplastic. The nails showed significant dyspla-
sia. He wore bilateral hearing aids and had a high-grade
myopia of – 8 diopters. The routine blood and urine tests,
serum electrolytes and rheumatoid tests (C-reactive pro-
tein, ESR, rheumatoid factor) were negative. Serum and
urinary oligosaccharides, mucopolysaccharides, serum
lactate, pyruvate, creatine phosphokinase, and chromo-
somal study were normal.
On the bases of the skeletal survey, lateral skull radio-
graph showed absent frontal sinus, mid-facial hypoplasia
and relative thickening of the calvaria. Anteroposterior
hand radiograph showed, short-stubby hand with large
carpal bones associated with pseudoepiphyses of the sec-
ond proximal metacarpophalangeal joint (fig 1). Lateral
spine radiograph showed platyspondyly associated with
anterior clefting of the vertebrae (fig 2). Anteroposterior
pelvis radiograph showed, coxa valga, a hypoplastic ileae,
acetabulo-femoral and metaphyseal dysplasia, with the
propensity for the development of slipped epiphyses asso-
ciated with multiple epiphyseal fragmentations/stippling.
The latter might lead for the development of Perthes dis-
ease. Early signs of early osteoarthritis were evident (fig 3).
Knee radiographs showed significant epi-metaphyseal
dysplasia associated with the development of cupped-
metaphyses of the distal tibio-fibular. A picture of ball and
socket ankle joint associated with features of early oste-
oarthritis.
Discussion
Approximately half of all individuals with Robin
sequence have an underlying syndrome, of which Stickler
syndrome is the most common. In one study, 34 of 100
individuals with Robin sequence had Stickler syndrome
[9]. Van den Elzen et al., [10] found that 15% of a series
Anteroposterior hand radiograph showed, short-stubby hand with large ca pal bo es associ ted with pseudoepiphyses of the second p ximal metacarpophalang al jointFigu e 1
Anteroposterior hand radiograph showed, short-
stubby hand with large carpal bones associated with 
pseudoepiphyses of the second proximal metacar-
pophalangeal joint.Page 2 of 4
(page number not for citation purposes)
Cases Journal 2008, 1:270 http://www.casesjournal.com/content/1/1/270of children with Pierre Robin association had Stickler syn-
drome. Holder-Espinasse et al., [11] also found that about
15% of cases presenting at birth with Pierre-Robin syn-
drome had Stickler syndrome. Radiological examination
at this time may reveal coronal clefts of the vertebrae, mild
platyspondyly and flaring of the metaphyses of the long
bones (features of the Weissenbacher-Zweymuller syn-
drome). As the child grows older these features become
normal, although a mild epiphyseal dysplasia may
develop. Weissenbacher-Zweymuller syndrome has been
described as "neonatal Stickler syndrome," but is actually
a distinct entity [12]. It is characterized by midface hypo-
plasia with a flat nasal bridge, small upturned nasal tip,
micrognathia, sensorineural hearing loss, and rhizomelic
limb shortening. Radiographic findings include dumb-
bell-shaped femora and humeri and vertebral coronal
clefts. The skeletal findings become less apparent in later
years, and catch-up growth after age two to three years is
common [5].
Stickler syndrome (hereditary arthro-ophthalmopathy)
first recognised by Stickler et al., [1,2] in a family with ocu-
lar, orofacial, auditory, and musculoskeletal abnormali-
ties. Variants of Stickler syndrome have been designated
STL1 (vitreous type with mutations in COL2A1 gene),
STL2 (early onset hearing loss and mutations in the COL
11A1 gene) and STL3 (non-ocular type caused by muta-
tions in the COL11A2 gene). Numerous genetic muta-
tions of Stickler syndrome cases are STL1 variety and are
caused by mutations in the COL2A1 gene. In practice,
however, there are difficulties in obtaining molecular
analysis because of the size, complexity and the number
of gene involved and the high cost of these investigations.
Francomano et al., [13] reported close linkage to COL2A1
in several families. COL2A1 mutations have been
reported in some families, including the original Stickler
kindred [14]
Individuals with Marshall syndrome manifest ocular
hypertelorism, hypoplasia of the maxilla and nasal bones,
flat nasal bridge, and small upturned nasal tip. Marshall
[3] reported 4 generations of a family in which 7 members
had, nasal defect and facies characteristic of anhidrotic
ectodermal dysplasia, congenital and juvenile cataracts,
myopia and fluid vitreous, spontaneous, sudden matura-
tion and absorption of congenital cataract, luxation of cat-
aract and congenital hearing loss. The transmission was
dominant. In contrast to Stickler syndrome, the flat facial
profile of Marshall syndrome is usually evident into adult-
Lateral spine radiograph showed platyspondyly associated wi h nterior clefting of the vertebraeFigure 2
Lateral spine radiograph showed platyspondyly asso-
ciated with anterior clefting of the vertebrae.
Anteroposterior pelvis radiograph showed, coxa valga, a hypoplastic ileae, acetabulo-femoral and metaphyseal dyspla-sia, with he propensity for the devel pmen  f slippe e i-physes associat d with multipl  epip yseal fr gmentations/ti plingFigu e 3
Anteroposterior pelvis radiograph showed, coxa 
valga, a hypoplastic ileae, acetabulo-femoral and 
metaphyseal dysplasia, with the propensity for the 
development of slipped epiphyses associated with 
multiple epiphyseal fragmentations/stippling. The lat-
ter might lead for the development of Perthes disease. Early 
signs of early osteoarthritis were evident.Page 3 of 4
(page number not for citation purposes)
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hood. Radiographs demonstrate hypoplasia of the nasal
sinuses and a thickened calvarium. Ocular manifestations
include high myopia, fluid vitreous humor, and early-
onset cataracts (subcapsular, cortical, nuclear, zonular, or
anterior axial embryonic sites). Sensorineural hearing loss
is common and can be progressive. Cleft palate, both as
part of the Pierre Robin sequence and as an isolated
anomaly, is seen. Other manifestations include short stat-
ure and early-onset arthritis. Skin manifestations include
mild hypotrichosis and hypohidrosis [5,6,15]. Splice site
mutations in the COL11A1 gene have been identified by
Griffith et al [15]
Conclusion
Both Stickler syndrome and Marshall syndrome are dom-
inantly inherited chondrodysplasias characterized by
midfacial hypoplasia, high myopia, and sensorineural
hearing deficit. Since the characteristics of these syn-
dromes overlap, it has been argued whether they are dis-
tinct entities or different manifestations of a single
syndrome. The majority of individuals with Stickler/Mar-
shal syndrome have inherited the mutant allele from a
parent. On the light of no similar conditions in the family
we might presume that our patient had developed the dis-
order as a result of a de novo gene mutation. Genetic
counselling in this family looks difficult to accomplish
since molecular genetic testing is usually not offered in the
absence of a known disease-causing mutation in a parent.
Finally we might propose that phenotypic overlap exists
to suggest that Marshal and Stickler syndrome are proba-
bly allelic expressions of the same locus.
Abbreviations
SD: Standard deviation; ESR: Erythrocyte sedimentation
rate; STL 1: Stickler syndrome type 1 and so forth;
COL2A1: Collagen 2 alpha 1 and so forth.
Consent
Written informed consent was obtained from the parents
for the purpose of publication of the manuscript and fig-
ures of their child. A copy of the written consent is availa-
ble for review by the editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All of the authors were involved in the clinico-radio-
graphic assessment and finalising the paper. All authors
have red and approved the final version of the paper.
Acknowledgements
We wish to thank Mis Rima Al Kaissi (University of Lyon 3-France) for 
preparation of the literature and the parents for their remarkable cooper-
ation.
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Significant ophthalmoarthropathy associated with ectodermal dysplasia in a child with Marshall-Stickler overlap: a case report

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Significant ophthalmoarthropathy associated with ectodermal dysplasia in a child with Marshall-Stickler overlap: a case report

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