Al Kaissi, Ali

Grill, Franz

Klaushofer, Klaus

Krebs, Alexander

English

PubMed

Springer - Publisher Connector

BioMed CentralCases Journal
ssOpen AcceCase Report
A novel malformation complex of bilateral and symmetric preaxial 
radial ray-thumb aplasia and lower limb defects with minimal facial 
dysmorphic features: a case report and literature review
Ali Al Kaissi*1,2, Klaus Klaushofer1, Alexander Krebs2 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; Klaus Klaushofer - klaus.klaushofer@osteologie.at; Alexander Krebs - krebs.alexander@oss.at; 
Franz Grill - franz.grill@oss.at
* Corresponding author    
Abstract
Introduction: Radial hemimelia is a congenital abnormality characterised by the partial or
complete absence of the radius. The longitudinal hemimelia indicates the absence of one or more
bones along the preaxial (medial) or postaxial (lateral) side of the limb. Preaxial limb defects
occurred more frequently with a combination of microtia, esophageal atresia, anorectal atresia,
heart defects, unilateral kidney dysgenesis, and some axial skeletal defects. Postaxial acrofacial
dysostoses are characterised by distinctive facies and postaxial limb deficiencies, involving the 5th
finger, metacarpal/ulnar/fibular/and metatarsal.
Case presentation: The patient, an 8-year-old-boy with minimal craniofacial dysmorphic features
but with profound upper limb defects of bilateral and symmetrical absence of the radius and the
thumbs respectively. In addition, there was a unilateral tibio-fibular hypoplasia (hemimelia)
associated with hypoplasia of the terminal phalanges and malsegmentation of the upper thoracic
vertebrae, causing effectively the development of thoracic kyphosis.
Conclusion: In the typical form of the preaxial acrofacial dysostosis, there are aberrations in the
development of the first and second branchial arches and limb buds. The craniofacial dysmorphic
features are characteristic such as micrognathia, zygomatic hypoplasia, cleft palate, and preaxial limb
defects. Nager and de Reynier in 1948, who used the term acrofacial dysostosis (AFD) to
distinguish the condition from mandibulofacial dysostosis. Neither the facial features nor the limb
defects in our present patient appear to be absolutely typical with the previously reported cases of
AFD. Our patient expands the phenotype of syndromic preaxial limb malformation complex. He
might represent a new syndromic entity of mild naso-maxillary malformation in connection with
axial and extra-axial malformation complex.
Introduction
Pre and or/postaxial limb abnormalities are syndromic
features in connection with AFD syndromes. The acrofa-
cial dysostoses are heterogenous disorders combining var-
ying severities of mandibulofacial dysostosis with pre
and/or postaxial limb abnormalities. Malar hypoplasia
Published: 24 October 2008
Cases Journal 2008, 1:271 doi:10.1186/1757-1626-1-271
Received: 29 August 2008
Accepted: 24 October 2008
This article is available from: http://www.casesjournal.com/content/1/1/271
© 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 5
(page number not for citation purposes)
Cases Journal 2008, 1:271 http://www.casesjournal.com/content/1/1/271and lower lid ectropion have been found in all patients.
Micrognathia is the rule and this tends to improve with
age. Cleft palate has been present in several cases [1-4].
Postaxial limb deficiencies include absence/hypoplasia/
dysplasia of the fifth fingers in all limbs together with
short forearms. Several syndromic entities have been
described in the literature namely Miller syndrome, which
must be differentiated from Treacher Collins and Nager
syndromes [5,6]. The majority of patients with preaxial
acrofacial dysostosis syndrome appear to represent spo-
radic occurrences. Nevertheless, substantial evidence sup-
ports an autosomal recessive pattern of inheritance and or
dominant inheritance [3,4]. Limb defects can occur in
connection with other forms of syndromic associations.
Unilateral defects occurred with anomalies suggesting
VACTERL association, facio-auriculo-radial anomaly, and
CHILD'S syndrome [7-9]. Bilateral defects occurred more
often in genetic or potentially genetic disorders such as
ectrodactyly-ectodermal dysplasia-tibial aplasia, oro-
mandibular-limb syndrome, and intercalary defects [10-
12]. Our present patient presented with minimal facial
features, but with profound limb defects of preaxial radial
ray-thumb aplasia entity. Autosomal recessive pattern of
inheritance was suggested in connection with parental
consanguinity.
Case presentation
The boy was referred to the orthopaedic department
because of multiple limb defects for clinical assessment
and treatment. He was a product of uneventful gestation.
At birth his growth parameters were around the 10 Th per-
centile. The mother was a 26-year-old gravida 2 abortus 0
married to a 28-year-old related man (first cousin). Preg-
nancy history was negative for exposure to drugs or tera-
togens. Family history was unremarkable. At birth a near
normal facies but with bilaterally dysplastic ears, associ-
ated with profound shortening of the upper limbs and a
unilateral lower limb defects were present. Bilateral and
symmetric radial ray and thumb aplasia associated with
lower limb inequality secondary to a unilateral tibiofibu-
lar hypoplasia and hypoplasia of the terminal phalanges
was the most prominent major abnormalities. He under-
went a series of orthopaedic interventions. Primarily, the
thumbs were absent on both sides (fig 1). The patient had
reconstruction of the thumbs with pollizisation of the sec-
ond finger. This means a rotation-osteotomy of the sec-
ond finger to the thumb position with reconstruction of
the commissural between the new reconstructed thumbs
and the second finger, which was originally the third fin-
ger. Anteroposterior radiograph of the upper limbs after
the reconstruction showed profound radial aplasia, meta-
physeal cupping associated with hypoplastic/defective
ossification of the carpal bones. Pseudoepiphyses with
proximally situated newly reconstructed thumb (fig 2)
At the age of 4 years Ilizarov technique was performed to
correct the lower limb defects (Distraction osteogenesis,
this refers to the induction of new bone between bone sur-
faces that are pulled apart in a gradual, controlled man-
Anteroposterior radiograph of the hand showed the absent thumbFigu e 1
Anteroposterior radiograph of the hand showed the 
absent thumb.
Anteroposterior radiograph of the upper limbs after the reconstruc ion showed profound radial aplasia, metap yseal cupping assoc ated ith hyp plastic/ ef ct ve ossific ion of the car l boneFigu e 2
Anteroposterior radiograph of the upper limbs after 
the reconstruction showed profound radial aplasia, 
metaphyseal cupping associated with hypoplastic/
defective ossification of the carpal bones. Pseudoepi-
physes with proximally situated newly reconstructed thumb. 
The patient had reconstruction of the thumbs with pollizisa-
tion of the second finger. This means a rotation-osteotomy 
of the second finger to the thumb position with reconstruc-
tion of the commissural between the new reconstructed 
thumbs and the second finger, which was originally the third 
finger.Page 2 of 5
(page number not for citation purposes)
Cases Journal 2008, 1:271 http://www.casesjournal.com/content/1/1/271ner). His subsequent course of development particularly
the motor and the fine movements have been of signifi-
cant retardation because of the profound limb defects. No
medical history of serious illnesses.
Examination at the age of eight years, showed a boy with
normal intelligence with normal speech, hearing and
vision. Craniofacially, his face was minimally dysmor-
phic. Bilateral dysplastic ears, and extension of his hair to
the lateral part of the forehead were present. Clinically the
nose looks normal but radiographically there was mild
nasomaxillary hypoplasia. The spine showed significant
thoracic kyphosis.
He had a short stature of -2 SD, profound and bilateral
mesomelic shortening of the upper limbs (absent radii)
associated with oligodactyly (bilateral absence of the first
fingers) and partial syndactyly. A unilateral tibiofibular
hypoplasia was evident with subsequent development of
ball and socket (ankle joint) deformity in connection with
absent talus. Mild hypoplasia of the terminal phalanges of
the deformed lower limb was present. Laboratory studies
showed normal white and red blood cell and platelet
counts, normal calcium, phosphorus, and alkaline phos-
phatase levels. Urine aminoacids and mucopolysaccha-
rides were normal, and he had a normal karyotype. No
specific genetic testing has been designated for this child.
Renal ultrasound and echocardiodoppler were normal.
On the bases of skeletal survey, the lateral skull radio-
graph showed unusual skull-base sclerosis associated with
J-shaped cella turcica and a large sphenoid sinus, multiple
patent sutures, mild nasomaxillary/mandibular hypopla-
sia and odontoid hypoplasia (fig 3). Lateral spine radio-
graph showed malsegmentation of the upper thoracic
vertebrae associated with scalloping of the posterior-end
plates of the lumbar vertebrae. There was exaggerating
lumbar lordosis associated with thoracic kyphosis (fig 4).
Anteroposterior radiograph of the lower limbs showed
profound unilateral tibiofibular hypoplasia with subse-
quent development of ball and socket ankle joint second-
ary to fibular-tarsal dysplasia. The right tibia showed
relative hypoplasia. Dysplasia of the tarsal and the meta-
tarsals and hypoplasia of the terminal phalanges were evi-
dent (fig 5). Ilizarov technique has been successfully
performed for the lower limb deformity. The discrepancy
in the muscle bulk of the lower limbs was secondary to
disuse atrophy (fig 6).
Discussion
Limb defects associated with other malformation com-
plex (whether it is major/minor) require prompt charac-
terisation. There have been a number of syndromic
malformation complex in connection with preaxial/
postaxial limb defects. Nager acrofacial dysostosis is an
oromandibular hypogenesis syndrome with associated
limb abnormalities. Although it shares some phenotypic
features with Treacher-Collins syndrome, it is recognized
as a separate disorder. The facial defects in Nager syn-
drome include an antimongoloid eye slant, malar and
mandibular hypoplasia and small, malformed or low-set
ears. The thumbs may be absent or hypoplastic and there
may be hypoplasia of the radius with radioulnar synosto-
sis. Limb defects, particularly preaxial anomalies, are of
diagnostic significance in Nager syndrome, and serve to
differentiate this condition from mandibulofacial dysos-
tosis. The radial defects are believed only to occur with
concurrent agenesis of the thumb. Defects of the lower
extremity also have been described. Heterogeneity of
apparently non-syndromal acrofacial dysostosis of both
types (Nager and Treacher-Collins) is powerful support
for the hypothesis that the AFDs are polytopic field defects
arising during balstogenesis [1-6]. Thompson et al., [13]
reported a case of preaxial acrofacial dysostosis with tetral-
ogy of Fallot. Fryns et al., [14] reported an adult with fea-
tures of the condition who had mild mental handicap.
Neurological examination revealed hemiparesis of the left
arm and severe spastic diplegia of the lower legs with gen-
eral hyperreflexia. Herrmann et al., [15] reported conduc-
tive hearing loss was noted in 90% of his cases.
Inheritance is uncertain because there is evidence for both
autosomal dominant and recessive inheritance in differ-
ent families. Guttmacher [16] reported a father, son and
daughter with unusual hand and foot abnormalities, and
hypospadias in the males. There was hypoplasia of the
Lateral skull radiograph showed diffuse skull-base sclerosis associated with J-sh ed cella turcica and a arge sph n id sinus, multiple patent sutures, mild nasom xillary/mandibular hypop a ia and odo oi ypoplas aFigure 3
Lateral skull radiograph showed diffuse skull-base 
sclerosis associated with J-shaped cella turcica and a 
large sphenoid sinus, multiple patent sutures, mild 
nasomaxillary/mandibular hypoplasia and odontoid 
hypoplasia.Page 3 of 5
(page number not for citation purposes)
Cases Journal 2008, 1:271 http://www.casesjournal.com/content/1/1/271thumbs and halluces with postaxial polydactyly. There
was also limitation of movement of the interphalangeal
joints of the thumbs in the daughter and prominent vas-
cularity on the posterior of her right forearm. The second
toes had one phalanx and absent nails. Lettice et al., [17]
studied a three-year-old girl with bilateral duplication of a
triphalangeal thumb and triplication of the great toe. She
had a de novo t(5,7)(q11, q36) translocation. The break-
points on 7q36 lay within the LMBR1 gene about 1 Mb
away from SHH. A similar translocation in the same
intron of Lmbr1 in the mouse was also associated with
preaxial polydactyly and genetic analysis in the mouse
suggested that the translocation directly interrupted a cis
acting regulator of SHH. None of the above mentioned
entities entails similar malformation complex as seen in
our present patient.
In summary
Limb defects are a diverse collection of conditions, each
developing through a different prenatal process, probably
with different underlying causes. Proper classification is
critical. Surgery is often needed in upper limb defects as
well as for lower limb defects to straighten and stabilize
the legs for prosthesis fitting. Finally we wish to stress that
the profound limb deformities in our present patient were
noteworthy. The extent of these malformations was not
compatible with any previously reported entities of syn-
dromic and non-syndromic forms of preaxial malforma-
tion complex.
Lateral spine radiograph showed significant thoracic kyphosis secondary to malsegmentation of the upper thoracic verte-bra  ssociated with scalloping post rior-end plates ofthe lumbar v rtebraeFigure 4
Lateral spine radiograph showed significant thoracic 
kyphosis secondary to malsegmentation of the upper 
thoracic vertebrae associated with scalloping of the 
posterior-end plates of the lumbar vertebrae. There 
was exaggerating lumbar lordosis associated with thoracic 
kyphosis.
Anteroposterior radiograph of the lower limbs showed pro-found unila al tibiofibular hypoplasia with subsequent dev lopment of ball and socket ank e joint secondary to fibu-lar-tarsal dysplasiaFigu e 5
Anteroposterior radiograph of the lower limbs 
showed profound unilateral tibiofibular hypoplasia 
with subsequent development of ball and socket 
ankle joint secondary to fibular-tarsal dysplasia. Dys-
plasia of the tarsal and the metatarsals and hypoplasia of the 
terminal phalanges were evident. There was relative left tibial 
hypoplasia.Page 4 of 5
(page number not for citation purposes)
Cases Journal 2008, 1:271 http://www.casesjournal.com/content/1/1/271Abbreviations
SD: Standard deviation; AFDs: Acrofacial dysostoses;
LMBR1: limb region 1 homolog (mouse); SHH: Sonic
hedgehog gene and protein.
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.
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.
Acknowledgements
We wish to thank Rima Al Kaissi (University of Lyon 3-France) for her help 
in literature preparation) we also thank the parents for their remarkable 
cooperation.
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Ilizarov technique has been successfully performed for the lower limb deformityFigu e 6
Ilizarov technique has been successfully performed 
for the lower limb deformity. The discrepancy in the 
muscle bulk of the lower limbs was secondary to disuse atro-
phy.Page 5 of 5
(page number not for citation purposes)


A novel malformation complex of bilateral and symmetric preaxial radial ray-thumb aplasia and lower limb defects with minimal facial dysmorphic features: a case report and literature review

Ali Al Kaissi

Klaus Klaushofer

Alexander Krebs

Franz Grill

Ali AliAl Kaissi

Springer

Autosomal dominant asymmetrical radial dysplasia, dysmorphic facies, and conductive hearing loss (facioauriculoradial dysplasia).

de Reynier: Das gehororgan bei den angeborenen kopfmissbildungen. Pract Otorhinolaryngol (Basel)

den: Nager acrofacial dysostosis. An adult male with severe neurological deficit. Genetic Counseling

DGD: Nager acrofacial dysostosis: minor familial manifestations supporting dominant inheritance. Clin Genet

DW: Otologic and audiologic features of Nager acrofacial dysostosis.

et al.: Disruption of a longrange cis-acting regulator for Shh causes preaxial polydactyly.

F: Femoral-tibial-synostosis in a child with Roberts syndrome (Pseudothalidomide). Cases Journal

Hypohidrotic ectodermal dysplasia with tibial aplasia. Clin Dysmorphol

Klaushofer K: Craniocervical junction malformation in a child with Oromandibular-limb hypogenesis-Möbius syndrome.

Missbildungs-Retardierungs-Syndrom mit Fehlen des 5. Strahls an Handen und Fussen, Gaumenspalte, dysplastischen Ohren und Augenlidern und radioulnarer Synostose. Klin Padiatr

Nager &quot;syndrome&quot; versus &quot;anomaly&quot; and its nosology with the postaxial acrofacial dysostosis syndrome of Genee and Wiedemann.

New syndrome. Autosomal dominant preaxial deficiency, postaxial polydactyly, and hypospadias.

Ophir D: Autosomal recessive inheritance of Nager acrofacial dysostosis.

The CHILD syndrome – congenital hemidysplasia with ichthyosiform erythroderma and limb defects. A case report. Acta Derm Venereol

The Nager acrofacial dysostosis syndrome with the tetralogy of Fallot.

Tibial aplasia – VACTERL association, a new syndrome? Clin Dysmorphol

Treacher Collins syndrome. Hum Mol Genet

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A novel malformation complex of bilateral and symmetric preaxial radial ray-thumb aplasia and lower limb defects with minimal facial dysmorphic features: a case report and literature review

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