2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:219–228 (2007)
Rapid Publication
Matthew-Wood Syndrome:
Report of Two New Cases Supporting Autosomal Recessive
Inheritance and Exclusion of FGF10 and FGFR2
Jelena Martinovic-Bouriel,1* Ce´line Bernabe´-Dupont,2 Christelle Golzio,4,5
Bettina Grattagliano-Bessie`res,3 Vale´rie Malan,1,4 Maryse Bonnie`re,1 Chantal Esculpavit,4
Catherine Fallet-Bianco,3 Ve´ronique Mirlesse,3 Jeroˆme Le Bidois,3 Marie-Ce´cile Aubry,2
Michel Vekemans,1,4,5 Nicole Morichon,1,4 Heather Etchevers,4,5 Tania Attie´-Bitach,1,4,5
Fe´re´chte´ Encha-Razavi,1,4 and Alexandra Benachi2,4
1Assistance Publique—Hoˆpitaux de Paris; Hoˆpital Necker—Enfants Malades, Department of Genetics,
Embryo-Fetal Pathology Unit, Paris, France
2Assistance Publique—Hoˆpitaux de Paris; Hoˆpital Necker—Enfants Malades, Department of Obstetrics, Paris, France
3Institut de Pue´riculture, Department of Fetal Pathology, Paris, France
4Universite´ Paris-Descartes; Hoˆpital Necker—Enfants Malades, Paris, France
5INSERM U781, Hoˆpital Necker—Enfants Malades, Paris, France
Received 28 July 2006; Accepted 27 October 2006
We describe two fetal cases of microphthalmia/anophthal-
mia, pulmonary agenesis, and diaphragmatic defect. This
rare association is known as Matthew-Wood syndrome
(MWS; MIM 601186) or by the acronym ‘‘PMD’’ (Pulmonary
agenesis, Microphthalmia, Diaphragmatic defect). Fewer
than ten pre- and perinatal diagnoses of Matthew-
Wood syndrome have been described to date. The cause is
unknown, and the mode of transmission remains unclear.
Most cases have been reported as isolated and sporadic,
although recurrence among sibs has been observed once.
Our two cases both occurred in consanguineous families,
further supporting autosomal recessive transmission. In
addition, in one family at least one of the elder sibs
presented an evocatively similar phenotype. The spatiotem-
poral expression pattern of the FGF10 and FGFR2 genes in
human embryos and the reported phenotypes of knockout
mice for these genes spurred us to examine their coding
sequences in our two cases of MWS. While in our patients, no
causative sequence variations were identified in FGF10 or
FGFR2, this cognate ligand-receptor pair and its downstream
effectors remain functional candidates for MWS and
similar associations of congenital ocular, diaphragmatic and
pulmonary malformations.
2007 Wiley-Liss, Inc.
Key words: microphthalmia; pulmonary hypoplasia; con-
genital diaphragmatic defect; polymalformative syndrome;
association; growth retardation; facial dysmorphy; prenatal
diagnosis; fibroblast growth factor; embryo
How to cite this article: Martinovic-Bouriel J, Bernabe´-Dupont C, Golzio C, Grattagliano-Bessie`res B,
Malan V, Bonnie`re M, Esculpavit C, Fallet-Bianco C, Mirlesse V, Le Bidois J, Aubry M-C, Vekemans M,
Morichon N, Etchevers H, Attie´-Bitach T, Encha-Razavi F, Benachi A. 2007. Matthew-Wood syndrome:
Report of two new cases supporting autosomal recessive inheritance and exclusion of FGF10 and
FGFR2. Am J Med Genet Part A 143A:219–228.
INTRODUCTION
A distinct association of pulmonary, ocular, and
diaphragmatic congenital malformations has been
reported occasionally over the last 25 years. Spear
et al. [1987] examined a patient with bilateral
pulmonary agenesis, eventration of the left dia-
phragm, bilateral microphthalmia, and a complex
cardiac defect with a ventricular septal defect and
absent pulmonary vessels. Engellenner et al. [1989]
Jelena Martinovic-Bouriel, Ce´line Bernabe´-Dupont, and Christelle
Golzio have contributed equally to this work.
Grant sponsor: Association Franc¸aise contre les Myopathies; Grant
sponsor: Institut National pour la Sante´ et la Recherche Me´dicale
(INSERM).
*Correspondence to: Dr. Jelena Martinovic-Bouriel, Embryo-Fetal
Pathology Unit, Department of Genetics, Hopital Necker-Enfants
Malades, 149 rue de Sevres, 75015 Paris, France.
E-mail: jelena.martinovic@nck.aphp.fr
DOI 10.1002/ajmg.a.31599

described another patient with bilateral pulmonary
agenesis, an inverted right diaphragm, right micro-
phthalmia and a small heart with absent pulmonary
veins. Seller et al. [1996] coined the term Matthew-
Wood syndrome (MWS) in reference to an associa-
tion of microphthalmia and pulmonary hypoplasia,
after the name of a firstborn sib. Berkenstadt
et al. [1999] reported the coincidence of unilateral
pulmonary agenesis, microphthalmia, diaphrag-
matic hernia, and intrauterine growth retardation
under the acronym ‘‘PMD.’’ The authors proposed
that PMD might be a new entity, and that MWS,
reported as anophthalmia and pulmonary hypo-
plasia, might represent an incomplete form of PMD.
A few cases have been observed in the peri- and
postnatal period [Spear et al., 1987; Enns et al., 1998;
Priolo et al., 2004; Li and Wei, 2006; Robert Lee et al.,
2006] as well as three cases of prenatal diagnosis of
the syndrome at the respective ages of 18, 22, and
36 weeks’ gestation [Engellenner et al., 1989; Seller
et al., 1996; Berkenstadt et al., 1999]. While most
cases were apparently sporadic and isolated, MWS
seems to have a genetic basis because of one report
of familial recurrence [Seller et al., 1996]. A similar
phenotype, presenting in addition with tetralogy of
Fallot, was observed in a patient with a balanced
reciprocal translocation de novo 46,XY,t(1;15) (q41;
21.2) [Smith et al., 1994]. No one animal model
recapitulates this particular human association.
However, knock-outs of the murine Fgf10 (fibroblast
growth factor 10) [Min et al., 1998; Sekine et al., 1999]
or its binding-specific receptor isoform, Fgfr2(IIIb)
[De Moerlooze et al., 2000], have multiple congenital
defects including pulmonary agenesis. Other organ
systems are affected including ablepharon for
Fgfr2b, atretic or stenotic colon [Fairbanks et al.,
2005] or imperforate anus, hypoplasic pituitary,
lacrimal and salivary glands, pancreas and spleen,
abnormal limbs and, inconsistently, kidneys [Ohuchi
et al., 1997; Min et al., 1998]. Cardiac outflow tract
malformations have also been noted.
Given a certain number of similarities between
these animal models and the clinical signs of
Matthew-Wood cases described here and elsewhere
in the literature, we therefore undertook a molecular
analysis of the FGF10 and FGFR2 genes in our two
patients and were able to exclude both genes as
pathogenic candidates in these individuals.
METHODS
Standard Karyotype and FISH (Fluorescence In
Situ Hybridization) Analysis on Chromosomes
Standard karyotyping using GTG and RHG band-
ing analysis was carried out on cultured amniotic
fluid cells according to standard procedures. FISH
was performed using BACs, RP11-297K5, RP11-
1149B18, RP11-239E10 spanning the GATA4
(8p23.1) and CHD2 (15q26.1) genes and the 1q41
region, respectively, to rule out any possible
deletions. BACs were selected from several data-
bases accessible through the Internet (UCSC, Uni-
versity of California, Santa Cruz http://www.
genome.ucsc.edu/ and NCBI, National centre for
Biotechnology Information http://www.ncbi.nlm.
nih.gov/). FISH experiments were performed on
chromosome preparations as described previously
[Romana et al., 1993].
In Situ Hybridization
Human embryos were collected from pregnancies
legally terminated using the mefiprestone protocol,
in concordance with French law 00-800 and hospital
ethics committee recommendations. Primers were
selected for PCR amplification (FGF10: [F] 50-
CTGGATGGCTTGTATCAAATG-30 [R] 50-TTGGCA-
AAAGAGCCATTGGT-30 corresponding to exon 3;
FGFR2(IIIb): [F] 50-CTTTAATGCCGCTGTTTAG-
30 [R] 50-TCTTTTCAGCTTCTATATCCAG-30 corre-
sponding to alternatively spliced exon 9, included
as the 8th exon in the IIIb RNA isoform). A T7
promotor sequence extension (TAATACGACTCAC-
TATAGGGAGA) was added at the 50 end of each
primer. T7F/R and F/T7R primer pairs allowed
the amplification of sense and antisense templates
respectively, specific to the FGF10 or the
FGFR2(IIIb) transcripts. Riboprobe labeling, tissue
fixation, hybridization, and developing were carried
out according to standard protocols, as previously
described [Wilkinson, 1992; Trueba et al., 2005].
DNA Analysis
Both cases had normal chromosomes according to
karyotype. DNA was extracted from thymus samples
after informed consent and autopsy using standard
protocols. PCRs were carried out using intronic
primers for the 3 exons of the FGF10 gene and the
18 coding exons (including the alternatively
included exons 8 and 9) for the FGFR2 gene;
sequences and conditions presented in Table II.
CLINICAL REPORT
Patient 1
A consanguineous healthy couple of Romanian
origin presented with a history of neonatal demise in
their two first-born children. The first child, a boy
delivered vaginally at 33 weeks’ gestation (birth-
weight: 800 g, <3rd centile), died on the first day
postpartum with no autopsy. The second child, a
girl delivered at 43 weeks’ gestation (birthweight:
2,800 g, 3rd centile), died within the first hour of life.
The parents brought to our attention her respiratory
220 MARTINOVIC-BOURIEL ET AL.
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

problems associated with a bilateral absence of
ocular globes. However, the parents had no medical
records and autopsy was not performed. Over
the following years, the mother had four healthy
children. Her seventh pregnancy ended in a volun-
tary interruption.
Their eighth child is a boy who developed ocular
troubles but he has had neither medical follow-up
nor an obvious diagnosis.
In the ninth pregnancy, at a maternal age of
34 years, the first sonogram, performed at 12 weeks’
gestation showed normal nuchal translucency and
no anomalies. A second sonogram at 23 weeks’
gestation showed bilateral anophthalmia (Fig. 1) and
gastro-duodenal dilatation in a male fetus. The
control ultrasound at 29 weeks’ gestation confirmed
the absence of ocular globes and jejunal distension.
In addition, polyhydramnios, a left diaphragmatic
defect (Fig. 2), and a short femoral length, measured
at the 3rd centile, were noted. A TORCH study was
negative. Amniocentesis showed a normal male
karyotype (46,XY). After genetic counseling, the
parents opted for termination of pregnancy at
31 weeks, in the light of a poor prognosis.
The fetus (birth weight: 1,250 g, <3rd centile;
length: 38 cm, 3rd centile; head circumference: 28
cm, 10th–25th centile) presented with bilateral
microphthalmia with recessed orbits, hypotelorism,
narrow palpebral fissures, short nose, large ears,
and retrognathia (Fig. 3A,B). Autopsy showed the
bilateral absence of bronchial and pulmonaryanlage
below blind-ended tracheae. The heart was normal,
except for the absence of pulmonary artery branches
and pulmonary veins. Bilateral diaphragmatic even-
tration, as well as stomach and duodenal dilatation
upstream of stenosis at the duodeno-jejunal junction
were confirmed (Fig. 4). In addition, a common
mesentery was noted. Microscopic ocular examina-
tion showed bilateral cataracts and the presence of
retinal tissue in severely hypoplastic globes. The
cerebral examination was normal, except for a
slightly hypoplastic lateral geniculate body. The
vermis displayed a few heterotopic Purkinje cells
(not shown).
Patient 2
A 32-year-old G2P2 (Tanner scale) woman
presented on her second pregnancy with no
particular medical history and a previous, healthy
FIG. 1. Ultrasonography at 29 SA in Patient 1 showing a left diaphragmatic
defect with an ascended stomach. [Color figure can be viewed in the online
issue, which is available at www.interscience.wiley.com.]
FIG. 2. 3D ultrasonography at 29 SA in Patient 1 showing bilateral
microphthalmia. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
FIG. 3. Facial gestalt in Patient 1 (A: front, B: profile) and Patient 2 (C: front,
D: profile) showing common features: narrow palpebral fissures with
microphthalmia, high forehead, short nose with anteverted nostrils. [Color
figure can be viewed in the online issue, which is available at www.
interscience.wiley.com.]
MATTHEW-WOOD SYNDROME 221
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

son. The couple is consanguineous, of Portuguese
origin.
The second sonogram, performed at 23 weeks’
gestation, showed a left diaphragmatic defect with
mediastinal shift, hypoechogenic digestive tract,
bilateral anophthalmia, long philtrum, abnormal
ears, and moderate renal dysplasia. Amniocentesis
yielded a normal female karyotype (46,XX).
Echocardiography showed atresia of the pulmonary
artery with ventricular septal defect. Given a very
poor prognosis, the parents opted for termination of
the pregnancy at 29 weeks.
The fetus (birthweight: 1,160g, 10th centile; length:
37 cm, 10th centile; HC: 27.5 cm, 25th–50th centile)
presented bilateral microphthalmia, a high forehead,
a flat nosewith antevertednares, a bifid uvula, a large
neck, and camptodactyly (Fig. 3C,D). The autopsy
showed bilateral pulmonary agenesis with no main
bronchi, bilateral diaphragmatic eventration, a hor-
izontalized heart with pulmonary artery agenesis and
perimembraneous septal defect (Fig. 5). In addition,
duodenal stenosis (Fig. 6), pancreatic agenesis, and a
multilobulated spleen were noted. Microscopic
ocular examination confirmed bilateral microphthal-
mia with retinal dysplasia and cataracts (Fig. 7). No
anomalies were found on neuropathologic exam-
ination.
MOLECULAR STUDIES
Standard Karyotype and FISH Analysis
In all 20 metaphases analyzed, chromosomal
analysis of the fetus 1 and 2 were normal. FISH
analysis with BAC clones RP11-297K5, RP11-
1149B18, RP11-239E10 showed two hybridization
signals on chromosomes 8, 15, and 1, respectively.
According to these results, a submicroscopicdeletion
was excluded.
In Situ Hybridization
The expression patterns of FGF10 and the
FGFR2(IIIb) isoform, corresponding to the only
receptor form to which FGF10 specifically binds,
FIG. 4. Diaphragmatic eventration and pulmonary agenesis in Patient 1.
[Color figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
FIG. 5. Pulmonary artery agenesis in Patient 2. [Color figure can be viewed in
the online issue, which is available at www.interscience.wiley.com.]
FIG. 6. Duodenal dilatation in Patient 1 (A) and Patient 2 (B). [Color figure
can be viewed in the online issue, which is available at www.interscience.
wiley.com.]
222 MARTINOVIC-BOURIEL ET AL.
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

were analyzed at multiple stages of development of
normal human embryos.
At Carnegie stage (C) 11 (24 days’ development,
not shown) FGF10was restricted to themesenchyme
of the secondary heart field (future outflow tract)
andweak expression began in the anlage of the
adenohypophysis; diffuse central nervous system
(CNS) expression was seen at C12 (26 days).
FGFR2(IIIb) was transcribed in both cardiac inflow
and outflow segments, throughout the CNS, and
strongly expressed in the pharyngeal endoderm and
lateral plate mesoderm. FGF10 transcripts were
observed at C13–C14 (28–32 days) in restricted
portions of the otic vesicle and pharyngeal arch
mesenchyme, as well as uniformly in fore- and
hindlimb bud mesenchyme in similar domains to
those already noted in vertebrate animal models.
FGFR2(IIIb)began to be expressed at higher levels in
both dorsal and ventral posterior diencephalon, in
the ventral CNS elsewhere, in the ectodermal/
endodermal epithelia of the pharyngeal arches, in
the gut endoderm, and in the otic vesicle. At C15 (34
days, not shown) and C19 (47 days), FGF10
expression was present in the nasal pit ectoderm as
well as in the neural retina (Fig. 8A, inset). An
equivalent retinal expression domain had not
hitherto been noted in the reports of spatiotemporal
transcript distribution in the mouse or chick.
Expression was maintained in the germinal layers
of the CNS for both FGF10 and FGFR2(IIIb) at C19.
Particularly intenseFGF10 signalwas observed in the
future hypothalamus (mirroring the strong receptor
expression visible between C12 and C15), while both
FGF10 and its receptor were expressed in the
developing adenohypophysis (ah; Fig. 8A–C). Com-
plementary patterns were observed in the facial
primordia,with strongFGF10 expression in the tooth
mesenchyme and tongue muscle (tb, to; Fig. 8C), and
morediscretely in thenasal andpalatialmesenchyme
(fm), while FGFR2(IIIb) was transcribed within the
buccal ectoderm (be) and pharyngeal endodermal
epithelia, within the thymic and thyroid primordia
(thry, tm), and around the condensing mesenchyme
of Meckel’s cartilage (MC; Fig. 8D). Intense FGF10
expression was found in the muscular layer of
the stomach (not shown), intestine and rectum
(int; Fig. 8A), and lower levels were observed in
the mesenchyme of the urogenital folds (uf);
FGFR2(IIIb) transcripts were localized to the uro-
genital fold epithelium (Fig. 8B) and their signal was
only abovebackgroundwithin the intestinalmucosal
epithelium. However, both ligand and receptor were
expressed in the muscular layer of the physiological
(at this stage) intestinal hernia into the umbilical cord
(Fig. 8A,B). Lung (lu) expression patterns were also
complementary, with FGF10 transcripts observed in
the interstitial mesenchyme between the developing
lobes (Fig. 8E), and FGFR2(IIIb) highly expressed in
the tracheal and bronchial epithelia (Fig. 8F). Both
genes were expressed in the pericartilaginous
condensations of the developing digits at this stage
(Fig. 8A,B).
FGF10 and FGFR2 Gene Analyses
Direct sequencing of both cases was carried out for
the FGF10 and FGFR2 genes. Case 1 had a hetero-
zygous, conservative substitution in FGFR2 at V534V,
inherited from his non-affected mother. FGF10 had
no sequence variations from the published sequence
(RefSeq NM_004465). Genescan analysis showed
that unaffected parents and affected fetus shared one
common allele encompassing the entire gene
and flanking regions (data not shown), rendering
an interstitial chromosomal deletion unlikely in the
face of probable familial recurrence.
Case 2 had no coding variations in FGF10
but demonstrated heterozygosity at IVS2-15g> c,
thereby excluding a heterozygous deletion of the
entire gene. For FGFR2, while no coding variations
were seen, a known SNP was identified at V232V
(dbSNP: rs17859273), allowing the same conclusion
to be drawn.
DISCUSSION
The principal clinical signs of hitherto reported
cases of MWS or PMD syndrome in comparison to
our two cases, are presented in Table I. In both our
cases, bilateral pulmonary agenesis is associated
FIG. 7. Ocular histology (hematoxylin/eosin) in Patient 2 showing retinal
dysplasia and cataract. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
MATTHEW-WOOD SYNDROME 223
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

with diaphragmatic eventration. In one case, the
pulmonary arterywas absent, in theother pulmonary
artery branches were missing. Two other cases
described previously had bilateral pulmonary agen-
esis associated with unilateral diaphragmatic even-
tration [Spear et al., 1987; Engellenner et al., 1989].
Similar facial gestalt exists in our cases, and included
a high forehead, short palpebral fissures and micro-
phthalmia, short nose with anteverted nostrils and a
small chin. Similar features such as flat face, long
philtrum, narrow palpebral fissures, prominent nose
have been observed by other groups [Seller et al.,
1996; Steiner et al., 2002].
It is noteworthy that duodenal stenosis was present
in both of our cases, though not previously reported.
Moreover, we have observed pancreatic agenesis
and a multilobulated spleen in the second case.
Seller et al. [1996] had observed a case with a
hypoplastic spleen. Two other cases presented with
renal dysplasia and malrotation [Engellenner et al.,
1989; Priolo et al., 2004]. In our second case, the
sonogram noted a moderate renal dysplasia which
was not confirmed at the autopsy.
Microphthalmia/anophthalmia in association with
diaphragmatic defect and pulmonary hypoplasia has
been reported in multiple syndromes, including
Fryns syndrome [Lubinsky et al., 1983], Fraser
syndrome, Goldenhar syndrome, and Goltz–Gorlin
syndrome [Kunze et al., 1979; Warburg et al., 1997].
Fryns syndrome is the best-characterized syndrome
of diaphragmatic defects with eye abnormalities
[reviewed in Fryns, 1987; Cunniff et al., 1998].
The combination of features in Fryns syndrome
was described as follows: hydramnios, coarse
face, cleft palate, distal limb hypoplasia, diaphrag-
matic defect, lung hypoplasia, cloudy cornea,
FIG. 8. In situ hybridization on human parasagittal embryo sections at Carnegie stage 19 (47 days) using ribosondes against FGF10 (A,C,E) or FGFR2(IIIb) (B,D,F).
Signal in white, aside from refringent red blood cells. Rostral left, ventral top. A: FGF10 transcripts are observed in this near-sagittal section in the germinal zone of the
CNS, in particular in the ventral diencephalon; in themuscle of the tongue, esophagus and intestine, with strong expression in the rectum, and in themesenchyme of the
urogenital folds. Inset: distinct expression is observed in the neural retina. B: An adjacent section hybridized with the FGFR2(IIIb) antisense probe. Transcripts are
observed in the endodermal and ectodermal epithelia, in the adenohypophysis, the urogenital fold and hindlimb ectoderm. C: A close-up of the craniofacial region
shows low FGF10 expression in the adenohypophysis, more intense signal in the tooth buds and forming salivary glands, and in the facial mesenchyme and
oesophageal muscles. D: FGFR2(IIIb) is expressed complementarily in the buccal ectoderm and pharyngeal endodermal epithelium; in the thyroid and thymic
primordia, and around but not within Meckel’s cartilage. E: FGF10 transcripts are seen at low levels in the muscular walls of the pulmonary artery and aorta, and in the
interlobar mesenchyme of the lung. F: Its receptor is transcribed within the tracheal and bronchial epithelia, but not in the great vessels. Non-specific, flocular signal is
seen at the sites of red blood cell accumulation.
224 MARTINOVIC-BOURIEL ET AL.
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

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American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

microphthalmia, renal dysplasia, and cerebral
malformations. It is interesting that primary pulmon-
ary hypoplasia without a diaphragmatic defect
has also been described in Fryns syndrome [Willems
et al., 1991; Wilgenbus et al., 1994]. Furthermore,
chromosomal abnormalities, such as deletions
of 15q26.2, 8p23.1, and 1q41-q42.12, have been
associated with the congenital diaphragmatic her-
niaof Fryns syndrome [Slavotinek et al., 2005;
Kantarci et al., 2006]. We excluded submicroscopic
deletions in these regions of both present patients
using FISH.
The hallmarks of Fraser syndrome are cryptoph-
talmos or anophthalmia (93%), laryngeal atresia with
enlarged lungs, cutaneous syndactyly of digits (54%),
genital or renal anomalies with frequent renal
agenesis (90%), abnormal ears and an anomaly of
cord implantation on the abdominal wall [Tibboel
and Gaag, 1996]. Almost half of the affected infants
are stillborn or die in infancy, and mental retardation
is common. In humans, this autosomal recessive
disorder is genetically heterogeneous. The FRAS1
gene maps to 4q21 and encodes a large extracellular
matrix protein highly homologous to the murine
equivalent [McGregor et al., 2003]. In two families
with Fraser syndrome unlinked to the FRAS1 gene,
Jadeja et al. [2005] found a missense mutation in the
FREM2 gene. Both proteins are involved in ectoder-
mal adhesion to underlying basal mesenchyme
during development [reviewed in Smyth and Scam-
bler, 2005]. The absence of characteristic signs of
Fraser syndrome, in particular, digital and renal
anomalies, support a different condition in our cases,
although they may be functionally related through
impaired epithelial-mesenchymal signaling during
fetal life.
The mode of transmission of the Matthew-Wood
syndrome has been a subject of debate. Most cases
reported in the literature appear to be isolated.
However, Seller et al. [1996] reported two sibs of
TABLE II. PCR Primers for Direct Sequencing of Human FGF10 and FGFR2
Name Temperature Amplicon size
TCCAGTATGTTCCTTCTGATG FGF10-1F 54.58C 424 bp
TGGGGGTGGATAATTGGAA FGF10-1R 54.58C
TTGCCGGGTTTTAAGACACA FGF10-2F 558C 332 bp
GGTAATGGTTTACTGGAGTGG FGF10-2R 558C
CTGGATGGCTTGTATCAAATG FGF10-3F 54.58C 319 bp
TTGGCAAAAGAGCCATTGGT FGF10-3R 54.58C
TCCCTGACTCGCCAATCTCTTTC FGFR2-EX2-F 558C 343 bp
TGCCCCCAGACAAATCCCAAAAC FGFR2-EX2-R 558C
CACTGACCTTTGTTGGACGTTC FGFR2-EX3-F 558C 380 bp
GAGAAGAGAGAGCATAGTGCTGG FGFR2-EX3-R 558C
TGGAGAAGGTCTCAGTTGTAGAT FGFR2-EX4-F 558C 232 bp
AGACAGGTGACAGGCAGAACT FGFR2-EX4-R 558C
CAAAGCGAAATGATCTTACCTG FGFR2-EX5-F 558C 291 bp
AGAAATGTGATGTTCTGAAAGC FGFR2-EX5-R 558C
GCTAGGATTGTTAAATAACCGCC FGFR2-EX6-F 558C 226 bp
AAACGAGTCAAGCAAGAATGGG FGFR2-EX6-R 558C
ACAGCCCTCTGGACAACACA FGFR2-EX7-F 558C 393 bp
CTGGCTAGTCAAAAAAGAGAA FGFR2-EX7-R 558C
CTTTAATGCCGCTGTTTAG FGFR2-EXIIIB-F 548C 333 bp
TCTTTTCAGCTTCTATATCCAG FGFR2-EXIIIB-R 548C
ATCATTCCTGTGTCGTCTAG FGFR2-EXIIIC-F 548C 224 bp
AAAAACCCAGAGAGAAAGAACAGTATA FGFR2-EXIIIC-R 548C
TGCGTCAGTCTGGTGTGCTAAC FGFR2-EX9-F 558C 341 bp
AGGACAAGATCCACAAGCTGGC FGFR2-EX9-R 558C
TGACTTCCAGCCTTCTCAGATG FGFR2-EX10-F 558C 252 bp
AGTCTCCATCCTGGGACATGG FGFR2-EX10-R 558C
CCCCATCACCAGATGCTATGTG FGFR2-EX11-F 558C 221 bp
TTGATAAGACTCTCCACCCAGCC FGFR2-EX11-R 558C
GAGGAAATGAACTGATTTGTG FGFR2-EX12-F 558C 192 bp
GCAGAGTATTTGGGCGAATG FGFR2-EX12-R 558C
CTGGATTCTCTCTTTAGGGAG FGFR2-EX13-F 558C 263 bp
CACCCAGCCAAGTAGAATG FGFR2-EX13-R 558C
ACATATTTCCTTTTTGTTCTGG FGFR2-EX14-F 558C 256 bp
TCTTCCTGGAACATTCTGAG FGFR2-EX14-R 558C
GAGCCTGCTAAGATAAATTCTT FGFR2-EX15-F 558C 180 bp
AGCTCAAGCCCAGGAAAAAG FGFR2-EX15-R 558C
GGTTTTGGCAACGTGGATGGG FGFR2-EX16-F 558C 254 bp
GAGAGGTATTACTGGTGTGGCAAG FGFR2-EX16-R 558C
ACACCACGTCCCCATATTGCC FGFR2-EX17-F 558C 243 bp
CTCACAAGACAACCAAGGACAAG FGFR2-EX17-R 558C
TCCCACGTCCAATACCCACAT FGFR2-EX18-F 558C 368 bp
TTCCCAGTGCTGTCCTGTTTGG FGFR2-EX18-R 558C
226 MARTINOVIC-BOURIEL ET AL.
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

a non-consanguineous Caucasian couple who
presented MWS. Both children had pulmonary
hypoplasia and anophthalmia. One also had a
number of other malformations, as micrognathia, a
cleft palate reminiscent of the bifid uvula in our
second case, a short upper lip and low-set ears. The
autopsy showeda single ventricle, anhypoplastic left
atrium, an hypoplastic spleen and a bicornuate
uterus.
Both our cases occurred in consanguineous
couples, as may have been the case for one of the
original reports comprising bilateral colobomatous
microphthalmia and diaphragmatic eventration
[Radhakrishnan, 1981], highly supporting a recessive
autosomal inheritance. Moreover, in our first case an
additional sibling presented with similar features
(respiratory anomalies and anophthalmia).
Our cases, together with previously published
cases with similar features, strongly support
the hypothesis that this combination of defects is
non-random [Steiner et al., 2002]. The spectrum of
malformations seems to correspond to organs
developing simultaneously from the fourth week of
gestation on [Priolo et al., 2004]. The expression
patterns in both animal models and humans of
FGF10 and FGFR2(IIIb) were evocative of the organ
systems affected in MWS, although coding anomalies
in these genes were excluded in our cases. The
presence of FGF10 transcripts in the human neural,
non-pigmented retina was novel relative to reports
made in animal models to date, demonstrating the
relevance of performing expression analysis in
human embryos. Further studies will be needed to
rule out mutations in the promoter regions of these
genes spread over large genomic territories, as well
as modified functional interactions with heparin
sulfate or intracellular effector gene candidates.
In summary, rare cases of microphthalmia/
anophthalmia associated with pulmonary hypopla-
sia/agenesis have been hitherto reported in the
literature. We report on two patients presenting
microphthalmia and pulmonary agenesis associated
with bilateral diaphragmatic eventration. In addition,
not previously reported, both cases presented
duodenal stenosis. Facial gestalt is rather similar to
hitherto reported cases. Most cases of Matthew-
Wood syndrome are described as sporadic. Our
cases occurred in consanguineous families with
recurrence among sibs in the first family. As in a
similar, published case [Seller et al., 1996], these
observations strongly support autosomal recessive
inheritance of the syndrome. However, additional
cases will be necessary to further delineate this
syndrome, as well as to provide some information
on its natural history. Further molecular studies
may help us understand these pleiotropic field
defects. Meanwhile, careful sonogram examination
in further pregnancies should be offered to the
families.
ACKNOWLEDGMENTS
We thank the medical staff of the Centre d’Ortho-
ge´nie at the Hoˆpital Broussais for their collaboration
and G. Goudefroye, C. Ozilou, and M. Alcaraz for
their excellent technical assistance. We offer our
appreciation to the families for participating in
this study. The support of A. Munnich is also
gratefully acknowledged. This work was supported
by the Association Franc¸aise contre les Myopathies,
the Institut National pour la Sante´ et la Recherche
Me´dicale (INSERM) ‘‘Avenir’’ program and the
Assistance Publique—Hoˆpitaux de Paris (AP-HP).
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