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American Journal of Medical Genetics 83:82–87 (1999)
Microcephaly, Colobomatous Microphthalmia,
Short Stature, and Severe Psychomotor
Retardation in Two Male Cousins: A New
MCA/MR Syndrome?
André Mégarbané,1* Soha Haddad-Zebouni,2 Rima Nabbout,3 Antoine H. Khoury,4 and
Elias I. Traboulsi5
Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon
Service de Radiologie, Hôtel-Dieu de France, Beirut, Lebanon
Service de Pédiatrie, Hôtel-Dieu de France, Beirut, Lebanon
Service d’Ophtalmologie, Hôtel-Dieu de France, Beirut, Lebanon
Center for Genetic Eye Diseases, Cleveland Clinic Eye Institute, Cleveland, Ohio
We report on 2 male cousins with minor facial anomalies, microcephaly, colobomatous
microphthalmia, psychomotor retardation,
short stature, and skeletal malformations.
The children belong to a highly inbred family. We conclude that these patients have a
previously undescribed autosomal-recessive syndrome. Am. J. Med. Genet. 83:82–87,
1999. © 1999 Wiley-Liss, Inc.
KEY WORDS: autosomal recessive; coloboma; consanguinity; mental
retardation; microcephaly;
microphthalmia; short stature
Colobomatous microphthalmia is a common malformation that may be present in many syndromes.
Nearly 150 conditions with microphthalmia have been
delineated [Warburg, 1993]. Many of these syndromes
have overlapping clinical findings, making differentiation difficult. Characteristic clinical findings, modes of
inheritance, or specific chromosome abnormalities facilitate diagnosis.
We describe 2 cousins with minor facial anomalies,
microcephaly, colobomatous microphthalmia, psychomotor retardation, short stature, and skeletal malfor-
Grant sponsor: Jérôme Lejeune Foundation.
*Correspondence to: André Mégarbané, M.D., Ph.D., Unité de
Génétique Médicale, Faculté de Médecine, Université SaintJoseph, 42 rue de Grenelle, 75007 Paris, France. E-mail:
[email protected]
Received 12 May 1998; Accepted 23 November 1998
© 1999 Wiley-Liss, Inc.
mations. We postulate that these patients have a hitherto unreported autosomal-recessive malformation
This kindred (Fig. 1) resides in southern Lebanon
and belongs to the Shiite Muslim community.
Case 1
H.J. (VI-3, Fig. 1) is the last child of healthy consanguineous parents. When he was born, the father and
the mother were 28 years old. Gestation was unremarkable and there was no exposure to toxins or
known teratogens. The baby was delivered by cephalic
presentation at 40 weeks. Birth weight was 2,500 g
(3rd centile), and length was 50 cm (50th centile). Microphthalmia OD, flexion deformity of the right knee,
right foot equinovarus, and tetralogy of Fallot were
noted at birth. At age 3 years he developed seizures
that are well-controlled with medication.
We first examined him at age 5 years. He weighed
8.5 kg, and had a length of 81 cm and an occipitofrontal
circumference (OFC) of 46.2 cm (all below the 3rd centile). Psychomotor delay was evident and he was unable to walk, speak, or react normally to simple orders.
He had a poor appetite.
The child was hypotonic. He had microcephaly, right
microphthalmia, horizontal nystagmus, an oedematous
eyelid on the right side, wide flat nasal bridge, anteverted nostrils, long philtrum, a high-arched palate,
and retrognathia (Fig. 2a,b). Teeth were normally
erupted for age but there were two conical lateral incisors. Dermatoglyphic palm patterns were unremarkable. The right lower limb was shorter than the left.
Colobomatous Microphthalmia MCA/MR Syndrome
Fig. 1. Pedigree of present family. Solid squares indicate affected individuals with colobomatous microphthalmia. Stippled square indicates the
affected boy with cataracts, and shaded circle indicates the affected girl without ocular malformations.
There was an undescended right testicle. Ophthalmological evaluation documented a right microphthalmia,
nystagmus, an esotropia of 10 prism diopters without
limitation of motility, and posterior synechiae for 360°
OD, with an elliptical pupil. The fundus was not visualized. There was a coloboma OS that involved the optic disc and was 5 disc diameters large.
Computed tomography of the brain showed mild
cortical atrophy, and a small right globe and orbit.
Electroencephalography disclosed multiple independent epileptic foci. The radiological examination of
the skeleton demonstrated thin diaphyses, thinning of
the lateral third of the clavicles, thin ribs, tall vertebral bodies, brachymetacarpy, cone-shaped epiphyses
of the distal phalanges of the third and fourth fingers
of the left hand, and a general aspect of amyotrophy
(Fig. 3a,c). Abdominal ultrasound findings and auditory brain-stem responses were normal. Echocardiography disclosed tetralogy of Fallot. He had irondeficiency anemia, but results of hemoglobin electrophoresis, blood glucose levels, urinalysis, amino-acid
studies of plasma and urine, and liver and thyroid
function studies were unremarkable. Chromosomes
(high-resolution G- and R-banding) were normal
Ophthalmological findings of the parents and their
other children were normal. Their physical findings
were normal as well, except for the sister of the propositus (VI-2, Fig. 1). She had been born at term with a
weight of 2,900 g (25th centile) and a length of 50 cm
(45th centile). She had bilateral congenital hip luxation, bilateral talipes equinovalgus, and an intolerance
to lactose. At age 8 years her weight was 18 kg (3rd
centile), height was 110 cm (<3rd centile), and OFC
was 49.7 cm (5th centile). There were normally formed
but carrious teeth, most probably due to prolonged
bottle feeding. She had a high-arched palate, and was
severely mentally retarded (Fig. 4). Radiographs
showed thin diaphyses, thinning of the lateral third of
the clavicles, thin ribs, brachymetacarpy of the fourth
and fifth digits, brachyphalangy of the middle phalanx
of the fourth digit, and cone-shaped epiphyses of the
first metacarpal. An EEG showed epileptic foci and disorganized tracing.
Case 2
A.J. (VI-7, Fig. 1), a boy, is the last child of healthy
consanguineous parents. When he was born, the father
was 36 and the mother 25 years old. Pregnancy and
delivery were normal. Birth weight was 3,000 g (25th
centile), length 50 cm (25th centile), and OFC 33 cm
(10th centile).
Mégarbané et al.
Fig. 2. a: Facial appearance of H.J. at age 5 years. b: Profile of H.J. Note micrognathia.
At the time of examination, he was 40 days old.
Weight was 3,500 g (50th centile), length 52 cm (25th
centile), and OFC 34 cm (10th centile). He was hypotonic, and had a round face, 3 × 3 cm anterior fontanel,
anteverted nares, normally positioned ears, long philtrum, micrognathia (Fig. 5a,b), undescended right testicle, bilateral microphthalmia more pronounced on the
right side, an inferior coloboma of the iris, and choroid
OU. Both pupils reacted normally to light.
A magnetic resonance imaging examination of the
head was performed and did not show malformations of
the brain. Echocardiogram and abdominal ultrasound
findings were normal. Results of complete blood count,
blood glucose, urinalysis, amino-acid studies of plasma
and urine, liver and thyroid function studies, and
TORCH screen were all unremarkable. Chromosomes
(high-resolution G- and R-banding) were normal
At age 6 months, his length was 64 cm (3rd centile),
weight 5,300 g (<3rd centile), and OFC 39.2 cm (3rd
centile). All cranial sutures were closed. The radiological findings of the skeleton were unremarkable.
His parents had previously given birth to 2 boys, and
a girl. The eldest boy (VI-4, Fig. 1) died at age 7 years
for unclear reasons. He was profoundly retarded, hypotonic, and very thin, and had congenital cataracts.
The other children and both parents are normal.
The 2 cousins who form the subject of this report both
have microcephaly, colobomatous microphthalmia,
psychomotor retardation, short stature, and for one of
them, various osseous malformations. Some of these
findings are also seen in Lenz microphthalmia syndrome, recessive Waardenburg microphthalmia syndrome, and CHARGE syndrome.
Lenz syndrome is a rare X-linked recessive condition
first reported by Lenz [1955]. Our patients also have
microphthalmia, coloboma, microcephaly, congenital
cardiac defects, mental retardation, and short stature.
The presence of congenital cataracts in patient VI-4
(Fig. 1) may be fortuitous but may also be considered as
a manifestation of the same abnormal gene that causes
microphthalmia. The mentally retarded girl (VI-2, Fig.
1) has most of the abnormalities of her affected brother
except for the ophthalmological findings. She could be
considered a carrier of an X-linked syndrome. Carrier
Fig. 3. a: X-ray of H.J.’s left hand. Note thin diaphyses, cone-shaped
epiphyses, brachymetacarpy, and a general aspect of amyotrophy. b: X-ray
of H.J.’s thorax, showing the thinning of the lateral third of the clavicles
and of the ribs. c: X-ray of pelvis, showing subluxation of the hips, thin
diaphyses, and amyotrophy.
Mégarbané et al.
Fig. 4.
Sister of propositus at age 8 years.
females in Lenz microphthalmia syndrome may have
short stature, microcephaly, and mental retardation
[Hermann and Opitz, 1969; Krishnamurthy et al.,
1998]. The absence of these manifestations in the
mothers of our patients could be explained by the Lyon
hypothesis. Nevertheless, the lack of some major components of Lenz syndrome [Traboulsi et al., 1988]
such as dental, digital, and urogenital anomalies, in
addition to the severe mental retardation, distinct facial appearance, and osseous malformations of the patients reported herein, make a diagnosis of Lenz syndrome unlikely. Although the pedigree is compatible
with X-linked inheritance, the high degree of consanguinity suggests autosomal-recessive inheritance instead.
In 1935, Waardenburg described a syndrome of
anophthalmia with malformations of hands and feet,
mental retardation, and short stature [Waardenburg,
1961]. Since then, 11 families have been reported with
different patterns of malformations, which helps to
extend the wide range of expressivity of this rare
syndrome. The patients of the present report do not
have any of the digital anomalies of Waardenburg syndrome [Mégarbané et al., 1998]. Furthermore, no cardiovascular or visceral malformations have been reported in the recessive Waardenburg microphthalmia
CHARGE syndrome is characterized by coloboma of
the iris or choroid, heart defects, atresia of the choanae,
growth and developmental retardation, genitourinary
Fig. 5. a: Face of A.J. at age 40 days. Note right microphthalmia, anteverted nares, and long philtrum. b: Profile of A.J. Note micrognathia.
Colobomatous Microphthalmia MCA/MR Syndrome
malformations, and ear abnormalities. A diagnosis is
made in the presence of 4 of the 6 major criteria, one of
which should be either choanal atresia or a coloboma.
Although our patients fulfill some of these criteria, autosomal-recessive inheritance of the CHARGE syndrome has not been reported.
Another rare condition that could be considered
in the differential diagnosis is the X-linked recessive
syndrome of microcephaly, microphthalmia, corneal
opacities, spastic quadriplegia, hypospadias, cryptorchidism, agenesis of the corpus callosum, and hydrocephaly described by Siber [1984]. Seemanova and
Lesny [1996] described a boy and his sister’s son
with microcephaly, microphthalmia, congenital cataract, upslanting palpebral fissures, high-arched
palate, retrognathia, severe mental deficiency, growth
retardation, hypogenitalism, and spasticity. Warburg
et al. [1993] reported on 2 sibs and a cousin, from
an inbred Pakistani family, with microcephaly, microcornea, congenital cataracts, optic nerve atrophy,
small pupils bound by posterior synechiae, prominent ears, hypertrichosis, agenesis of the corpus callosum, severe mental retardation, and hypogenitalism. None of these syndromes fit the patients reported herein. Finally, Al Frayh and Haque [1987]
described a mentally retarded boy with anophthalmia/microphthalmia, coloboma of the iris, microcephaly, hypogonadism, cardiac malformation, and short
stature, but no osseous abnormalities or seizures
and with different facial abnormalities, helping us to
differentiate this syndrome from the one reported
Thus, our patients represent a new recessive syndrome with intrafamilial variability in expression of
the genetic defect that might be secondary to epigenetic
factors. On the other hand, it is also possible that this
inbred family possesses two genetic malformation syndromes, the sister of the proband showing one, and the
proband both of them, while the cousin of the proband
has only the syndrome of microcephaly, colobomatous
microphthalmia, psychomotor retardation, and short
We are indebted to Ms. Valérie Delague and Ms.
Nabiha Salem for their technical assistance.
Al Frayh AR, Haque KN. 1987. Anophthalmia, microcephaly, hypotonia,
hypogonadism, failure to thrive and developmental delay. Dysmorphol
Clin Genet 1:64–66.
Hermann J, Opitz JM. 1969. The Lenz microphthalmia syndrome. BD:OAS
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Mégarbané A, Souraty N, Tamraz J. 1998. Ophthalmo-acromelic syndrome
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