American Journal of Medical Genetics 73:144–149 (1997)
Severe Brain and Limb Defects With Possible
Autosomal Recessive Inheritance: A Series of Six
Cases and Review of the Literature
Philippe Labrune,1* Pascale Trioche,1 Catherine Fallet-Bianco,2 Joëlle Roume,3 Françoise Narcy,4
and Martine Le Merrer5
1
Service de Pédiatrie, Hôpital Antoine Béclère, Clamart, France
2
Laboratoire d’Anatomie Pathologique, Hôpital Robert Debré, Paris, France
3
Laboratoire de Foetopathologie, Hôpital Saint Antoine, Paris, France
4
Laboratoire d’Anatomie Pathologique, Hôpital Cochin, Paris, France
5
Service de Génétique Médicale, Hôpital des Enfants Malades, Paris, France
Six fetuses with normal chromosomes were
found to have severe craniofacial, limb, and
visceral malformations during the second
trimester of pregnancy. Two of these fetuses
were monozygotic twins while a third one
had a healthy dizygotic twin brother. A case
with familial recurrence was also observed.
Autopsy and skeletal radiographs suggested
several diagnoses such as neural tube defect
with limb defects or XK aprosencephaly.The
development of these severe conditions in
monozygotic twins and familial recurrence
emphasize the difficulties of genetic coun-
seling in such situations. These cases may
suggest autosomal recessive inheritance.
Am. J. Med. Genet. 73:144–149, 1997.
© 1997 Wiley-Liss, Inc.
KEY WORDS: neural tube defect; XK apros-
encephaly; limb defect; auto-
somal recessive
INTRODUCTION
Several syndromes have been reported which include
severe brain defects and upper limb abnormalities. In a
review of 141 cases with anencephaly, Rodriguez et al.
[1992] found 8 cases with limb defects. Amelia may also
be associated with holoprosencephaly [Cohen, 1989],
hydrocephaly, and agenesis of the corpus callosum
[Dobyns, 1985]. In connection with this, Garcia and
Duncan [1977] reported on an infant with atelence-
phalic microcephaly, hypoplastic thumbs, and abnor-
mal genitalia. Two years later, Lurie et al. [1979] pub-
*Correspondence to: P. Labrune, M.D., Ph.D., Service de Pédia-
trie, Hôpital Antoine Béclère, BP 405, 92141 Clamart Cedex,
France.
Received 27 May 1996; Accepted 5 June 1997
© 1997 Wiley-Liss, Inc.
lished a similar case and proposed to call this condition
the XK aprosencephaly syndrome. All these reports but
one concerned sporadic cases [Adkins and Kaveggia,
1979]; however, Townes et al. [1988] reported the co-
existence of anencephaly and aprosencephaly within a
sibship, thus suggesting that XK aprosencephaly
might be an autosomal recessive condition. We report
on 6 fetuses with an association of severe brain mal-
formations and limb defects, including 3 in twins (2
monozygotic and 1 of 2 dizygotic fetuses) and 2 in sibs.
CLINICAL REPORTS
Case 1
These female monozygotic twins were the product of
the first pregnancy of a healthy young woman. The
parents were not consanguineous. At 21 weeks, ultra-
sonography showed one fetus to be dead (fetus B),
whereas severe hydrocephalus and absent thumbs
were suspected in the other (fetus A). Fetal chromo-
somes were normal, 46,XX. Pregnancy was terminated
a few days later.
The placenta was normal for gestation. Fetus A
weighed 300 g, head circumference was 18 cm, and
there were severe craniofacial malformations. Both up-
per and lower eyelids were fused and no ocular globes
were palpable (Fig. 1a). Sloping forehead with bilateral
prominences and hypertelorism were also noted. The
mouth was small with a normal lower lip, whereas the
upper lip was not recognizable. The superior maxillary
was absent and no nasal structure was detectable.
Physical examination also showed bilateral club hands
with absence of thumbs. Both legs ended with a single
long toe with no recognizable feet; a left lower limb
pterygium was also present (Fig. 1a). The anus was
normal but the genitalia only included a blind vagina
without labia. Skeletal roentgenograms showed 11
pairs of ribs, vertebral anomalies, confirmed limb
anomalies, and showed the absence of ossification of
the cranial vault (Fig. 1b). Autopsy findings included a
normal heart, lungs, liver, and ovaries. The whole cra-
nial content weighed 54 g. Both olfactory nerves were

Fig. 1. Case 1. a: Anterior view showing craniofacial malformations, abnormal upper and lower limbs. b: Skeletal roentgenograms: note the absence
of ossification of the cranial vault.
absent and the optic chiasma was small. The corpus
callosum and the cerebellar vermis were also absent.
The lateral ventricles were enlarged, whereas the third
and fourth ventricles were of normal size. Histological
structure of cerebral and cerebellar tissues was nor-
mal. Light microscopy examination of frontal promi-
nences showed a respiratory-like epithelium with sero-
mucous glandular structures.
Fetus B weighed 30 g and was hardly examinable.
However, craniofacial malformations were similar to
those of fetus A. Nuchal hygroma was also noted. Both
forearms were hypoplastic and both hands were radi-
ally deviated with only 3 fingers. Both feet were in
equinism with only 4 toes on the right one. No anus
was recognizable and the genitalia included a vaginal
opening and a small genital tubercle. Autopsy findings
did not show visceral malformations. Histological ex-
amination was not possible due to autolysis.
Case 2
These dizygotic twins were the product of the first
pregnancy (in vitro fertilization) of a 33-year-old
healthy woman. The parents were not consanguineous.
At 15 weeks of amenorrhea, fetal ultrasound examina-
tion showed anencephaly, dilated bladder, and oligohy-
dramnios in fetus A, whereas fetus B was normal. At
37.5 weeks, both babies were delivered vaginally. Both
placentas were normal for gestation. Baby B weighed
3,280 g and was clinically normal. Baby A was still-
born, weighing 1,800 g. Physical examination showed
Brain and Limb Defects 145
severe and complex craniofacial malformations similar
to those of aprosopia in early embryos (Fig. 2a). The
lower jaw was markedly abnormal with hypertrophic
gums and a small median lingual bud. There was no
recognizable upper jaw, so that the mouth was replaced
by a stomodeal cavity. The eyes, nose, and ears were
not recognizable. The right hand had only 4 fingers,
with no thumb. Both lower limbs showed irreducible
flexion; both feet were in equinism with malformations
of toes. The penis was small and neither testis was
palpable. Skeletal roentgenograms showed right radial
aplasia with no thumb, left radiocubital synostosis, 11
pairs of ribs, and vertebral anomalies. There was no
ossification of the cranial vault (Fig. 2b). Autopsy find-
ings showed atresia of the esophagus (type IV), com-
plex cardiopathy including transposition of the great
vessels, abnormal pulmonary venous return into the
coronary sinus, interventricular septal defect, and pul-
monary stenosis. No adrenals were found. The skull
contained only lysed cerebral tissue. Light microscopy
examination of this tissue showed that it probably cor-
responded to a voluminous single ventricle bordered by
ependymal cells. Choroid plexi were surrounded by
glial tissue containing numerous calcifications. The
spinal cord was normal.
Case 3
At 19 weeks of amenorrhea, the first pregnancy of a
25-year-old woman was terminated after the discovery
of microcephaly and right kidney agenesis on ultraso-
146 Labrune et al.
Fig. 2. Case 2. a: Anterior view showing craniofacial malformations, club feet, abnormal genitalia, and abnormal right hand. b: Skeletal roentgeno-
grams illustrating the absence of right thumb and the absence of ossification of the cranial vault.
nography. Fetal chromosomes were normal, 46,XY.
Physical examination showed extreme microcephaly
(<1st centile) with ethmocephaly, agenesis of the left
thumb and hypoplasia of the right thumb. Autopsy
findings included right kidney agenesis and bilateral
adrenal gland hypoplasia. Neuropathologic examina-
tion showed that the central nervous system resembled
the primitive neural tube with only a few cerebellar
lamellar-like structures within the rhombic labia.
Case 4
At 23.5 weeks of amenorrhea, the first pregnancy of
this 28-year-old woman was terminated after fetal ul-
trasonography had shown a voluminous frontal menin-
goencephalocele associated with cleft lip and palate
and bilateral ectrodactyly. Fetal chromosomes were
normal, 46,XY. The fetus weighed 511 g and physical
examination showed a voluminous frontal encephalo-
cele. Both eyelids were fused and no ocular globes were
palpable (Fig. 3a). The nose was markedly hypoplastic
associated with a large cleft lip and palate reaching the
nostril, and bilateral ectrodactyly was noted. Skeletal
roentgenograms confirmed ectrodactyly, showed 11
pairs of ribs, and the absence of ossification of the cra-
nial vault except in the occipital part (Fig. 3b). Autopsy
findings demonstrated a large atrial septal defect;
there were no other visceral malformations. Both olfac-
tory nerves were absent while both optic nerves were
very small. The encephalocele contained markedly dys-
plastic cerebral tissue, and scattered microfoci of calci-
fications were present.
Four years later, the mother, whose second child was
normal, was seen at 16 weeks of amenorrhea. Fetal
ultrasound examination showed the absence of both
upper limbs and severe craniofacial malformations,
suggestive of exencephaly. Fetal chromosomes were
normal, 46,XX; the pregnancy was terminated. The fe-
tus weighed 46 g and physical examination showed ab-
sence of upper limbs and anencephaly (Fig. 4a). Skel-
etal roentgenograms confirmed bilateral amelia with
only the presence of scapulae and clavicles, and showed
11 pairs of ribs (Fig. 4b). Autopsy showed adrenal hy-
poplasia but no other visceral malformations.
DISCUSSION
We report on 6 fetuses in whom ultrasound exami-
nation showed severe craniofacial, limb and, in all
cases but one visceral malformations. However, even if
these cases share several clinical findings, they might
still represent different syndromes.
Case 1A and 1B had the same syndrome. The ab-
sence of the upper lip, superior maxillary, and nose,
combined with a failure in the closure of that area,
could be considered a neural tube defect. On the other
hand, it might also be considered as a forme fruste of
XK aprosencephaly [Garcia and Duncan, 1977; Lurie et
al., 1979]. Case 2 had an absence of face and head,
including the skull and seems to be a neural tube de-
fect; the cranial abnormalities of this fetus are similar
to the manifestations of aprosopia in early embryos.
Case 3 seems to be a ‘‘standard’’ XK aprosencephaly.
Finally, case 4 is an association of early neural tube
defect with limb underdevelopment in sibs; it may be a
new entity or it may represent a familial variant of
previously reported conditions [Rodriguez et al., 1992;
Zimmer et al., 1985].
Several syndromes include early brain defects and

Fig. 3. Case 4 (first familial case). a: Anterior view showing bilateral ectrodactyly, frontal meningoencephalocele, and the absence of ocular globes.
b: Skeletal roentgengrams: note the near-total absence of ossification of the cranial vault.
abnormalities of radial structures. Steinfeld [1982] de-
scribed a female infant with holoprosencephaly, short-
ness of radii, and absent thumbs; an autosomal domi-
nant syndrome was postulated in this report. In con-
nection with this, limb underdevelopment is known to
occur in association with several severe brain malfor-
mations such as hydrocephaly with fusion of the cere-
bral hemispheres [Yim and Ebbin, 1982], holoprosen-
cephaly [Thomas and Donnai, 1994], arhinencephaly,
and agenesis of the corpus callosum [Zimmer et al.,
1985]. Furthermore, Rodriguez et al. [1992] reported
on 8 patients with limb defects and anencephaly, and
Norman and Donnai [1992] described the association of
hydranencephaly and hypoplastic thumbs.
Since the first description of XK aprosencephaly, this
syndrome has been reported rarely [Garcia and Dun-
can, 1977; Lurie et al., 1979, 1980; Martin and Carey,
1982; Towfighi et al., 1987; Kim et al., 1990; Goldsmith
et al., 1993]. Bearing in mind the patients reported so
far, craniofacial malformations, abnormal genitalia,
and limb abnormalities appear to be hallmarks of the
XK aprosencephaly syndrome. In all cases, there is ex-
treme microcephaly. The face is similar to that of a
severe form of holoprosencephaly; the ocular globes are
abnormal or absent and cyclopia may be encountered;
in connection with this, there is profound nasal hypo-
plasia [Hunter, 1993; Ivanainen et al., 1977; Siebert et
al., 1987; Shewmon et al., 1984]. Abnormal genitalia
are an almost constant finding. In males, it may range
from undescended testes to hypospadias or hypoplastic
penis. In females, the recognition of genital abnormali-
ties may be more difficult. Abnormalities of the upper
Brain and Limb Defects 147
limbs may range from hypoplastic thumbs to absent
radial ray; they have been found in all but 2 reported
cases [Garcia and Duncan, 1977; Lurie et al., 1979,
1980; Martin and Carey, 1982; Towfighi et al., 1987;
Kim et al., 1990; Goldsmith et al., 1993; Harris et al.,
1994]. Congenital heart disease and anorectal malfor-
mations are less constant, even though they may be
part of this syndrome. Adrenal hypoplasia or dysplasia
[Harris et al., 1994] has also been reported.
The origin of such syndromes is still unknown [Dan-
ner et al., 1985]. Embryologically, case 2 seems to be
the earliest form; case 3 and case 1 are likely to be due
to latest events during embryogenesis. Case 4 is likely
to be another syndrome. Recently, Florell et al. [1996]
have postulated that a defect in a gene important in
brain development was at the origin of aprosencephaly
in sibs born to consanguineous parents. They have
looked for mutations in the OTX2 gene (a homeodo-
main-containing gene expressed in the prosencepha-
lon), but no sequence variations were found. However,
mutation of both OTX2 alleles in the mouse results in
the loss of the forebrain and midbrain [Acampora et al.,
1995]. In connection with this, the identification of mu-
tations in the human Sonic Hedgehog in holoprosen-
cephaly may shed some light on the origin of severe
brain defects, irrespective of their association with
limb defects [Roessler et al., 1996]. As for the origin of
XK aprosencephaly, it is still unknown. Several reports
have speculated that XK aprosencephaly is due to a
destructive process [Siebert et al., 1986; Towfighi et al.,
1987; Kim et al., 1990; Harris et al., 1994]. Further-
more, Garcia and Duncan [1977], then Kim et al. [1990]
148 Labrune et al.
Fig. 4. Case 4 (familial recurrence). a: Anterior view showing the absence of both upper limbs and anencephaly. b: Skeletal roentgengrams confirming
bilateral amelia and the absence of ossification of the cranial vault.
have provided evidence for a vasculopathy since they
described calcifications. However, it is not clear wheth-
er a primary vasculopathy occurs in XK aprosen-
cephaly or whether an encephaloclastic process, infec-
tion, or vasculopathy causes destruction of the brain in
addition to the vascular change [Harris et al., 1994].
Finally, Brown et al. [1993] first suggested that the
13q32 region was involved in malformations including
brain, eyes, and thumbs; recently, they confirmed that
band 13q32 is a critical deletion region [Brown et al.,
1995]. In connection with this, Towfighi et al. [1987]
reported a case of XK aprosencephaly with del(13q),
then Goldsmith et al. [1993] a similar case with a mo-
saic ring 13 karyotype; Goldsmith et al. [1994] sug-
gested that cytogenetic cases could represent the dele-
tion of contiguous genes and that the syndromic cases
could represent submicroscopic deletions of the same
region, even though a mutation of a dominant gene was
also possible, as previously suggested [Benke, 1989].
These findings would justify careful cytogenetic studies
in patients with XK aprosencephaly. The use of mo-
lecular probes for the region 13q32 would be of great
interest [Harris et al., 1994]. Finally, the description of
aprosencephaly in 2 sibs whose parents were first cous-
ins would rather suggest a genetic origin [Florell et al.,
1996].
Genetic counseling is difficult in such situations.
There has been a report of a patient with the XK apros-
encephaly syndrome in a family where 2 sibs had neu-
ral tube defects [Townes et al., 1988]. A case of XK
aprosencephaly with severe defects of the lower limbs
was found in a fetus from a twin-pair [Young et al.,
1986]. Along the same line, 2 fetuses conceived from a
consanguineous couple had aprosencephaly and cer-
ebellar dysgenesis [Florell et al., 1996]. Thus, it ap-
pears that in such cases (as in case 4), autosomal re-
cessive inheritance may be postulated, thus leading to
careful genetic counseling.
ACKNOWLEDGMENTS
We thank Alan Strickland for his help in the prepa-
ration of the manuscript.
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