Pediatric and Developmental Pathology 1, 314–318, 1998

Pediatric and Developmental Pathology

r1998 Society for Pediatric Pathology

CASE REPORTS

Cleidocranial Dysplasia with Neonatal
Death Due to Central Nervous
System Injury in Utero: Case Report
and Literature Review
CALVIN E. OYER ,1* NINA G. TATEVOSYANTS,1 SELINA C. CORTEZ,2
ABBY HORNSTEIN,2 AND MICHAEL WALLACH3
1Department of Pathology, Brown University School of Medicine, Rhode Island Hospital, Women and Infants’

Hospital, 101 Dudley Street, Providence, RI 02905, USA
2Department of Pathology, Brown University School of Medicine, Rhode Island Hospital, 593 Eddy Street,

Providence, RI 02903, USA
3Department of Radiology, Brown University School of Medicine, Rhode Island Hospital, Women and Infants’

Hospital, 101 Dudley Street, Providence, RI 02905, USA
Received April 23, 1997; accepted July 24, 1997.

ABSTRACT
Cleidocranial dysplasia (CCD), an uncommon disorder
involving membranous bones, is rarely lethal in early life.
The calvaria is defective and wormian bones are present.
Abnormalities of the clavicles vary in severity from a
minor unilateral defect to bilateral absence. This report
concerns pre- and postmortem anatomical and radiological findings in a 15-day-old female neonate with CCD.
Her postnatal course was characterized by seizures and
recognition of hydrocephalus during the first day of life.
The calvaria was hypoplastic with numerous wormian
bones. A pseudofracture of the right clavicle was present.
Hydrocephalus was present in the brachycephalic brain
which had a severely thinned cerebral cortex. Hemosiderin in the ventricular lining and marked subependymal
gliosis were interpreted as evidence of old intraventricular hemorrhage that had occurred in utero. A CCDrelated condition, Yunis-Varon syndrome (YVS), is noted
for early lethality and for developmental and secondary
abnormalities of the central nervous system. The present
*Corresponding author, at 17 Emeline Street, Providence, RI 02906, USA

case only partially matches the phenotype of YVS and
might represent a part of a spectrum of phenotypic
variants ranging from viable CCD to lethal YVS.
Key words: cleidocranial dysplasia, wormian bones,
neonate, hydrocephalus, pseudofracture of clavicle

INTRODUCTION
Cleidocranial dysplasia (CCD), also known as MarieSainton disease and formerly called cleidocranial
dysostosis, is an uncommon disorder of the skeleton with prominent abnormalities of membranous bones, especially the skull and clavicles. Early
lethality is rare. We report a neonate with death at
15 days secondary to in utero insults to the central
nervous system.

CASE REPORT
This female neonate, who died at 15 days of age,
had been delivered vaginally at 37 weeks of gesta-

tion by a 29-year-old mother who had undergone
treatment for Hodgkin’s disease 3 years previously.
The prenatal course of this pregnancy was uneventful. Maternal glucose tolerance was normal. AFP
screening was refused. The 1980 gram infant had
Apgar scores of 2 and 3 at 1 and 5 min, respectively,
and required intubation. Dysmorphic features were
noted. X-rays revealed abnormal skull and right
clavicle and 11 ribs bilaterally. The course was
complicated by hypoglycemia, diuresis with hyponatremia, intraventricular hemorrhages, and
thrombocytopenia. Seizures began shortly after
birth. An electroencephalogram showed lateralized
discharges from the right occipital region. Ultrasound examinations performed on day 1 of life
revealed moderate hydrocephalus and dilatation of
the renal collecting systems. The latter abnormality
was thought secondary to clinically evident diabetes insipidus. A cranial CT scan on day 4 showed
moderate dilatation of the lateral ventricles, greater
in the left lateral ventricular body and temporal
horn. The third ventricle was mildly dilated. Though
the presence of blood was not documented on the
study, hydrocephalus was considered to be secondary to previous intraventricular hemorrhage. An
MRI on day 8 confirmed these findings and revealed brachycephaly and a thin corpus callosum.
Karyotype determined from lymphocytes was
46,XX.

PATHOLOGIC FINDINGS
Postmortem examination revealed the following
measurements: head circumference 28.1 cm,
crown–rump length 31.5 cm, crown–heel length
40.8 cm, foot length 6.25 cm, and chest circumference 28.2 cm. The body weighed 2164 grams.
Dysmorphic craniofacial features included a small,
round skull with thin, flexible bone. The fontanelles
were confluent and large with the space partially
occupied by wormian bones forming a mosaic
pattern. Micrognathia, narrow palpebral fissures,
and a wide nose with anteverted nostrils were
present (Fig. 1). Arthrogryposis in the distal upper
extremities and bilateral talipes equinovarus were
noted. X-rays revealed a pseudofracture in the
midportion of the right clavicle and confirmed
wormian bones in the skull (Fig. 2a,b). Lateral view
of the skull allowed only poor visualization of the

Figure 1. Dysmorphic features included a small, round
skull, micrognathia, and anteverted nostrils.

clivus due to superimposition of the dense petrous
portion of the temporal bone.
There were a few pleural petechiae. Mild
hydronephrosis was noted on the right. The bladder and ureters were dilated but free of obstruction. As the calvaria was removed in a circular
manner, the thin cerebral cortex was lacerated and
a large amount of serosanguinous cerebrospinal
fluid escaped under pressure. The brain was brachycephalic. After fluid removal, it weighed only 160
grams (reference weights 337 6 91). The cerebral
cortex was markedly thin, especially in the posterior parietal, temporal, and occipital regions. The
white matter was extensively attenuated. The deep
gray structures, including basal ganglia, thalami,
and hippocampi were not identifiable. All ventricular chambers were markedly dilated. The ventricular lining was thick and brown with small focal
collections of blood. The brainstem and cerebellum
were well formed. However, the basis pontis was
slightly flattened and the pyramids were symmetriCCD WITH NEONATAL DEATH

315

Figure 3. Photomicrograph of midportion of right
clavicle. The abnormal lateral portion is on the left; the
relatively normal medial portion is on the right. The two
portions are separated by intervening fibrovascular connection (1). Objective magnification 32.

Figure 2. a: X-ray showing pseudofracture of right
clavicle. b: X-ray of removed upper portion of skull with
anterior portion to the left in the photograph. Note
wormian bones (w).

cally small. A small, recent parenchymal hemorrhage was noted in the left lobe of the cerebellum.
Microscopically, the right clavicle consisted of
two disconnected portions of tubular bone. The
space between the two portions of bone contained
an abnormal area of fibrovascular connective tissue. The portion nearest the sternum was essentially normal. The lateral portion had a disorganized surface, simulating a growth plate, with
zones of proliferation, calcification, and endochondral ossification arranged in a haphazard fashion.
The cartilage, however, was hypertrophied and
disorganized with haphazardly arranged foci undergoing enchondral ossification (Fig. 3). The process
was interpreted as dysplastic rather than representative of a healing fracture. The bone of the calvaria
was histologically undergoing normal membra316

C.E. OYER ET AL.

Figure 4. Photomicrograph of lining of lateral ventricle. Surface epithelium is absent. The subependyma
shows ependymal rosettes and gliosis. Objective magnification 320.

nous ossification. The abnormality was quantitative with increased amounts of fibrous tissue connecting the islands of membrane bone.
The cerebral cortex showed normal laminar
architecture but with extensive hypoxic/ischemic
damage consisting of pericellular vacuolation,
nuclear pyknosis, and gliosis. The white matter was
attenuated with extensive fibrillary astrocytosis
confirmed by immunostaining for glial fibrillary
acidic protein. The ventricular lining was multifocally disrupted and in many subependymal locations gliosis and occasional ependymal rosettes
were present (Fig. 4). Hemosiderin was noted and
confirmed by stain for iron (Prussian blue). Small
periventricular cysts were seen in the frontal region. Hypoxic/ischemic changes were present in
the basal ganglia, brainstem (including cranial

nerve nuclei), and cerebellum. The pyramidal tracts
were atrophic, most likely secondary to extensive
white matter destruction. The spinal cord, including the anterior horn cells at all levels, showed mild
to moderate hypoxic/ischemic changes with no
neuronal loss as compared with two age-matched
controls. No microglial nodules or inflammatory
infiltrates were seen. The small recent hemorrhage
in the cerebellum was confirmed. These neuropathological findings were consistent with severe
hydrocephalus secondary to old hemorrhage, severe telencephalic leukoencephalopathy, diffuse hypoxic/ischemic changes, and recent focal hemorrhages. With no evidence of developmental
malformation, all abnormalities were thought to
have been acquired secondary to insult(s) beginning in utero, an interpretation supported by the
clinical recognition of hydrocephalus on the first
day of life.

DISCUSSION AND REVIEW
Clinical, radiological, and pathological findings in
this neonate are consistent with cleidocranial dysplasia (CCD), a condition with abnormal development of membranous bones. Membranous bones
are formed via a collagen model and include the
neurocranium, a portion of the clavicles, and some
facial bones including the mandible. In CCD, first
described in the late 19th century [1], the calvaria
shows generalized failure of midline ossification.
Wormian bones are present. A term newborn with
CCD has a skull comparable to that of a normal
fetus in the midtrimester [2]. The condition is
usually associated with viability. The skull undergoes gradual postnatal mineralization but some
defects persist for at least the first 7 years [2].
Non-union of the mandibular symphysis and nasal
bone deficiencies can be seen [3]. Abnormal clavicular development is a major feature and can range
from complete absence of both clavicles to a small
unilateral defect [4]. Usually the middle third is
affected, suggesting that the disorder begins before
the two ossification centers unite [5]. Though skeletal abnormalities are usually most evident in
membranous bones, enchondral bone formation
can also be involved with abnormalities of the
digits [6] and clivus [7]. The observation that CCD
is not a simple malformation syndrome has resulted in the change in designation from a dysosto-

sis to a dysplasia [6]. A mouse model with mutation
320, induced by radiation, has been shown to have
skeletal abnormalities very similar to those of
CCD [6].
Cases of CCD can occur sporadically but
many are inherited, with at least some families
exhibiting an autosomal inheritance pattern [8]. An
autosomal dominant pattern has also been noted
with one-third being new mutations [9]. Linkage
studies in families with CCD have mapped the gene
for autosomal dominant CCD to the short arm of
chromosome 6 [10]. Rearrangement involving chromosome 8 has been described in three unrelated
cases, all of whom had additional abnormalities
not usually associated with CCD [11]. Our patient
had a normal female karyotype with no evidence of
that chromosomal abnormality.
Wormian bones are small, irregular bones
that are found most often in the region of the
lambdoidal sutures. They may be normal variants
and are determined genetically in certain populations [12]. They are associated with many congenital abnormalities and syndromes, the four most
prominent of which are CCD, osteogenesis imperfecta, congenital hypothyroidism, and hypophosphatasia [13]. In view of the clavicular involvement
in the present case, the latter three diagnoses were
not seriously considered. One study found that 90%
of children with wormian bones had disorders of
the central nervous system (CNS), suggesting that
wormian bones are markers for CNS abnormalities
[14]. CNS problems noted in patients with wormian bones include hydrocephalus, microcephaly,
macrocephaly, craniostenosis, cerebral palsy, mental retardation (MR), and convulsive disorders [14].
Though most patients with CCD have normal
intelligence and a good prognosis, malformations
and/or malfunctions of the CNS have been described. These include hypertonia, MR, hydrocephalus, ‘‘atrophy’’ of the rostral end of the corpus callosum and cingulate gyrus, and syringomyelia [4,15].
Most reported cases are those of adults or
children. Descriptions of neonatal cases, particularly lethal ones, are rare and fetal cases have not
been reported [2,11,16]. In spite of the severely
abnormal skulls, there have been only rare reports
of cerebral injury related to birth, including rupture of the superior sagittal sinus [17]. In our case,
CCD WITH NEONATAL DEATH

317

we assign the mechanism of death to severe in
utero central nervous system injury secondary to
hemorrhage and hypoxia/ischemia. We base this
conclusion on the absence of developmental CNS
abnormalities, the clinical findings already present
at birth, and the pathological findings indicative of
a prolonged process. We can only speculate that the
skull abnormality contributed to vulnerability to
this catastrophic event or events.
One CCD-related condition, the Yunis-Varon
syndrome (YVS), is associated with neurologic
findings similar to those in our case. In this condition there can be agenesis of the corpus callosum
with dilatation of the occipital horns of the lateral
ventricles, hematomas, and/or changes resulting
from hypoxia with neuronal loss involving the
cerebral cortex, basal ganglia, cerebellar dentate
nuclei, medullary olives, and the anterior horns
[18]. Patients with YVS additionally display severe
micrognathia and abnormalities of the distal extremities [18,19]. Our case does not adequately
match the phenotype of YVS. Whether the phenotypic differences of CCD and YVS are related to an
identical or to related genetic defects awaits future
clarification. Yunis and Varon [20] described a
recessively inherited disorder with features not
seen in CCD, emphasized specific hand anomalies,
and considered the disorder to be an entity separate from CCD. The possibility that this case represents a portion of a spectrum of phenotypic variation ranging from CCD to YVS cannot be excluded
at this time.

3.
4.

5.

6.

7.

8.

9.

10.

11.

12.
13.

14.
15.

16.
17.
18.

R EFERENCES
1. Barlow. Congenital absence of both clavicles and malformation of cranium. Br Med J 1883;I:909. Cited by Fitchet SM.
Cleidocranial dysostosis: hereditary and familial. J Bone
Surg 1929;11:838–866.
2. Jensen BL, Kreiborg S. Development of the skull in infants
with cleidocranial dysplasia. J Craniofac Dev Biol 1993;13:
89–97.

318

C.E. OYER ET AL.

19.

20.

Jensen BL. Somatic development in cleidocranial dysplasia. Am J Med Genet 1990;35:69–74.
Staffeldt ES. On dysostosis cleido-cranialis with other
malformations: a short account of the nature of the disease, and a report of a case. Acta Med Scand 1955;151:329–
331.
Ogden JA, Conlogue GJ, Bronson ML. Radiology of postnatal skeletal development. III. The clavicle. Skel Radiol
1979;4:196–203.
Sillence DO, Ritchie HE, Selby PB. Animal model: skeletal
anomalies in mice with cleidocranial dysplasia. Am J Med
Genet 1987;27:75–85.
Kreiborg S, Jensen BL, Bjork A, Skieller V. Abnormalities
of the cranial base in cleidocranial dysplasia. Am J Orthod
1981;79:549–557.
Goodman RM, Tadmor R, Zaritsky A, Becker SA. Evidence
for an autosomal recessive form of cleidocranial dysostosis. Clin Genet 1975;8:20–29.
Myers TL. Cleidocranial dysplasia. In: Buyse ML, ed. Birth
Defects Encyclopedia. Dover, MA: Center for Birth Defects
Information Services, Inc, 1990;417.
Feldman GJ, Robin NH, Brueton, et al. A gene for cleidocranial dysplasia maps to the short arm of chromosome 6. Am
J Med Genet 1995;56:938–943.
Brueton LA, Reeve A, Ellis R, Husband P, Thompson EM,
Kingston HM. Apparent cleidocranial dysplasia associated
with abnormalities of 8q22 in three individuals. Am J Med
Genet 1992;43:612–618.
Bennett KA. The etiology and genetics of wormian bones.
Am J Phys Anthropol 1965;23:255–260.
Kaplan SB, Kemp SS, Oh KS. Radiographic manifestations of congenital anomalies of the skull. Radiol Clin
North Am 1991;29:195–218.
Pryles CV, Khan AJ. Wormian bones: a marker of CNS
abnormality? Am J Dis Child 1979;133:380–382.
Hall BD. Syndromes and situations associated with congenital clavicular hypoplasia or agenesis. Prog Clin Biol
Res 1982;104:279–288.
Fitchet SM. Cleidocranial dysostosis: hereditary and familial. J Bone Surg 1929;11:838–866.
Caffey J. Pediatric X-ray Diagnosis. London: Lloyd-Luke,
Ltd, 1973;53–54.
Garrett C, Berry AC, Simpson RH, Hall CM. Yunis-Varon
syndrome with severe osteodysplasty. J Med Genet 1990;27:
114–121.
Partington MW. Yunis-Varon syndrome. In: Buyse ML, ed.
Birth Defects Encyclopedia. Dover, MA: Center for Birth
Defects Information Services, Inc, 1990;1806.
Yunis E, Varon H. Cleidocranial dysostosis, severe micrognathism, bilateral absence of thumbs and first metatarsal
bone, and distal aphalangia: a new genetic syndrome. Am J
Dis Child 1980;134:651–653.