American Journal of Medical Genetics 139A:212 –215 (2005)

Clinical Report
Majewski Osteodysplastic Primordial
Dwarfism Type II (MOPD II) Complicated by Stroke:
Clinical Report and Review of Cerebral Vascular Anomalies
Francesco Brancati,1,2,3 Marco Castori,2,3 Rita Mingarelli,3 and Bruno Dallapiccola2,3*
1

Department of Biological Sciences, University ‘‘G. D’Annunzio’’, Chieti, Italy
Department of Experimental Medicine and Pathology, University ‘‘La Sapienza’’, Rome, Italy
3
CSS Hospital, IRCCS, San Giovanni Rotondo and CSS Mendel Institute, Rome, Italy
2

We report on a 2 9/12-year-old boy with disproportionate short stature, microcephaly, subtle craniofacial dysmorphisms, and generalized skeletal
dysplasia, who developed a left hemiparesis.
Brain neuroimaging disclosed a complex cerebral
vascular anomaly (CVA) with stenosis of the right
anterior cerebral artery and telangiectatic collateral vessels supplying the cerebral cortex, consistent with moyamoya disease. Based on clinical
and skeletal features, a diagnosis of Majewski
osteodysplastic primordial dwarfism type II
(MOPD II) was established. Review of 16 published patients with CVA affected by either Seckel
syndrome or MOPD II suggested that CVA is
preferentially associated to the latter subtype
affecting about 1/4 of the patients.
ß 2005 Wiley-Liss, Inc.

KEY WORDS: MPD; MOPD; Seckel; cerebral;
vascular; stroke

skin pigmentation, and obesity may also be observed together
with cerebral vascular anomalies (CVA) [Hall et al., 2004].
CVA are life threatening complications reported in patients
diagnosed with either MOPD II or, rarely, Seckel syndrome.
Observed vascular changes include moyamoya disease, tortuous vessels, multiple intracranial aneurysms, and polyarteritis nodosa (PAN) with irregular narrowing of cerebral arteries
[D’Angelo et al., 1998; Sorof et al., 1999; Di Bartolomeo et al.,
2003; Nishimura et al., 2003; Hall et al., 2004; Kannu et al.,
2004; Kutlu et al., 2004; Young et al., 2004]. The natural
history and pathogenesis of such complications are still unclear, although a systemic vascular disease affecting both
intracranial and extracranial arteries could be the underlying
mechanism, as reported in otherwise healthy children with
moyamoya disease [Aoyagi et al., 1996]. The importance of a
timely diagnosis and management of CVA in MOPD II patients
has been recently emphasized as they can be a major cause of
stroke and early death [Hall et al., 2004].
Here, we describe a novel MOPD II boy affected by moyamoya
disease complicated by stroke. Review of published MPD
patients with CVA, outlined a rather wide spectrum of anomalies and suggested a distinct association with a MPD subtype.

INTRODUCTION
Microcephalic primordial dwarfisms (MPDs) are autosomal
recessive disorders characterized by pre- and post-natal
growth retardation, microcephaly, and distinct facial gestalt
with prominent beaked nose, receding forehead, and micrognathia [Majewski and Goecke, 1982; Majewski et al.,
1982a,b]. MPDs comprise (1) Seckel syndrome, with no signs
of skeletal dysplasia, and (2) Majewski (also termed microcephalic) osteodysplastic primordial dwarfisms (MOPDs),
which are constitutional bone disorders [Hall, 2002; Hall
et al., 2004]. Three types of MOPDs (I–III) have been
delineated both on clinical and skeletal features. Type II
MOPD is the most common type with more than 60 patients
reported so far [Hall et al., 2004; Kannu et al., 2004; Young
et al., 2004; Ozawa et al., 2005]. Characteristic features of
MOPD II are peculiar growth pattern with very severe IUGR
and adult height below 110 cm, neonatal proportioned head
size later progressing to microcephaly, absent or mild mental
retardation, and typical bone dysplasia. Abnormal dentition,

Grant sponsor: Italian Ministry of Health.
*Correspondence to: Bruno Dallapiccola, University of Rome
‘‘La Sapienza’’, C.S.S. Mendel Institute, Viale Regina Margherita,
261, I-00198 Rome, Italy. E-mail: dallapiccola@css-mendel.it
Received 19 May 2005; Accepted 31 August 2005
DOI 10.1002/ajmg.a.31009

ß 2005 Wiley-Liss, Inc.

CLINICAL REPORT
9

This is a 2 /12-year-old boy, first child of healthy, nonconsanguineous parents. The mother was a 29-year-old and
the father 33. Pregnancy was complicated by intrauterine
growth retardation, first noticed at 17 weeks. Prenatal infections were tested negative and no teratogenic exposure was
reported. The baby was born by caesarean in the 31st
gestational week because of poor growth with weight 752 g,
length 32 cm, and OFC 23.5 cm (all below the 3rd centile). At
birth, growth retardation was symmetrical and cutis marmorata observed over the trunk and limbs. Cranial fontanelles
were closed. Reported dysmorphisms included prominent nose,
small mouth, micrognathia and bilateral simian crease.
Persistent ductus arteriosus resolved spontaneously. Bilateral
cryptorchidism was also present.
Skeletal X-rays, performed at 6 and 18 months, showed a
marked bone age retardation (corresponding to the neonatal
period in both measurements), without any other abnormality
but brachydactyly and precocious closure of the cranial
sutures. Psychomotor development was mildly retarded. He
rolled over at age 9 months and sat alone at 10 months, stood
with support at 1½ year(s) and walked alone at 23/12. A highpitched voice was recorded. At age 2 years, he developed a
sudden-onset left hemiparesis and presented to the emergency
room. Blood pressure was 100/40 mmHg. A brain CT scan
revealed a right anterior cerebral ischemic lesion while on
magnetic resonance angiography (MRA) a marked stenosis of
the right anterior cerebral artery and associated telangiectatic
collateral vessels, which supply the cortex (moyamoya disease)

American Journal of Medical Genetics: DOI 10.1002/ajmg.a
Cerebral Vascular Anomalies in MOPD II

213

The teeth were small and reduced in number with signs of
enamel hypoplasia. Skin examination disclosed generalized
cutis marmorata over the trunk and limbs (Fig. 2). Reevaluation of the skeletal exams (performed at age 6 and
18 months) showed long bones overtubulation with shortening
of the middle segments of upper and lower limbs, brachytelephalangia I–V and brachymesophalangia II–V on hands and
feet, clinodactylous fifth fingers, proximally placed thumbs,
moderately high lumbar vertebrae, narrow and high iliac
wings, narrow ischial and pubic bones, triangular distal
femoral epiphyses, and metaphyseal flaring particularly
involving the distal femoral metaphyses which assumes a
‘‘delta’’ appearance (Fig. 3).
DISCUSSION
Fig. 1. Frontal (a) and lateral (b) facial appearance of the patient with
large eyes, sparse eyebrows, hypoplastic nasal tip and thin alae nasi,
prominent cheeks, attached ear lobules and micrognathia. [Color figure can
be viewed in the online issue, which is available at www.interscience.
wiley.com.]

This patient is affected by MOPD II phenotype based on clinical
and radiographic findings (Figs. 1 and 3). The diagnostic
criteria of MOPD II were only recently outlined [Hall et al.,
2004], while in the past, there had been some confusion

were present. Results of blood tests for thyroid hormones, IGF1, and endocrinological test for growth hormone after clonidine
load were all normal. Karyotype was 46,XY at standard level.
At this time, the diagnosis of Seckel syndrome was suggested.
At time of examination at age 29/12 years, he was a friendly
boy who pronounced simple words with a high-pitched voice.
He was able to walk with a tendency to falling due to residual
left weakness. He did not present other neurological abnormalities. His weight was 6,200 g, head circumference 41.5 cm,
and length 65.5 cm (all values below the 3rd centile).
Disproportionate short limbs with respect to the trunk and
brachydactyly were evident. Craniofacial characteristics
included micro-brachycephaly, prominent eyes and cheeks,
broad nasal root with wide nasal bridge, hypoplastic alae
nasi and nostrils, microstomia and receding chin (Fig. 1).

Fig. 2. Cutis marmorata over the trunk and thighs. Note cryptorchidism. [Color figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]

Fig. 3. Skeletal survey of the patient at 18 months shows absent carpal
ossification centers, proximally placed thumb and clinodactylous fifth finger
(a), hypo/aplastic middle and distal phalanges (a, b), mesomelic shortening
of the limbs (c), overtubulated long bones (a–c), ‘‘delta’’-shaped distal
femoral metaphysis and triangular distal epiphysis (d). Pelvis (at 6 months)
showing high iliac wings, narrow ischia, and pubis (e).

D’Angelo et al.
[1998]*
Female

Sorof et al.
[1999]
Male

Di Bartolomeo
et al. [2003]
Male

Seckel syndrome
Kutlu et al.
[2004]
Male

Nishimura
Kannu et al.
et al. [2003]* [2004]
Male
Female

Hall et al.
[2004]*
Four males
and five
females*

MOPD II
Young et al.
[2004]
Female

Male

Present case

BD, brachydactyly with brachymeso- or brachytelemeso-phalanges; BR, bowed radius; CM, cutis marmorata; CV, coxa vara; DC, dilated cardiomyopathy; H, hypertension; MF, metaphiseal flaring of the knee
with delta-shaped distal femoral metaphyses; MSL, mesomelic shortening of the limbs; NIIP, narrow iliac, ischial and pubic bones; OLB, overtubulated long bones; PAN, polyarteritis nodosa; TFE, triangular
distal femoral epiphyses; TH, trident hand; MPDs, microcephalic primordial dwarfisms; CVA, cerebral vascular anomaly, y, year(s); m, month(s).
a: Reportedly abnormal in Hall et al. [2004] but data on skeletal abnormalities were unavailable, as also in (b) Sorof et al. [1999].
*Two out of eleven patients with CVA reviewed by Hall et al. [2004] are described apart in the table (see D’Angelo et al. [1998] and Nishimura et al. [2003]).

17 y
19 y
10 y
9y
7y
7 y and 3 m
6 y and 9 m 2 y and 9 m
Multiple
Multiple
Multiple aneurysms Irregular
Moyamoya
Moyamoya
Overgrowth Moyamoya
Moyamoya
aneurysms,
aneurysms (19 y)
and teleangiectases narrowing
disease
disease
of the CNS
disease (2 y
disease (2 y)
elongated
(10 y)
of arteries in
(4 y and 5 m) (2 y and 11 m)
vessels
and 6 m)
and twisted
presence of
(prenatal
vessels (11 y)
PAN (9 y)
25 y)
Other vascular
DC; H
DC; H
DC; H; mesenteric/
CM
CM
complications
renal arteries
aneurysms
Outcome
Hemiparesis
Death
Disphasia
Hemiparesis
Hemiparesis
Hemiparesis
Intrauterine Disability,
Hemiparesis
and headaches
vascular
aphasia,
accident;
seizures
emiparesis;
death
Skeletal survey a
Evidence of
CV, MSL (with BR), Unavailable
CV, BD,
BD, CV, MF,
Unavailable BD, MF, NIIP BD, MF, MSL,
osteodysplasia, b
NIIP, TH
MF, OLB
MSL, NIIP,
NIIP, OLB,
TFE
TFE
Suggested
MOPD II
Unclassified MOPD MOPD II
Unclassified MPD
diagnosis

Age
CVA (age at
diagnosis)

Sex

Reference

Diagnosis

TABLE I. Patients With MPDs and CVA

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

American Journal of Medical Genetics: DOI 10.1002/ajmg.a
Cerebral Vascular Anomalies in MOPD II

between MOPD II and other MPDs (i.e., Seckel syndrome). The
first patients with MOPD II were in fact diagnosed retrospectively by Majewski and Goecke [1982] in two patients
referred to as Seckel syndrome [Brizard et al., 1973; Anoussakis et al., 1974]. Moreover, one of the MOPD II patients
reviewed by Hall et al. [2004] was previously diagnosed with
Seckel syndrome. Interestingly, this patient had multiple
intracranial aneurysms with elongated and twisted vessels
[D’Angelo et al., 1998]. This observation prompted us to review
published patients with CVA having received a diagnosis of
any type of MPD. Di Bartolomeo et al. [2003] diagnosed Seckel
syndrome in a patient with sparse scalp hair, generalized
skeletal dysplasia (i.e., high and narrow iliac wings, narrow
ischial, and pubic bones, bilateral coxa vara, proximal femoral
epyphisiolysis, bowed radius, ulnar deviation of hand and
wrist, and trident hand) and facial gestalt consistent with
MOPD II. Also this patient had chronic severe hypertension
and multiple intracranial aneurysms with telangiectatic
vessels. A similar CVA was diagnosed in an additional Seckel
syndrome patient with ‘‘evidence of osteodysplasia,’’ although
no radiographs were shown [Sorof et al., 1999]. Based on
published diagnostic criteria, there was insufficient clinical
information to allow reasonable classification of the MOPD in
this patient [Majewski et al., 1982a; Hall et al., 2004]. Finally,
no skeletal survey was available in the Seckel syndrome
patient by Kutlu et al. [2004], who had multiple CVAs secondary to PAN. Thus, in two patients a diagnosis of MOPD II was
suggested, while two cases could not be classified. The clinical
characteristics of three further patients diagnosed with MOPD
II who had CVAs, added to the list of nine individuals reported
by Hall et al. [2004], are summarized in Table I. We are
unaware of patients with either MOPD I or III presenting with
CVAs. Hence, including our patient, a total number of 17 cases
of MPD with CVA have been reported (Table I).
Observed CVAs included multiple aneurysms or moyamoya
disease, invariably complicated by neurological impairment
ranging from residual dysphasia to sudden death. Patients
with moyamoya disease show an earlier age at onset of these
complications compared to the group with intracranial aneurysms although, this latter subset of subjects had a worse
prognosis due to chronic severe hypertension and dilatative
cardiomyopathy [Sorof et al., 1999; Di Bartolomeo et al., 2003].
Chronic hypertension has not been previously described in
MOPD II. Despite its current apparent rarity and given its
significant morbidity, blood pressure monitoring should
become part of the regular surveillance of MOPD II patients,
particularly in adolescence and adult life. Interestingly, in two
patients (including ours) moyamoya disease was associated
with cutis marmorata [Kannu et al., 2004]. Finally, one
individual had PAN with abnormal CNS vessels [Kutlu et al.,
2004]. It is still unclear whether PAN is part of the CVA
spectrum associated with MPDs as this is the only reported
patient showing extra CNS vascular involvement.
Overall, among these 17 patients, a final diagnosis of MOPD II
was established in 15, while two had an unclassified MOPD.
The prevalence of CVAs in MOPD II among a total of 62
published patients [Hall et al., 2004; Kannu et al., 2004; Young
et al., 2004; Ozawa et al., 2005] was then calculated at 23.8%
(15/63), including the present case.

215

In conclusion, present results strengthen CVAs as frequent,
life threatening complications of MOPD type II, and highlight
the importance of a timely CNS vascular imaging in the clinical
management of these patients.

ACKNOWLEDGMENTS
This work was supported by funding from the Italian Ministry
of Health grant ‘‘Ricerca Corrente 2005’’ and approved by the
local ethic committee.

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