Microcephalic osteodysplastic primordial dwarfism type 1
(MOPD1) is a genetic condition that is mainly characterized by intrauterine and
post-natal growth retardation; an abnormally small head size (microcephaly);
abnormal bone growth (skeletal dysplasia); distinctive facial features; and
brain anomalies. Other signs and symptoms include sparse hair and eyebrows; dry
skin; short limbs; dislocation of the hips and elbows; seizures; and
intellectual disability. It is caused by mutations in the RNU4ATAC gene and is
inherited in an autosomal recessive manner. Treatment is supportive only. The
prognosis is poor with most affected individuals dying within the first year of
life. MOPD types 1 and 3 were originally thought to be separate entities, but
more recent reports have confirmed that the two forms are part of the same
Microcephalic osteodysplastic primordial dwarfism (MOPD)
types 1 and 3 are characterized by intrauterine and postnatal growth
retardation, microcephaly, facial dysmorphism, skeletal dysplasia, low-birth
weight and brain anomalies. Although MOPD types 1 and 3 were originally
described as two separate entities on the basis of radiological criteria
(notably small differences in pelvic and long bone structure), later reports
confirmed that the two forms represent different modes of expression of the
The prevalence is unknown but less than 30 cases have been
described in the literature so far.
The facial dysmorphism is characterized by a prominent nose
with a flat nasal bridge, protruding eyes, a sloping forehead, and
micrognathia. Sparse hair and eyebrows, dry skin, short limbs and dislocation
of the hips and elbows are other common features. The most frequent
neurological manifestations are seizures and intellectual deficit, and reported
brain anomalies include lissencephaly, hypoplastic frontal lobes, and agenesis
of the corpus callosum or cerebellar vermis.
Although the causative gene remains unknown, homozygosity
mapping has allowed identification of a candidate gene region on chromosome 2q
(2q14.2-q14.3). Histological studies suggest that MOPD types 1 and 3 result
from a basic defect in cell proliferation and tissue differentiation.
Diagnosis is made on the basis of the clinical and
radiological phenotype, with common radiological features including short
tubular bones, enlarged metaphyses, vertebral and pelvic anomalies, elongated
clavicles, bowing of the long bones and cleft vertebral arches.
The differential diagnosis should include MOPD type 2 (see
this term) and other syndromes associated with primordial dwarfism (such as
Seckel syndrome; see this term).
Prenatal diagnosis, by ultrasonography at around 20 weeks of
gestation, has been reported in affected families.
MOPD types 1 and 3 are transmitted as autosomal recessive
Treatment is supportive only.
The prognosis is poor with most of the reported patients
dying within the first year of life.
Microcephalic osteodysplastic primordial dwarfism type 2
(MOPD2) is a condition characterized by short stature (dwarfism), skeletal
abnormalities and an unusually small head size (microcephaly). Other signs and
symptoms of MOPD2 may include hip dysplasia; thinning of the bones in the arms
and legs; scoliosis; shortened wrist bones; a high-pitched voice; distinctive
facial features (prominent nose, full cheeks, a long midface, and a small jaw);
small teeth; abnormal skin pigmentation; and blood vessel abnormalities.
Intellectual development is typically normal. It is caused by mutations in the
PCNT gene and is inherited in an autosomal recessive manner.
'Microcephalic osteodysplastic primordial dwarfism type II
(MOPDII) is a form of microcephalic primordial dwarfism (MPD; see this term)
characterized by severe pre- and postnatal growth retardation, with marked
microcephaly in proportion to body size, skeletal dysplasia, abnormal
dentition, insulin resistance, and increased risk for cerebrovascular disease.'
MOPDII is one of the most common forms of MPD and accounts
for more than 150 cases worldwide.
'MOPDII is congenital and is characterized by severe pre-
and postnatal growth retardation, with proportionate severe microcephaly,
skeletal dysplasia, abnormal dentition, an increased risk for cerebrovascular
disease (aneurysms and Moya Moya disease (see this term) in 19%-52% of cases)
and insulin resistance. Intrauterine growth restriction (IUGR) is common. The
average length, weight, and head occipitofrontal circumference (OFC) at birth
are respectively 7.0, 3.9, and 4.6 SDs below the population mean (after
correcting for gestational age <37 weeks). Head growth appears to stop by 18
months of age giving rise to the appearance of progressive microcephaly. At
maturity, the average height, weight, and OFC are respectively 10.3, 14.3, and
8.5 SDs below the population mean. Skeletal dysplasia with progressive
scoliosis, radial head dislocation and coxa vara, may be seen. Distinct
craniofacial features include prominent, small pinnae with attached lobes;
small, dysplastic and poorly rooted, opalescent dentition and sparse hair.
Further hallmarks of MOPD II include high-pitched nasal voice, areas of hypo-
and hyperpigmentation (with cafÈ-au-lait spots), poikiloderma and acanthosis
nigricans. A disorder initially named primordial short
stature-microdontia-opalescent and rootless teeth was originally and mistakenly
reported to have distinct MOPD, but it is now recognized to be the same entity
as MOPD II.'
MOPD II is caused by mutations in PCNT (21q22.3), encoding
pericentrin, which anchors a wide range of centrosomal proteins and protein
complexes during cell division. Disruption of pericentrin is thought to cause
mitotic spindle defects, and impaired cell proliferation. A role in ATR DNA
damage dependent signaling has also been proposed.
Diagnosis relies on clinical features, radiographic
examinations of bone age that usually show disharmonic maturation of centers
and a retarded bone age. Diagnosis is confirmed by genetic screening of PCNT.
Some individuals have elevated platelet counts.
Differential diagnosis includes Meier-Gorlin syndrome, LIG4
syndrome, Seckel syndrome, MOPD types I and III, SHORT syndrome, Schimke
immuno-osseous dysplasia, and Dubowitz syndrome (see these terms).
Pregnancies with affected children are often complicated by
the observation of IUGR. Early age of delivery is noted. C-sections may be
performed at earlier ages due to the IUGR. Prenatal diagnosis is possible if
the causative mutation(s) in PCNT have been identified in the carrier parents.
Transmission is autosomal recessive and genetic counseling
Management is mainly symptomatic. Screening for CNS vascular
abnormalities with brain MRI and MR angiography is recommended at diagnosis and
every 12 to 18 months. Yearly screening for signs of insulin resistance
including a lipid profile should be performed (beginning at grade school age),
as well as monitoring for anemia, platelet counts, and hip and spine anomalies.
Life expectancy is generally decreased, but individuals live
into their 30s. Many complications arise, but most can be handled by adapting
modern medical techniques to the diminutive size. A common complication is
vascular anomalies which as well as affecting neurovasculature in childhood,
can also affect renal and coronary arteries in adulthood, which may be life