Thursday, June 30, 2016

MOPD1 versus MOPD2


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 syndrome.

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 same syndrome.

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 traits.

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 is possible.

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 threatening.

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