Microcephalic Osteodysplastic Primordial Dwarfism Type Ii

A rare bone disease and a form of microcephalic primordial dwarfism 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.

Epidemiology

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is one of the most common forms of microcephalic primordial dwarfism (MPD) and accounts for more than 150 cases worldwide.

Clinical description

MOPDII is congenital, with a perinatal and infancy onset. It 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 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 café-au-lait spots), poikiloderma, acanthosis nigricans, and truncal obesity in adolescence and adulthood. 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.

Etiology

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.

Diagnostic methods

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

Differential diagnosis includes Meier-Gorlin syndrome, LIG4 syndrome, XRCC4 deficiency, Seckel syndrome, MOPD types I and III, SHORT syndrome, Schimke immuno-osseous dysplasia, and Dubowitz syndrome.

Antenatal diagnosis

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.

Genetic counseling

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.

Management and treatment

Management is mainly symptomatic. Screening for CNS vascular abnormalities with brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) 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.

Prognosis

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. Vascular anomalies are a common complication. They may involve neurovasculature in childhood, and renal and coronary arteries in adulthood, the latter of which may be life-threatening.