Microcephalic Osteodysplastic Primordial Dwarfism Type II

Clinical characteristics: Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common form of microcephalic primordial dwarfism, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and that may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities.

Diagnosis/testing: The diagnosis of MOPDII is established in a proband with suggestive findings and biallelic loss-of-function pathogenic variants in PCNT identified by molecular genetic testing.

Management: Treatment of manifestations: Relies on symptomatic care from multidisciplinary specialists in pediatrics, orthopedics, dentistry, neurosurgery, cardiology, nephrology, endocrinology, and medical genetics, and from educators when learning difficulties are an issue.

Surveillance: Routine follow up of growth and development as well as monitoring of any known or potential complications regarding hip or spine deformity, dental abnormalities, cerebrovascular disease, coronary artery disease, hypertension and/or renal disease, diabetes mellitus, and/or educational issues.

Agents/circumstances to avoid: Growth hormone supplementation in the absence of growth hormone deficiency; excessive nutritional supplementation in infancy.

Genetic counseling: MOPDII is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PCNT pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the PCNT pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.