Microcephalic osteodysplastic primordial dwarfism types I and III (ORPHA:2636)
A rare, severe, primary bone dysplasia characterized by intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, skeletal dysplasia, low-birth weight and brain anomalies.
Epidemiology
Less than 60 cases have been described in the literature so far.
Clinical description
The facial dysmorphism is characterized by a round face, metopic ridge, small anterior fontanelle, a sloping forehead, prominent occiput, protruding eyes, prominent nose, small dysplastic ears and micrognathia. The neck is short. Sparse hair and eyebrows, and dry skin are frequently observed. Skeletal anomalies include short limbs, brachydactyly, flexion contractures markedly delayed epiphyseal ossification and, more variably, dislocation of the hips and elbows. The most frequent neurological manifestations are intellectual deficit and seizures, and reported brain anomalies include brain hypoplasia, lissencephaly or pachygyria, hypoplastic frontal lobes, arachnoid cysts, agenesis of the corpus callosum or and mild cerebellar vermis hypoplasia. Cardiac anomalies and retinal dystrophy are more variably reported.
Etiology
Caused by bi-allelic mutations of RNU4ATAC (2q14.2), a gene encoding a small nuclear RNA involved in minor (U12) splicing. Mutations in the same gene also cause Roifman syndrome in which there are many overlapping features but Roifman is distinguished by immunodeficiency.
Diagnostic methods
Diagnosis is made on the basis of the clinical and radiological phenotype including marked growth retardation and microcephaly, severe brain anomalies and common radiological bone features including delayed epiphyseal ossification, short and bowed tubular bones, enlarged metaphyses, elongated clavicles, mild platyspondyly, cleft vertebral arches, short fingers and toes and small iliac wings.
Differential diagnosis
The differential diagnosis should include MOPD type 2 and other syndromes associated with primordial dwarfism, such as Seckel syndrome and microcephalic primordial dwarfism due to RTTN deficiency.
Antenatal diagnosis
Prenatal diagnosis, by ultrasonography showing brain anomalies, IUGR and short distal limb at around 20 weeks of gestation, has been reported in affected families.
Genetic counseling
MOPD type I/III is transmitted as an autosomal recessive trait. Genetic counseling should be offered to at risk families (where each parent is an unaffected carrier) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is supportive only. Particular attention should be provided to growth and psychomotor development. Medical care and management should be provided according to malformations and intellectual deficiency. Great attention should be paid to apparently mild medical events (fever, drowsiness), especially in the first three years of life.
Prognosis
The prognosis is poor with most of the reported patients dying either in utero or unexpectedly as a result of a fever or an apparently mild medical event within the first 3 years of life. Several RNU4ATAC mutations appear to be compatible with prolonged survival, sometimes until adulthood.

                            Last update: 
                            November 2020


                            - Expert reviewer(s): 
                            Pr Patrick EDERY | ITHACA* - Dr Audrey PUTOUX 


                                * European Reference Network