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A rare developmental defect during embryogenesis characterized by moderate to severe prenatal and postnatal growth retardation, microcephaly, a distinctive facial appearance, profound psychomotor delay, hip and knee contractures and rockerbottom feet.
ORPHA:1270Classification level: Disorder
Bowen-Conradi syndrome (BCS) birth prevalence is estimated at 1 per 355 within the Hutterite population living in small farming colonies in the Prairie provinces and Great Plains of North America with a carrier frequency as high as 1/10 in the Hutterite population. Outside this population, BCS is considered very rare and has only been reported clinically in 9 patients worldwide to date. To date, there are no non-Hutterite patients reported with biallelic EMG1 pathogenic variants.
Prenatally BCS is characterized by intrauterine growth retardation and often a breech presentation. BCS patients fail to thrive, experience severe feeding problems and seldom live past infancy. Distinctive malformations of the head and craniofacial region describe microcephaly at birth, micrognathia and a prominent nose with a noticeable lack of glabellar angle. BCS patients have a severe psychomotor delay, stiff joints, campodactyly or clinodactyly of the little finger and rockerbottom feet. Finger, hip and knee flexion contractures are frequently present. Less common BCS features described include cryptorchidism, seizures, cleft lip with or without cleft palate, congenital heart defect, hypospadias, renal, brain, or other malformations.
In the Hutterite population, BCS is over-represented secondary to a founder effect, and is due to a missense mutation in the EMG1 gene located to 12p13.3, leading to disturbances in ribosomal biosynthesis.
Diagnosis is typically made postnatally based on clinical manifestations and can then be confirmed with molecular testing. The diagnosis can first be identified on antenatal ultrasound; however the findings (particularly in a non-Hutterite infant) are non-specific and would likely not suggest BCS. In a Hutterite fetus, even in the absence of a positive family history, findings such as microcephaly, contractures, and rocker-bottom feet would be strongly suggestive of BCS.
Differential diagnosis includes trisomy 18, COFS syndrome and fetal akinesia deformation sequence. Other conditions with microcephaly and severe growth and developmental delay such as chromosome breakage disorders, DNA damage repair disorders, microcephalic primordial dwarfisms and certain forms of carbohydrate deficient glycoprotein syndromes may also show some overlap.
In cases with a family history, prenatal diagnosis is available and possible by amniocentesis or chorionic villus sampling and DNA analysis. Targeted mutation analysis of the Hutterite mutation is available prenatally (although rarely pursued) and in some instances carrier testing of both Hutterite parents of a presumed affected pregnancy can strengthen the possibility of diagnosis
BCS transmission is autosomal recessive. With the discovery of the causative mutation in the Hutterite population, carrier testing is available. 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
Treatment is merely symptomatic. Feeding is significantly compromised, and most infants require tube feeding. No curative treatment is presently available. The natural history is similar to aneuploidy syndromes such as trisomy 18 and the discussion of palliative care is appropriate.
Prognosis is extremely poor. Most children die within the first 2 years of life (range 1 day-9 years). Those who survive beyond 1 year of age show extreme growth failure.