Clinical, cytogenetic and epidemiological approaches to the genetic heterogeneity of holoprosencephaly. Buenos Aires, 1988–1997

Abstract

Introduction :Holoprosencephaly (HPE) is a midline developmental field defect of prosencephalon and craniofacial structures that presents great clinical variability and etiologic heterogeneity. The epidemiology is poorly known due to the paucity of population-based studies.

Aims: 1) To describe clinical, cytogenetic and epidemiological aspects of this malformation using cases identified through the Garrahan Hospital Genetic Registry from 1988 to 1997 ; 2) To evaluate the predictive value of the facial anomalies for the detection of HPE ; 3) To compare all these data with those previously reported in other populations.

Results: We describe the craniofacial abnormalities, present their relative frequencies, coocurrence and their correlation with the severity of the brain defects including the presence of midline porencephalic cysts.

The facial abnormalities allowed the prediction of the brain defect in 85.7% of our cases, being hipotelorism the most reliable clinical sing. Among the different etiologies of HPE, from a total of 35 cases, we found that: 34.3% had isolated HPE, 45.7% presented a named syndrome, 8.6% were due to the exposure to teratogenic agents and 11.4% had a chromosomal abnormality including trisomy of chromosome 13 and structural rearrangements of chromosome 7. Prevalence among girls was nearly double that of boys in concordance with previous reports. Also, there was no maternal or paternal age effect.

Conclusions: 1) The prevalence of named syndromes in our population is unusually higher; 2) The predictive value of the facial anomalies is extremely high, 3) The frequent coocurrence of neural tube defects NTDs and HPE and the high rates of NTDs among relatives of our cases suggest that this is more than the association of two common malformations ; 4) The midline porencephalic cysts have to be considered as a part of the holoprosencephaly spectrum. This is, to our knowledge, the first clinical, cytogenetic and epidemiological study of this malformation in our population Our results highlight the need for a thorough assessment of the patient and family, realizing the clinical variability and etiologic heterogeneity of HPE.