2nd NIH Conference on Holoprosencephaly and Early Embryonic Development

Siobhan Dolan, MD


June 07, 2002

In This Article

Clinical Aspects of HPE

A National Study to Discover the Causes of Birth Defects

Dr. Sonja Rasmussen from the National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention in Atlanta, Georgia, spoke about the National Birth Defects Prevention Study (NBDPS). This study is an ongoing case-control study that identifies cases of birth defects through birth defects surveillance systems in 8 states -- Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, and Texas. Controls are randomly selected from birth records in those states. Data from this study has previously been published.[8]

Dr. Rasmussen reported that previous epidemiologic studies of birth defects were problematic in that they had small numbers and there was no clear distinction between isolated cases of a birth defect and those with multiple malformations or a syndrome. For this reason, the CDC began the NBDPS, a case-control study, in 1997. The goal is to evaluate genetic and environmental factors associated with birth defects. There is a list of all the defects included in NBDPS and, these must be accurately identified by 6 weeks of age. Single-gene conditions and chromosome abnormalities are excluded. The focus is on teratogens, genes, and gene-environment interactions.

The NBDPS clinical database is extensive. It contains case information abstracted from medical records as well as clinical data. All data is entered into a standardized database. The case definition requires confirmatory diagnostic procedures and specific exclusions. The NBDPS includes a computer-assisted telephone interview with the mothers of cases. This is a structured questionnaire in English or Spanish that includes questions about pregnancy and medical history, diet, lifestyle, occupational and environmental exposures, and medication use. Verbal consent is obtained. The interview is conducted with women whose infants are between 6 weeks and 2 years of age and the woman is reimbursed $20 for completing the interview. The final component of the study design is the NBDPS biologics (DNA) collection. A kit, which includes a brush for cheek cell collection, is mailed to each participating family. Buccal cells are collected from the infant, mother, and father via cytobrushes. DNA is extracted and quality control is performed at each center.

The study has been ongoing for 4 years. There are 10,768 eligible births and, of those, 7178 eligible case infants have completed interviews and 66 of these have HPE. Of those with buccal smears completed, 2318 are eligible case infants, 888 are eligible control infants, and 20 of the case infants have HPE. To date, the strengths of the study are that it contains a large, ethnically and geographically diverse population. The case definitions are well described and standardized, and DNA is being collected for study. Still, however, there are a small number of cases, as HPE is a rare disorder, and the accuracy of hospital records is debatable.

HPE: The Brain Predicts the Outcome

Erin M. Simon, MD, OTR, Assistant Professor of Radiology of the Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, defines HPE as lack of separation of the forebrain. She states that although the face predicts the brain in about 80% of cases, the brain definitely predicts the outcome. Dr. Simon works on research that combines basic science with brain morphology from a large cohort of patients with HPE.

The goal of this imaging research is to develop a rating scale with a reproducible scoring system that can be a good predictor of neurologic function and neurodevelopmental outcome. Dr. Simon has undertaken the imaging diagnoses by carefully assessing the telencephalic structures, particularly the basal regions, for noncleavage. She has found that 40% of cases referred with "HPE" are not in fact consistent with that diagnosis. This has significant implications for care because the patients may or may not need shunting based on their diagnosis. Also, Sylvian fissures have been evaluated and shown to be at a larger angle in alobar and severe semilobar HPE .[9] Work from these studies can be downloaded at no charge via www.ajnr.org.

Jin S. Hahn, MD, from the Neurology Department of Stanford University Medical Center and Packard Children's Hospital and the Carter Centers for Brain Research in Holoprosencephaly and Related Malformations, discussed the clinical spectrum of HPE.[10] Dr. Hahn pointed out that there is very little information about the course and outcome of HPE. Dr. Hahn's research has been attempting to describe the clinical spectrum of HPE in a large series of cases and to correlate this with imaging studies.

In one study conducted between 1998 and 2001, he investigated 68 patients with classic HPE. Evaluation included 7 clinical variables (seizure, endocrinopathy, temperature dysregulation, craniofacial abnormalities, etc), 3 developmental variables, and 4 motor variables. The variables were graded on a scale of 0 to 3. Neuroimaging was undertaken by Dr. Simon and Dr. Barkovich; 61 MRIs and 7 CTs were also reviewed and graded.

The results showed that of 68 patients, 13 had alobar HPE (mean age .86), 43 had semilobar HPE (mean age 3.8), and 12 had lobar HPE (mean age 5.8). The male to female ratio was 35:33. All patients had nonsyndromic HPE. In the area of seizures, 49% had at least 1 seizure. Half of these were considered difficult-to-control seizures, and there was a correlation noted between seizure severity and grade of HPE. In this study, 72% of patients had endocrine dysfunction, with diabetes insipidus being very common. The severity of endocrinopathy correlated with degree of hypothalamic nonseparation (P = .029) but not with the degree of pituitary abnormality (P = .73).

In addition, 68% had at least some craniofacial abnormalities and 73% had microcephaly. In general, the face predicts the brain, but not always. In terms of motor function, none of the patients with alobar HPE were able to sit. Patients with semilobar HPE had slightly better motor function and about half of patients with lobar HPE could walk. Language assessment revealed that patients with alobar HPE vocalized only vowel sounds. Only 4 patients in the semilobar and lobar HPE groups were able to speak multiword sentences or more.

In conclusion, seizures correlated with severity of HPE, the degree of endocrinopathy correlated with the degree of hypothalamic nonseparation, and language and motor function correlated with severity of HPE. There is a wide spectrum of neurologic outcomes in HPE, and above all else, children with HPE continue to develop and learn.


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