Clinical and Genetic Studies on Holoprosencephaly

Holoprosencephaly (HPE) is a defect of midline forebrain development that occurs soon after
conception. It has a prevalence of 1 in 250 during early embryonic development, and 1 in
10,000 to 1 in 20,000 at term. In live born infants, the abnormalities associated with HPE
are divided into three main categories: alobar, semilobar, and lobar HPE. A fourth variant,
middle interhemispheric variant, has also been recognized. The purpose of this study is to
increase our understanding of the genetic and clinical manifestations of HPE through detailed
physical, psychological, developmental, neurologic, endocrinologic, and radiologic studies.
We will examine the spectrum of clinical characteristics of HPE to facilitate early diagnosis
and clinical management, including genetic counseling. Finally, we plan to assess the
psychosocial impact of HPE on the family as a unit. Most patients and their families will be
seen at the NIH Clinical Center. A subset may be examined outside the NIH, and a further
subset, for the psychosocial studies, may be interviewed by phone.

- INCLUSION CRITERIA:

1. Depending on their willingness to participate, subjects may enroll in DNA
laboratory-only (98-HG-0249), psychosocial-only, or clinical-only. However, to
conserve resources and meet study objectives, subjects with known mutations will
be given priority in selection for extensive clinical studies. All races and
genders are known to be at risk for HPE, anywhere in the world. Nationality or
place of origin is not specific barrier to participation.

2. Direct blood relatives (typically parents, and occasionally siblings of affected
individuals) of patients with HPE are also eligible to participate.

EXCLUSION CRITERIA:

1. Anyone unwilling to provide informed consent (for themselves as adults, or on behalf
of their children as minors) or assent.

2. Medical condition(s) or mental retardation are not in themselves reason for exclusion
if in the judgment of the referring physician this would involve no more than minimal
risk. We anticipate that children with mental handicaps would be included in the
research population. We will make every effort to explain the study for the purpose of
assent in a manner that the family feels is both age and developmentally appropriate
for that child.

3. We generally review a brief clinical description from the referring physician about a
potential research subject to determine that the subject is appropriate to enter into
the study. We reserve the right to exclude cases that are clearly not HPE or related
to our direct research interests (e.g. HPE cases that are syndromic like Smith Lemli
Opitz syndrome, Trisomy 13, Trisomy 18, drug-related, or teratogen-related). This
almost never happens, and we would attempt to make referrals to a more appropriate
investigator.

It is our intention to try to remove as many economic, cultural, geographic, racial, and
gender barriers as we reasonably can to promote participation of HPE cases for research
purposes.

Description and justification of clinical inclusion/exclusion criteria for environmental
study arm control group (individuals with Williams syndrome) :

Participants must have a confirmed diagnosis of Williams syndrome caused by deletions in
chromosome 7q11 involving the Williams-Beuren Syndrome Critical Region (WBSCR). Children
should be less than 6 years of age to allow for improved maternal recall of prenatal

environmental exposures. The Williams syndrome cohort (PI: Dr. Beth Kozel; National Heart
Lung Blood Institute) was chosen to allow for inherent biases in mothers who have children
with multiple anomaly syndromes.