Phenotype and Etiology of Pallister-Hall Syndrome

We aim to use the power of modern molecular genetics and clinical research to delineate the

range of severity, natural history, molecular etiology, and pathophysiology of a number of

congenital anomaly syndromes. The goal of the research is to develop a knowledge base that
allows proper clinical and molecular diagnosis of patients with rare congenital anomaly

disorders. Our paradigm is the previous work we have done with Pallister-Hall syndrome (PHS)
and Greig cephalopolysyndactyly syndrome (GCPS), where we have successfully used a combined
clinical-molecular approach. Using this strategy, we have brought 50-100 patients or families
with these disorders to the NIH clinical center (NIH CC) for a comprehensive clinical
evaluation with follow-up at a frequency appropriate to the disorder. We have also clinically
and/or molecularly evaluated many additional patients with atypical or non-classic
presentations of PHS and GCPS and have conducted exploratory studies of other phenotypes to
determine how they might fit into the more general models generated to explain PHS and GCPS.
We are currently generalizing this approach to a number of disorders including talipes
equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava
(TARP) syndrome. Specimens from patients participating in both the laboratory and clinical
arms of the protocol will be collected and evaluated in the laboratory by linkage analysis,
physical mapping, candidate gene characterization, mutation screening and targeted exome
sequencing, and cell biologic studies of normal and mutant proteins.

- INCLUSION CRITERIA:

Subjects with clinical manifestations of a congenital anomaly or craniofacial syndrome, or
a single congenital anomaly that is also seen as part of a congenital anomaly syndrome will
be considered eligible for participation in this protocol.

Blood will also be requested on unaffected relatives that could be informative for linkage
studies or for determining co-segregation of mutations within families. Subjects of either
gender and all ethnic and racial groups will be accepted.

Prenatal specimens (amniocentesis or CVS) will be accepted if they are previously acquired
for clinically indicated reasons. Cord blood or placenta specimens may be accepted if they
(or a part of them) are not needed for clinical purposes.

Specimens from patients collected at outside institutions may be accepted into the study if
they were collected under an IRB-approved protocol at an MPA or FWA institution.

Coded specimens (specimens linked to identifiers but without personal identifiers attached
to the sample) may be acquired from other NIH investigators, analyzed, and returned as
research results to that investigator.

EXCLUSION CRITERIA:

Patients with typical GCPS or PHS who have demonstrated GLI3 mutations may be excluded from
this study. Patients with phenotypes and disorders with a high risk/benefit ratio such as
late-onset, neurodegenerative, psychiatric, and cancer-predisposition disorders will be
excluded from participation. Similarly, patients who are medically fragile or unable to
tolerate travel to the NIH CC will not routinely be eligible for participation. Probands
who are adults and decisionally-impaired are ineligible if they do not have a legal
guardian who has authority to sign a consent form on their behalf.