Molecular Basis of Parry-Romberg syndrome

Parry-Romberg syndrome consists of slowly progressive atrophy of bone and the
soft tissues of essentially half the face accompanied most frequently by
contralateral Jacksonian epilepsy, trigeminal neuralgia, and ipsilateral
changes in the eyes and hair. The consequences for the disorder for individual
patients is significant due to the often enormous disfigurement it causes. The
cause is inkonwn, no therapy is available.

We have recently hypothesized that Parry-Romberg syndrome might be a
laminopathy. Laminopathies are a series of disorders caused by abnormal
functioning of lamin A/C which is an important part of the cytoskeleton of both
the nucleus and lamina within the cells. The classical phenotype is
Hutchinson-Gilford progeria syndrome but other entities such as restrictive
dermopathy, familial partial lipodystrophy and dilated cardiomyopathy are well
known as well
We reasoned that in Parry-Romberg syndrome there is not only atrophy of skin,
subcutaneous fat tissue and facial muscles, but also of bone. We had access to
a biopsy taken from the affected part of a face of a patient obtained during
surgery for patient care purposes. Indeed the main characteristics of a
laminopathy were found. These were only present in the cells from the affected
part of the face and not in peripheral blood cells, indicating mosaicism. The
genes known to cause laminopathies were tested and found to be negative.

The present study is aimed to evaluate this in a few more patients, and perform
next generation sequencing techniques in both fibroblasts derived from the
affected facial area and from leukocytes, and search for differences between
the genomes from the two tissues. Results of patients who show signs of
abnormal nuclear morphology in affected tissues will be coupled and compared,
which increases the chance to detect the causative gene.

Our first aim is to find the cause of Parry-Romberg syndrome. The subsequent
aim is to study the pathogenesis of the entity. The final aim is to find an
effective management for the disorder.

Prior to be enrolled in the study, all individuals known with Parry-Romberg
syndrome known to us will receive written information about and invitation to
participate in the study. Subsequently they will be contacted by phone and if
the possible participant is considering participating, he/she will be invited
to the clinic.
Blood sampling will be performed by experienced technicians in either AMC or
VUmc. Skin biopsies will be taken by an experienced oral surgeon under local
anaesthesia. The site will be chosen together with the participant.
Histological studies to show abnormal nuclear morphology will be performed in
all skin biopsies (Prof Nicolas Levy, Marseille, France).
Total genome sequencing using the 454 or Solid Genome Analyzer will be
performed in at least one Parry-Romberg individual in DNA derived from the
affected face region and from leukocytes. If inconclusive results will be
obtained from this individual, the DNA of other participants from the affected
facial region will be studied this way as well. If the total genome sequencing
leads to discovery of a gene that is likely to be causative for Parry-Romberg
syndrome, Sanger sequencing of this gene will be repeated in the DNA derived
from the affected facial region in all available patients.
Depending on the nature of the detected gene further functional studies will be
performed in a lab (Dr Carlos Lopez-Otin, Burgos, Spain) that has an
extraordinary experience in performing such studies in laminopathies.

Possible adverse event: blood sampling can result in minor hematoma. The
(small) biopsy wound may develop into scar tissue but this is unlikely to
happen in an atrophic skin. If possible the biopsy will be taken in the
anterior hairline or other localization that is less well visible. The
localization of the biopsy will be chosen together with the participant. The
biopsy is an essential part of the study. Personal contacts with patients have
learned us that the affected persons are eager to find the cause of the
disorder and know well no management strategy exists at present. The impact of
the disorder of the patients on their life is significant and therefore we
think taking small biopsies in as few patients as possible is acceptable. There
are no literature data that taking a biopsy accelerates (or decelerates) the
disease process.