Miller-Dieker syndrome. Detection of a cryptic chromosome translocation using in situ hybridization in a family with multiple affected offspring
M. Alvarado, H. N. Bass, S. Caldwell, M. Jamehdor, A. A. Miller and P. Jacob
Department of Medical Genetics, Kaiser Permanente Medical Center, Panorama City, CA 91402-5497.
OBJECTIVE--To describe a family in whom fluorescence in situ hybridization
allowed for accurate diagnosis of Miller-Dieker syndrome in an at-risk
pregnancy and determination of parental carrier status.
DESIGN--Retrospective case analysis and application of a new molecular tool
to evaluate the family. SETTING--Health maintenance organization. The
family was followed up by the Departments of Medical Genetics, Pediatrics,
and Obstetrics and Gynecology, Kaiser Permanente Medical Center, Panorama
City, Calif. PARTICIPANTS--Members of a single family.
INTERVENTIONS--Clinical evaluation and neuroimaging studies of the proband.
Prenatal diagnosis via ultrasonography and amniocentesis. Chromosomal
evaluation of the couple and their offspring. In situ hybridization studies
in both parents and an affected fetus. MEASUREMENTS/MAIN RESULTS--We
describe a family in whom fluorescence in situ hybridization detected a
submicroscopic deletion of the Miller-Dieker syndrome critical region
17p13.3 arising from a cryptic translocation in one of the parents. The
proband was determined at birth owing to the presence of multiple
congenital anomalies, including low birth weight, microcephaly, agenesis of
the corpus callosum, lissencephaly, cerebral atrophy, unilateral ptosis,
polydactyly, and omphalocele. High-resolution chromosome-banding analysis
findings were normal in the parents and proband, who died at age 4 years.
There were four subsequent pregnancies: two ended in first-trimester
spontaneous abortion, and in the other two, large omphaloceles were
detected in fetuses at 15 and 13 weeks' gestation. Both pregnancies were
terminated. Fluorescence in situ hybridization probes for 17p13.3 had
become available before the most recent pregnancy and were used to study
parental and fetal cells. As a result, a balanced cryptic translocation
between chromosome 17 and chromosome 19 was identified in the father:
46,XY,t(17;19)(p13.3q13.33). An unbalanced form of the translocation,
involving a deletion of 17p13.3, was detected with fluorescence in situ
hybridization in the fetus. This finding was in accordance with a clinical
diagnosis of Miller-Dieker syndrome. CONCLUSIONS--Molecular cytogenetic
technology should be used in cases of suspected Miller-Dieker syndrome when
high-resolution cytogenetic analysis fails to detect del(17) (p13.3).
Positive findings should be followed up with parental studies. In addition,
omphalocele should be included among the list of malformations that make up
the Miller-Dieker syndrome.
