Case Report
The proband is a healthy 35-year-old currently G9P4054 who presented
after the demise of her second baby to discuss reproductive options.
Prior to her first pregnancy, she had sought genetic counseling because
of her striking family history. Her older sister (Figure 1B and II 6 in
Figure 3), who was profoundly impaired, carried the diagnosis of
Cornelia de Lange syndrome, and because Cornelia de Lange syndrome is
most often due to de-novo dominantly acting mutations, she was reassured
that recurrence was unlikely. She also reported that she had had
identical twin brothers, born at 28 weeks gestation (Figure 2, I 1 and
2). One twin died in infancy, while the other survived until age 20 with
severe cognitive impairment (Figure 1C). Because her brother’s
impairment had been ascribed to complications of severe prematurity, she
was reassured that this too was unlikely to recur. Her first pregnancy
was uneventful and ended in the full-term delivery of a healthy female
infant. During her second pregnancy, ultrasound showed normal fetal
anatomy in the second trimester and fetal growth restriction in the
third trimester. After an uncomplicated vaginal delivery, the female
infant was noted to be small for gestational age (SGA) at 2,005 grams,
and was noted to have microcephaly, a high arched palate, widely spaced
eyes, a low set right ear and a wide sacral dimple (Figure 1A). Multiple
rib and vertebral anomalies were seen on X-ray, and bilateral ankle
eversions were noted. Echocardiogram revealed an atrial septal defect,
patent ductus arteriosus, tricuspid regurgitation, and poly-valvular
thickening. The infant was admitted to the neonatal intensive care unit
at 18 hours of life with concern for seizures. Electroencephalography
(EEG) was not consistent with seizures, but capillary blood gas revealed
severe metabolic acidosis with a pH of 6.76. Despite appropriate
therapy, the acidosis was unremitting. Lactic acid was > 24
mmol/L and ammonia was mildly elevated at 218 micromole/L. Evaluation
for possible inherited causes of metabolic acidosis was undertaken,
however, no cause was identified. The infant died at 51 hours of life.
The presumed cause was an inborn error of metabolism, with the
differential including pyruvate dehydrogenase deficiency, pyruvate
carboxylase deficiency or holocarboxylase deficiency. An autopsy was
performed, and notable findings included diffuse lipid vacuolization in
hepatocytes, small kidneys, an atrial septal defect, and hypoplasia of
the corpus callosum. Enzyme studies performed on fibroblast cultures
from skin showed normal enzyme activity for pyruvate dehydrogenase and
pyruvate carboxylase.
Because a recessively inherited cause for metabolic acidosis was
suspected, whole exome sequencing of the mother, father and baby was
undertaken. Potentially causative sequence variants were not identified,
but a sub-telomeric duplication of 12 Mb of chromosome 6q26q27
(chr6:161696380-170911240), in conjunction with a deletion of 11.7 Mb of
distal chromosome 1q43q44 (chr1:237461414-249168732) was reported. This
finding led to the cytogenetic investigation of both parents using
sub-telomeric FISH probes for chromosomes 6q and 1q. The mother was
identified as a carrier of an apparently balanced translocation between
distal chromosome 6q and distal chromosome 1q, consistent with the
deletion/duplication present in her child (Figure 2). Both the deletion
and the duplication contained multiple genes and provided a sufficient
explanation for the growth restriction, malformations, and dysmorphic
features. However, a definitive explanation for the fatal metabolic
acidosis was not identified.
The patient was informed of the substantial risk of chromosome imbalance
in future pregnancies, and conventional prenatal diagnosis with CVS and
microarray as well as IVF with preimplantation aneuploidy testing were
offered. During this discussion, it was noted that chromosome imbalance
due to a parental translocation might be the explanation of both of her
siblings’ severe cognitive impairment. Her sister’s evaluation that
resulted in the diagnosis of Cornelia de Lange syndrome had occurred
many years earlier, long before the availability of microarray, and her
brother had never received a genetic evaluation.
With this possibility in mind, the patient’s parents were
cytogenetically evaluated using sub-telomeric FISH probes, and her
mother (I 1 in Figure 3) was found to carry the translocation. This
knowledge prompted the testing of the sister with de Lange Syndrome, who
was shown to have the same chromosome 1q deletion/6q duplication that
was identified in the proband’s deceased daughter. Neither of the
proband’s unaffected siblings carried the translocation. She conceived a
3rd pregnancy that was evaluated by CVS/microarray at
11 weeks gestation and was found to have partial 1q deletion and 6q
duplication, consistent with the translocation. She elected to terminate
the pregnancy. Unfortunately, her 4th pregnancy was
similarly affected, and again, she elected termination. She had an
unaffected 5th pregnancy with a term spontaneous
vaginal delivery. Her 6th pregnancy resulted in a
spontaneous abortion that occurred prior to genetic evaluation, and her
7th and 8th pregnancies were shown
by CVS/microarray to be affected by the 1q deletion/6q duplication,
resulting in elective termination. Most recently, her
9th pregnancy resulted in an uncomplicated cesarean
delivery of dichorionic diamniotic twins following 1sttrimester CVS that confirmed normal microarray results for both twins.