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.