Reciprocal translocations are commonly balanced exchanges between homologous chromosomes usually associated in carriers with normal phenotype.
Heterozygous carriers of translocations can result in abnormal meiosis, thus resulting in an increase rate of miscarriage1. The pregnancy lost is related to meiotic segregation since the meiosis in heterozygous for translocation may generate gametes with unbalanced rearrangements such as duplications and deletions.
Unbalanced chromosomal rearrangements can be studied by Comparative Genomic Hybridization (array-CGH) that is able to identify at high resolution (5-10 Mb) the genetics causes of complex phenotypes usually only partially detectable (9.5%) by classical cytogenetics2-5. When the CGH array was not discovered these genomic alterations were called "idiopathic syndromes".
Moreover, array-CGH is a technique faster than fluorescence in situ hybridization in detecting in one experiment, chromosomal unbalanced rearrangements without a priori knowledge. On the other hand, array-CGH has a relevant limitation in detecting balanced rearrangements where instead classical and molecular cytogenetics (Fluorescence in situ hybridization) are used as still elective strategies.
Here, we present the first report of a patient with 7q35q36.3 deletion and 20q13.2q13.33 duplication detected by array-CGH and deeply studied by reiterative FISH experiments, and associated with dysmorphism, delayed development, Long QT syndrome (LQTS), complex congenital heart disease, pulmonary hypertension, hypotonia, respiratory distress and cognitive deficit. The unbalanced rearrangements resulted as adjacent 1 segregation of the balanced translocation (7q;20q) carried by the mother of the patient. We detected the translocation in the mother and characterized by FISH an unbalanced rearrangement involving the same chromosomes in the mother’s brother of the patient (D.A.), thus showing traces of the presence of the translocation in the grandparent’s patient.
The subject of this study is a girl (D.A.) six months old (Figure 1: family tree III4). The mother (L.M.) reported four pregnancies two of which terminated in the first trimester as abortion, one gave birth D.M. (Figure 1: family tree III3) and from the last pregnancy was born D.A. (index case). In addition, L.M. reported to have a 27-year-old brother L.F. (Figure 1: family tree II3) who, at the age of ten, was diagnosed with a suspicion of Dandy Walker syndrome Rubinstein Taybi syndrome by two different groups of clinicians. These syndromes have never been confirmed through the use of biomolecular investigations.
L.M. prenatal history showed no evidence of teratogen exposure or any other relevant exposures or pathologies. Ultrasound reports during weeks 14 and 25 of gestation showed no morphological alterations.
The delivery was natural, and the baby born at term (39 weeks and six days) with a weight of 2230 grams. She showed APGAR indices of 6, 7 and 8 at one minute, five and ten minutes respectively after birth. D.A. was transferred to the Neonatal Intensive Care Unit (NICU) due to the low weight (<2500 grams) and the presence of dismorphic elements (microcephaly, ears and cup, hypotelorism, squat and short neck, clenched hands with overlapping fingers, active and passive hypertonus of the limbs, absent cry, posture with extended lower limbs and tense and abducted upper limbs). Furthermore, she showed tense and not very palpable abdomen, the heart rate at 140 beats/minute, respiratory rate at 45 acts/minute and blood pressure at 53/43 mmHg.
Blood tests showed an increase in transaminases (GOT: 537 IU/L, GPT: 247 IU/L), leukocytes (36970 cells/uL), creatininemia (1.8 mg/dL), Reactive Protein C (8,9 mg/dL), creatinkinase (CK or CPK: 217 IU/L), creatine kinase MB (CK-MB: 42.9 IU/L) and a decrease in sodium levels (125 mmol/L). In addition, the newborn girl had been subjected to antibiotic therapy due to Escherichia coli detection on blood culture and pharyngeal swab.
Upon entering UTIN, continuous monitoring of tissue oxygenation (kidney and brain) was detected through the Near-Infrared Spectroscopy (NIRS), while brain electrical activity was monitored through the use of Cerebral Function Monitoring (CFM). Given the difficulty in breathing highlighted since birth, the Nasal Continuous Positive Airway Pressure (nCPAP) was applied to the small D.A. Echocardiography showed: situs solitus, levocardia; atrial septal defect (DIA) near the superior vena cava (high caval), moderate tricuspid insufficiency which indicates a high blood pressure (PAPs about 80mmHg); normal-sized left heart chambers; preserved biventricular kinesis; pulmonary artery of normal caliber and with normoconfluent branches; patent arterial duct with moderate bidirectional shunt; aortic arch and aortic isthmus of normal caliber and flowmetry; normopulsing abdominal aorta; absence of pericardial effusion. To treat pulmonary hypertension, the following therapy has been implemented: Dobutamine and Milrinone with continuous infusion.
In seventh day of life given the persistence of high lung pressure associated with an unconvincing radiographic picture, the little D.A. was intubated and treatment with High Frequency Oscillation (HFO) with nitric oxide (No) was started. At the following echocardiographic control there was a sharp drop in lung resistance (right ventricle pressure: 25 mmHg) and the presence of two muscle interventricular defects apical (DIV). The nitric oxide dosage was reduced and suspended after about 24 hours, followed by suspension of Milrinone after a few days. On this occasion, a bronchoalveolar lavage was performed which resulted negative for Clamidya, Ureoplasma and Mycoplasma.
On the tenth day of life, an electrocardiogram (ECG) was performed detecting: presence of a QTc (QT corrected according to the frequency) lengthened by 480 msec in V5 (normal values: 350-440 msec). For this reason, D.A. started therapy with propanolol hydrochloride (beta blocker) initially at a dosage of 1mg/Kg/die and then reached a dose of 7mg/Kg/die in three administrations for the persistence of the extended QTc (values between 440 and 490 msec). In addition, the ECG detected the presence of ventricular pre-excitation (delta wave at the beginning of the QRS complex).
The abdominal ultrasound showed: liver of dimensions within the limits of norm without appreciable ecostructural alterations. Gallbladder with endoluminal biliary mud and moderate concentric thickening of the walls. Hint of ectasia of the intrahepatic biliary tract. Pancreas not explorable. Spleen within normal limits. Kidneys in size within the limits with regular eco-structure.
The magnetic resonance imaging (MRI) of the brain showed: semibrachycephalic caput. The corpus callosum was thin and incomplete, with reduced thickness of the splenium and not recognizable rostrum; a moderately squared aspect of the posterior sectors of the lateral ventricles was associated. Mild hypoplasia of the cerebellar worm and consensual megacisterna magna. No significant signal alterations of the nerve tissue, regular progression of myelination. Substantially regular the volume of the ventricular system. Regular amplitude of the pericerebral spaces. Neonatal screenings for phenylketonuria, hypothyroidism and cystic fibrosis were negative.
The girl, after two months of hospitalization, was discharged with suitable therapy. Physical examination in resignation revealed a weight of 3240 grams, pink color, good state of hydration, regular cardiorespiratory objectivity, abdomen treatable, moderate hypertonus to the four limbs. The discharge diagnosis was: newborn with dysmorphism, development delay, Long QT syndrome (LQTS), complex congenital heart disease, pulmonary hypertension, hypotonia, respiratory distress, cognitive deficit. In order to evaluate the possible presence of genomic alterations, genomic analysis was carried out using Comparative Genomic Hybridization (a-CGH) arrays, karyotype and molecular cytogenetics.