A newborn boy born at 37 weeks’ gestation was referred to the paediatric cardiology service while in the neonatal intensive care unit because of bradycardia. Maternal history was significant for hypothyroidism treated with levothyroxine, chronic idiopathic thrombocytopenic purpura identified during pregnancy and treated with prednisone, and cholestasis during pregnancy. Bradycardia was initially detected prenatally; however, regular ultrasounds, fetal echocardiogram and biophysical profiles were normal. Maternal testing was negative for antinuclear antibody, anti-Rho and anti-La antibodies. On delivery, the infant’s heart rate was 100 beats/min and he was transferred to a level 2 nursery.
On further history, it was noted that the parents were consanguineous (the parents were first cousins, and the maternal grandmother was the sister of the paternal grandfather), and there was a family history of thrombocytopenia in the father, paternal uncle and paternal grandfather. There was no reported history of arrhythmias, sudden death, unexplained car accidents or drownings in the family. The patient’s four-year-old sister was healthy. On examination, the infant did not exhibit any dysmorphic features. Cardiovascular examination was normal, and there were no signs of heart failure. Further investigations established the diagnosis.
CASE 1 DIAGNOSIS: JERVELL AND LANGE-NIELSEN SYNDROME
Initial investigations after birth were significant for multiple electrocardiograms (ECG) revealing a prolonged QT interval (approximately 600 ms to 650 ms) (Figure 1). With this finding, in addition to a Holter monitor, ECGs of the parents and sister, as well as a genetics consultation were requested. The differential diagnosis included primary myopathies due to metabolic abnormalities, or channelopathies due to autosomal dominant prolonged QT syndromes and autosomal recessive prolonged QT syndromes.
Figure 1).
Electrocardiogram of the patient on day 1 of life, showing a prolonged QT interval
Echocardiography revealed a structurally normal heart. Holter monitor recordings demonstrated poor variability, T alternans, a low heart rate with an average of 96 beats/min and a prolonged QT interval. Very low heart rates are an important sign of long QT syndromes (1). Newborn screening was negative for metabolic disorders. A genetics consultation suggested a genetic long QT syndrome as the most likely diagnosis. The parents’ ECGs were normal, and the sister’s ECG demonstrated a slightly increased corrected QT interval at higher heart rates.
The electrophysiology service was consulted soon after birth and decided on treatment with propranolol (2 mg/kg/day). Beta-blockers have been found to be of some benefit in Jervell and Lange-Nielsen syndrome (JLNS) (2); however, a significant risk for sudden death remains. Use of an implantable cardioverter defibrillator was considered, but anatomical considerations in a small infant and the risk of inappropriate shocks were limiting factors.
At one month of age, the propranolol dose was increased to 4 mg/kg/day and the parents were educated in the use of an automatic external defibrillator.
At 3.5 months of age, genetic analysis revealed that the baby was homozygous for KCNQ1 364dupT (Cys122LeufsX163), which is an autosomal recessive mutation known to cause long QT syndrome and consistent with a diagnosis of JLNS. JLNS is known to be associated with bilateral sensorineural hearing loss. Interestingly, although a routine newborn hearing screen was normal, a formal audiology examination demonstrated profound bilateral sensorineural loss. Subsequently, arrangements were made for bilateral cochlear implants. The parents were counselled about the increased risk of syncope, cardiac arrest and sudden death, as well as the rarity of the diagnosis (1.6 to 6 per million individuals worldwide [3]). The lifelong use of beta-blockers was emphasized and the possibility of the use of an implantable cardioverter defibrillator in the future was discussed. Furthermore, the parents were made aware of risk factors for exacerbation of the illness – specifically, increased physical activity and medications that prolong QT. The parents were informed about their risk for future children with JLNS (one in four), and genetic counselling for the family was arranged.
At 18 months of age, the beta-blocker was changed to nadolol 12 mg orally twice daily (2.3 mg/kg/day). Bilateral cochlear implants were functioning normally, and the child was regularly participating in activation therapy.
CLINICAL PEARLS
Significant bradycardia in infancy should prompt consideration of congenital long QT syndromes.
Sensorineural hearing loss is associated with JLNS.
Treatment must be individualized, and the risk of life-threatening arrhythmias remains.
REFERENCES
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