Romano-Ward syndrome

Description

Congenital (autosomal dominant) long QT syndrome (LQTS). Unlike Jervell-Lange-Nielsen syndrome, there is no congenital hearing loss present.

• Multiple genetic mutations identified linked to cardiac potassium and beta-adrenergic channels.
• Mainstay of treatment is beta-blockers.
• Risk of sudden cardiac death – if any syncope or sustained ventricular arrhythmias for ablation / ICD implantation.

History of Romano-Ward syndrome

1963-1964: Independently described in 1963 by Cesarino Romano, Italian Paediatrician, and by Irish paediatrician Owen Conor Ward. Both reported an autosomal dominant long-term QT syndrome, later known as Romano-Ward syndrome.

1963 – Romano described an inherited functional syncopal heart disorder with prolonged QT interval in a 3-month-old female patient (“Aritmie cardiache rare dell’eta’pediatrica”). Two brothers of his patient had exhibited the same symptoms and died suddenly one at 44 days and one at 4 months of age.

1963 – Ward reported to the Royal Academy of Medicine in Ireland the clinical details of a family in whom prolongation of the QT interval in the ECG was associated in two cases with attacks of loss of consciousness due to ventricular fibrillation.

1964 – Ward published in the Journal of the Irish Medical Association regarding a syndrome observed in an Irish family the main features including:

• Prolonged, but variable QT interval in the ECG at rest
• Attacks of ventricular flutter or fibrillation fol­lowing exertion or emotional disturbance;
• Normal interval between heart sounds:
• Absence of valvular or gross myocardial disease;
• Familial incidence

He detailed the case of a 6 year old girl (BH) suffering from recurrent syncope whenever she was distressed or exerted herself, from the age of 16 months. Her GP sent her for a cardiology review; she was admitted to hospital and her symptoms recreated by running her around the ward where she collapsed, pulseless and unconscious.

Her ECG changes included marked QT prolongation at baseline (fig 1) and ‘bizarre’ ventricular extrasystoles degenerating into ventricular fibrillation of an ‘abnormal configuration’ (fig 2). We now know this to be torsades de pointes, first defined by François Dessertenne in 1966.

Shortening the QT with digoxin, beta blockers and carbamazepine did not prevent her attacks. Regrettably, at the age of 14, she had a further single attack which proved fatal.

Her younger brother (MH) suffered similar attacks from the age of 15 months, associated with emotional distress. He was treated with thioridizine (Melleril) in association with a beta-blocker. He died in an attack a few months before the publication of the first paper identifying QT prolongation as an adverse effect of thioridizine.

The children’s mother, who was completely symptom free, had marked prolongation of her QT interval. Their father’s ECG was normal. These findings were taken to indicate that the condition had been inherited as a dominant trait.

Autopsy examination revealed no pathological change in the heart muscle or in the conducting system, and no vascular structural abnormality.

1964 – An editorial review of Ward’s article appeared in the July 4 edition of the Lancet as ‘Congenital cardiac arrhythmia‘ noting this be the ‘first time this condition had been described’ and recommending that an ECG be carried out on all fainting children. 

This prompted a series of letter responses from Romano in Italy (2), Barlow in South Africa (5), and Gamstorp in Sweden (1) taking the global case tally to 10.

1964 – Barlow, Bosman and CraigCochrane published a family tree of three generations in
South Africa and five cases in which prolongation of the QT interval was associated with attacks of loss of consciousness, presumably duc to a cardiac arrhythmia.

1965 – Romano’s letter to the Lancet, March 20 1965 in response to Jervell,  Lange-Nielsen and Ward’s findings:

We pointed to the resemblance between our case and the syndrome of deafmutism, syncopal attacks, lengthening of the QT interval, and sudden death, but, as in Ward’s case, there was no evidence of deafmutism in our patient or in her family. The syndrome reported by us and by Ward may be a distinct entity.

[Romano C, 1963] [Ward OC, 1964]

1970 – Karhunen et al published the eleventh case and referred to the condition as the Romano-Ward Syndrome, a term which became widely adopted thereafter 

1979 – International Long-QT Syndrome Registry (ILQTSR) was initiated to collect data on any patient with LQTS.

2001 – Advances in research with paper by Schwrartz et al concluded that life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.

2005 – 25th Anniversary International LQTS Registry collating clinical discoveries from the past 25 years and setting ongoing aims for future research in this challenging field: ‘Our quest for uncovering the secrets of LQTS continues‘

Associated Persons

• Cesarino Romano (1924-2008)
• Owen Conor Ward (1923-2021)
• Anton Jervell (1901-1987)
• Fred Lange-Nielsen (1919-1989)
• François Dessertenne (1917-2006)

Alternative names

• Ward-Romano Syndrome; Ward’s syndrome
• Congenital cardiac arrhythmia
• Congenital Long QT syndrome without deafness

References

Historical articles

• Berg KJ. Multifocal ventricular extrasytoles with Adams-Stokes syndrome in siblings. American Heart Journal, 1960; 60(6): 965–970
• Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare dell’eta pediatrica. [Rare cardiac arrhythmia of the pediatric age II, syncopal attacks due to paroxysmal ventricular fibrillation]. Clin Pediatr (Bologna) 1963; 45: 656–683.
• Ward OC. New familial cardiac syndrome in children. J Ir Med Assoc. 1964 Apr;54:103-6.
• Editorial. Congenital cardiac arrhythmia Lancet 1964; 284(7349): 26-27
• Barlow JB, Bosman CK, Craig Cochrane JW. Congenital cardiac arrhythmia. Lancet 1964; 284(7358): 531
• Gamstorp I. Nilsén R, Westling H. Congenital cardiac arrhythmia. Lancet, 1964; 284(7366): 965
• Romano C. Congenital Cardiac Arrhythmia. Lancet 1965; 285(7386): 658-9
• Ward OC. The electrocardiographic abnormality in familial cardiac arrhythmia. Irish Journal of Medical Science 1966; 41: 553–557
• Karhunen P, Luomanmäki K, Heikkilä J, Eisalo A. Syncope and Q-T prolongation without deafness: the Romano-Ward syndrome. Am Heart J. 1970 Dec;80(6):820-3.

Review articles

• Kelly HG, Fay JE, Laverty SG. Thioridizine Hydrochloride (Mellaril): Its effect on the electrocardiogram and a report of two fatalities with electrocardiographic abnormalities Canad. Med. Ass. J. 1963;89:546-554
• Kringelbach J, Wennevold A. Prolonged Q-T interval and cardiac syncope (Ward’s syndrome). Acta Paediatr Scand. 1971 Mar;60(2):248-9.
• Weintraub RG, Gow RM, Wilkinson JL. The congenital long QT syndromes in childhood. J Am Coll Cardiol. 1990 Sep; 16(3): 674-80.
• Vincent GM. Hypothesis for the molecular physiology of the Romano-Ward long QT syndrome. J Am Coll Cardiol. 1992 Aug;20(2):500-3
• Schwartz PJ et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001 Jan 2;103(1):89-95.
• Ward OC. Long QT syndromes: the Irish dimension. Ir Med J 2005;98: 120–2.
• Mizusawa Y, Horie M, Wilde AA. Genetic and clinical advances in congenital long QT syndrome. Circ J. 2014; 78(12): 2827-33.
• Hodkinson EC, Hill AP, Vandenberg JI. The Romano-Ward syndrome – 1964 – 2014: 50 years of progress. Irish Medical Journal 2014; 107(4): 122-4.
• Cadogan M. History of the Electrocardiogram. LITFL

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