Ir Med J. 2005 Apr;98(4):120-2           


In a recent editorial Murphy commented on the importance of QT prolongation as an adverse effect of drug therapy¹. He drew attention to the 1964 publication referring to the recognition of inheritance of Long QT as a risk factor for life-threatening cardiac arrhythmia². The topic has been reviewed extensively in the medical literature. Viskin among others has drawn attention to the interaction between congenital and drug-induced QT prolongation.³ On this basis for example cisapride has been withdrawn for the treatment of vomiting in infancy^4,5.

Observations on two siblings with congenital QT prolongation were originally published at the suggestion of Harry Counihan, former editor of the Journal of the Irish Medical Association following a clinical presentation of their cases at the Royal Academy of Medicine in the autumn of 1963. A little girl, then aged six years, had suffered from attacks of loss of consciousness whenever she was distressed and whenever she exerted herself from the age of 16 months.Dr. Kevin Greenan, her family doctor, persisted in his search for a diagnosis and consulted widely on her case. Ultimately Dr John Stack, who had seen her for a psychiatric consultation, requested cardiac assessment in Our Lady’s Hospital for Sick Children.

The 1964 report outlined the clinical details. Her condition was discussed at a student teaching round on June 22nd 1962.The focus was on the importance of the history in difficult cases. This was to be put to the test. The patient was got out of bed and taken by the hand to run around the ward. To the alarm of all concerned, she fell down unconscious and pulseless. A subsequent trial of the effect of exercise under controlled conditions confirmed that she was suffering from episodes of bizarre ventricular arrhythmia, later to be called torsades de pointes. Her resting ECG showed marked prolongation of the QT interval. Shortening the QT with digoxin did not prevent her attacks.⁶ Treatment with the early beta-blockers proved ineffective but the patient had a one-year remission of symptoms at the age of thirteen on carbamazepine, an anticonvulsant drug chosen because it had also been noted experimentally to shorten the QT interval.⁷ Regrettably she had a further single attack which proved fatal. She died at the age of 14 years.

Her younger brother commenced to suffer from similar attacks at the age of 15 months. Most of his attacks were associated with emotional distress. On advice he was given prophylactic treatment 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.⁸ With hindsight his drug treatment was inappropriate. Finding two siblings with prolonged QT prompted investigation of the parents. 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 was carried out on both children by Professor Dermot Holland. He reported that there was no pathological change in the heart muscle or in the conducting system. Professor Brendan Coakley, who was at that time engaged in studying the cardiac conducting system was in agreement.⁹ When the materials were later reviewed at the National Heart Hospital by Reginald Hudson, Professor of Cardiac Pathology, he also concurred. Queries had been raised about the possibility of impaired arterial supply to the conducting system. His final conclusion was that there was no vascular structural abnormality(Personal communication March 8th 1972)

When the original report was published, the Internet had not as yet been developed. The Lancet employed a staff of readers to review journals for new developments. The 1964 Dublin paper was trawled up by one of the readers and brought to the attention of Dr Ian Munro, then the Deputy Editor. He telephoned the author and suggested a meeting in London. He outlined the editorial comment which he proposed to publish . He planned to call the condition familial cardiac arrhythmia. He would not declare it to be an eponymous disorder.

His recent designation of Mongolian idiocy as Down’s syndrome had attracted criticism¹⁰. Moreover there was an established convention that it was inappropriate to use eponyms during the lifetime of an author¹¹.The convention has not been uniformly observed ¹¹. LQTS occurs in two separate populations.A recessive form was described by Jervell and Lange Nielsen in children with congenital deafness and the second is the dominant disorder presently under discussion. No formal case has been made for abandoning the descriptive term proposed by Munro. In practice however LQTS is now commonly used as a generic term covering both forms, each type being designated by a subsidiary eponym.

The editorial review duly appeared ¹³. Correspondence followed. Romano wrote from Italy.¹⁴ He drew attention to his 1963 publication, in association with two colleagues, describing three early infant deaths in one family, and with a confirmed association with prolonged Q T and torsades de pointes.¹⁵ The index case was old enough for deafness to be excluded, eliminating the Jervell Lange Nielen syndrome. ECG records of the parents were not included in the publication, leaving a question as to whether the condition had been confirmed to be identical or whether there might conceivably have been some other reason for the long QT reported. Felicitously Cesare Romano was a fellow paediatrician, and director of the paediatric department of the University of Genova. Regrettably our paths never crossed.

Further correspondence followed. Details of five cases in South Africa were described by Barlow, Bosman and Craig Cochran.

¹⁶ Gamsthorp, Nielsen and Westling wrote from Sweden drawing attention to the scientific work of Paul Cannon on the after- potentials in the electrocardiogram which accounted for T wave abnormalities experimentally.¹⁷Cannon was later to suggest the use of betablockers and digoxin¹⁸. By good fortune Professor (now Sir Peter) Froggatt and his associates were already involved in a major international study on the Jervell and Lange Nielsen syndrome. They had developed a regression formula for the correction of the Q T according to sex, age, and heart rate.¹⁹ One of his co-investigators, Tom Murphy, at that time Professor of Social Medicine in University College, went on later to become President of the College.

Using the Froggatt formula Edward Tempany, the first Senior Research Fellow at the Children’s Research Centre, travelled around the country carrying out ECG recordings on members of the extended family. These confirmed with certainty that the condition was an autosomal dominant. No abnormal electrocardiograms were identified among the father’s relatives but several among the mother’s. Additionally a sister of the mother had died in early life and autopsy had excluded structural cardiac disease.

Peter Froggatt continued to contribute advice and information over the years while his own research was being completed. In due course he issued an invitation for the reporting of the Dublin investigations in the Whitla Hall in the Queen’s University in 1972, listed. in the university calendar as a Distinguished Scholar’s Lecture. He maintained an interest in the overall significance of prolonged QT in medicine and delivered the Foundation Day Lecture in Our Lady’s Hospital in 1977 on the suggested relation between QT and cot death.²¹

Reports from many countries followed over the years. By 1971 a total of 51 patients had been reported by Kringlebach and Wennevold with QT prolongation without deafness.²² The report referred to it as Ward’s syndrome. The first attribution of joint eponymity came in the same year.²³ The sole use of the Romano name, excluding the names of his Italian co-authors, was not criticised, Romano having been the solitary signatory to the seminal letter to the Lancet, nor did the absence of confirmation of dominant inheritance. Others followed.²⁴ Nowadays the eponyms usually used as a subsidiary descriptive term. The eponym is listed in standard textbooks of genetics. Mc Kusick uses the term Ward Romano syndrome as his first choice of the options available²⁵ and Towbin lists it as an optional descriptive term.²⁶ One internet website identifies it as one of eleven eponymous conditions described in Dublin over the last two centuries ²⁷ and Wormer’s text lists it as one of four Irish cardiac eponyms.²⁸

As pointed out by Murphy the condition is uncommon¹ The incidence is estimated at 1/10,000 births. No further familial cases came under the author's care. Three sporadic non familial single cases were noted. One was a girl who survived a near-drowning episode, a well recognised presentation. Another was a toddler whose older brother noticed that he was pulseless in what had been thought to have been a breath holding attack and the third was an adolescent who had been thought at first to have epilepsy, another misleading presentation. A cardiac ion channel disorder may account for 20% of sudden infant deaths.²⁹ Long QT syndrome accounts for only a small number of unexpected exercise related deaths in young people, but without molecular genetic analysis the true incidence cannot be defined ^{30, 31}. Autopsy examination without genetic molecular analysis in such cases must be considered to be incomplete³².

Desmond Duff published details of two further affected Irish families and emphasised the need to do an ECG in cases of atypical seizure or syncope especially if precipitated by exercise or anxiety.³³ While on a postgraduate fellowship in Baylor College in Houston he had contributed to an investigation of the genetics of the condition.³⁴ Large scale international studies have established a firm basis for diagnosis in typical cases. From the same group. Moss et al reported on 328 families, including the Dublin cases, with 3,343 members, and found that the prognosis was better in females³⁵.Further studies have stratified the risks to affected individuals. A combination of female sex and a QT of greater than 50 msecs identifies a risk of a serious cardiac event before the age of forty of at least 50%.³⁶ The individual underlying cellular potassium and sodium ion transport channel anomalies are now well understood.³⁷ The ECG diagnosis can be difficult and the extension of easy access to molecular genetic testing should have a high priority.

Many distinguished colleagues have made major contributions to the clarification of the QT problem. A crucial fact remains. It was the tenacious insistence of an experienced family doctor which led to the initial clinical diagnosis. He recognised a history which was a mismatch for any proposed diagnosis and insisted that an answer be found. Family doctors remain the curators of the traditions of clinical medicine.

Correspondence: Conor Ward,
18 Thamespoint, Teddington,
Middlesex TW11 9PP, UK.
Email: [email protected]

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