Romano-Ward syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Synonyms and keywords: Autosomal dominant long QT syndrome; long QT syndrome without deafness; romano-ward long QT syndrome; ward-romano syndrome; romano-ward syndrome; LQTS; RWS

Overview

Romano-Ward syndrome is a rare congenital genetic condition with autosomal dominant inheritance pattern which leads to abnormal ventricular myocardial repolarization which results in long QT syndrome (LQTS). Among all other long QT syndrome (LQTS) Romano-Ward syndrome is the most common one. Romano-Ward syndrome is due to mutation in LQT1, LQT2 and LQT3 genes. Romano-Ward syndrome has a purely cardiac phenotype of QT prolongation in contrast to Jervell and Lange-Nielsen syndrome which has both sensorineural deafness and cardiac events.

Historical Perspective

• In 1963, Romano and in 1964, Ward was the first to discover almost similar condition like Jervell and Lange-Nielsen syndrome and they named it as Romano-Ward syndrome.
• In 1990, LQTS 1, LQTS 2 and LQTS 3 the three main types of LQTS and their genes involved and proteins involved are identified for the first time.

Classification

• 

  LQT1-associated S3 mutants traffic to the plasma membrane in ltk− cells. (A) Western blot of WT and mutant KCNQ1+KCNE1 proteins expressed in ltk− cells, untreated and treated with proteinase K (PK) to distinguish surface-expressed channel from internal. After normalization to actin for control of loading, the percent surface protein was determined from the density of bands before and after proteinase K treatment (n = 3) and was found to be: WT, 73%; D202H, 91%; D202N, 80%; I204F, 80%; I204M, 90%; V205M, 75%; S209F, 82%; V215M, 75%. (B) Model of KCNQ1 tetrameric channels showing the locations of S3 mutations in space fill from the side and the extracellular face, with each subunit a different color. Case courtesy by Jodene Eldstrom et al

  The Long QT syndrome (LQTS) may be classified into several subtypes:

LQT	Gene Involved	Chromosome involved	Protein Involved	Ion channel Involved
LQT 1	KCNQ1	11p15.5	Iks a subunit	Iks
LQT 2	HERG	7q35-36	Ikr a subunit	Ikr
LQT 3	SCN5A	3q21-24	Sodium channel	INa
LQT 4	NOT KNOWN	4q25-27	Unknown	Unknown
LQT 5	KCNE1	21q22.1-2	Iks a subunit	Iks
LQT 6	KCNE2	21q22.1	Ikr b subunit	Ikr

Pathophysiology

• Mutations in the ANK2, KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A genes cause Romano-Ward syndrome
• The proteins made by most of these genes form channels that transport positively-charged ions, such as potassium and sodium, in and out of cells
• In cardiac muscle, these potassium and sodium ion channels play critical roles in maintaining the heart's normal rhythm
• Mutations in any of these genes alter the structure or function of channels, which changes the flow of ions between cells and results in abnormal heart rhythm
• A disruption in ion transport alters the way the heartbeats, leading to the abnormal heart rhythm characteristic of Romano-Ward syndrome
• Unlike most genes involved in Romano-Ward syndrome, the ANK2 gene does not produce an ion channel but instead the protein made by the ANK2 gene ensures that other proteins, particularly ion channels, are inserted into the cell membrane appropriately

• Then the truncated protein results in impairing potassium channel function, which is known to result in long QT syndrome.

Causes

Genetic Causes

• Romano-Ward syndrome is caused by a mutation in the ANK2, KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A genes.

Differentiating Romano-Ward syndrome from other Diseases

Romano-Ward syndrome must be differentiated from Jervell and Lange-Nielsen syndrome (JLNS), Timothy syndrome, Andersen-Tawil syndrome, Brugada syndrome, and Sudden infant death syndrome (SIDS).

Epidemiology and Demographics

Incidence

• The incidence of Romano-Ward syndrome is approximately 1 in 2,000 people worldwide individuals worldwide.

Prevalence

• The prevalence of Romano-Ward syndrome is approximately 1:20 000 to 1:5000 individuals worldwide.
• The prevalence of Romano-Ward syndrome is approximately 1 in 2000 live births.

Race

• There is no racial predilection to Romano-Ward syndrome.

Gender

• Romano-Ward syndrome affects men and women equally.

Risk Factors

• Apart from the genetic mutations in ANK2, KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A genes, there are some risk factors associated with Romano-Ward syndrome.
• Other common risk factors in the development of Romano-Ward syndrome symptoms include sudden sleep arousal, exercise and intense or sudden emotion which include the following:
  • Competitive sports, amusement park rides, frightening movies, jumping into cold water etc

• Based on the genotype the triggering events may differ, for example:
  • In patients with LQT1 genotype exercise or swimming is the trigger for cardiac events due to stimulation of vasovagal reflex
  • In patients with LQT2 genotype emotions, exposure to auditory stimuli like door bells, telephone ring can trigger the cardiac events
  • In patients with LQT3 genotype cardiac events can be triggered during sleep

Screening

• There is insufficient evidence to recommend routine screening for Romano-Ward syndrome.

Natural History, Complications and Prognosis

Natural History

• The symptoms of Romano-Ward syndrome usually develop in the second decade of life, and start with symptoms such as syncope and palpitations.
• The symptoms of Romano-Ward syndrome typically decreases with increase in the age, after the age of 40 years the symptoms are less common than usual.

Complications

• Common complications of Romano-Ward syndrome include:
  • Cardiac arrhythmias
  • Cardiac arrest
  • Seizures
  • Sudden cardiac death: Most commonly occurs during the sleep

Prognosis

• The prognosis varies with the type of genes and mutations involved in the pathogenesis of the Romano-Ward syndrome patients. However, the prognosis is generally range from poor to good

Diagnosis

Diagnostic study of choice

• Along with clinical features and molecular genetic testing is the gold standard test for the diagnosis of Romano-Ward syndrome which includes single-gene testing, use of a multigene testing panel, and more comprehensive genomic testing.

• The following result of molecular genetic testing is confirmatory of Jervell and Lange-Nielsen syndrome (JLNS):
  • ANK2, KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A genes variants identification

History and Symptoms

Common Symptoms

Common symptoms of Romano-Ward syndrome include:

• Presyncope
• Syncope
• Palpitations: All the first three symptoms are normally self limiting and may reoccur most of the time
• Tachycardia
• Ventricular arrhythmia
• Torsade de pointes

Less Common Symptoms

Less common symptoms of Romano-Ward syndrome include

• Ventricular fibrillation
• Seizures: Patients with seizures in Romano-Ward syndrome usally not respond to anti-epileptic medications.
• Atrial fibrillation

Physical Examination

• In patients with long QT syndrome (LQTS) physical examination usually limited and do not indicate a diagnosis of long QT syndrome (LQTS).

Vital Signs

• Bradycardia with regular pulse for their age

Heart

• Cardiovascular examination of patients with Romano-Ward syndrome should be done to rule out other causes of arrhythmic and syncopal events which include the diseases like heart murmurs caused by hypertrophic cardiomyopathy, valvular defects

LQT1 patient ECG showing a normal T wave pattern and average QTc of about more than 480 msec. Case courtesy by G. Michael Vincent, MD

Laboratory Findings

• There are no diagnostic laboratory findings associated with Romano-Ward syndrome.

• Laboratory findings that should be considered and checked routinely in Romano-Ward syndrome include:
  • Serum potassium levels
  • Serum magnesium levels

Electrocardiogram

• 

  Romano-Ward syndrome with the broad-based T pattern. Case courtesy by G. Michael Vincent, MD

  An ECG may be helpful in the diagnosis of Romano-Ward syndrome. Findings on an ECG diagnostic of Romano-Ward syndrome include the following:
  • Prolongation of the QTc interval greater than 500 msec
    • Usually defined as longer than 440 ms for males and 460 ms for females on the electrocardiogram
  • Tachyarrhythmias: due to abnormal cardiac depolarization and cardiac repolarization
  • Ventricular tachycardia
  • Torsade de pointes ventricular tachycardia
  • Ventricular fibrillation

• Stress ECG or a treadmill ECG testing also may be helpful in the diagnosis of Romano-Ward syndrome

X-Ray

Representative electrocardiograms (ECG) from members of a family with LQTS. Top, ECG from a normal family member (I-1); Middle, ECG from a heterozygous mutation carrier; Bottom, ECG from a homozygous mutation carrier.

• There are no x-ray findings associated with Romano-Ward syndrome.

Ultrasound

• 

  Transthoracic echocardiogram showing severe dilation and systolic dysfunction of the left ventricle. Case courtesy by Kiona Y. Allen, MD

  Ultrasound may be helpful in the excluding diagnosis of Romano-Ward syndrome with other diseases that may cause the arrhythmias which include:
  • Hypertrophic cardiomyopathy
  • Arrhythmogenic right ventricular cardiomyopathy

MRI

• Chest MRI may be helpful in the excluding diagnosis of Romano-Ward syndrome with other diseases that may cause the arrhythmias which include:
  • Hypertrophic cardiomyopathy
  • Arrhythmogenic right ventricular cardiomyopathy

Treatment

Medical Therapy

• Patients with Romano-Ward syndrome are treated with beta-adrenergic blockers as the first line in the management of the disease.
• In patients with Romano-Ward syndrome despite treated with the beta-blockers risk of cardiac events still persists.
• Using metoprolol in patients with Romano-Ward syndrome are at a significantly higher risk for breakthrough cardiac events (BCE). So it's better to not use in patients with symptomatic LQT1 and LQT2 syndromes.
• Propranolol and nadolol are the beta-blockers of choice when treating a patient with Romano-Ward syndrome. Of the two nadolol is the preference of choice due to less favorable pharmacokinetic profile of propranolol.
• Beta blockers works by inhibiting adrenergic stimulation of the heart via the beta-receptors.
  • Preferred regimen (1): Nadolol 1–1.5 mg/kg/day administered once a day in patients ≥12 years of age, divided twice daily in infants and children
  • Preferred regimen (2): Propranolol 3 mg/kg/day

• In patients with Romano-Ward syndrome potassium and magnesium deficiency should be corrected.
• In patients with Romano-Ward syndrome LQT3 genotype sodium channel blockers which include mexiletine, flecainide, and ranolazine could be considered as the treatment options.

Acute Management of Torsades de pointes

• The treatment of choice for hemodynamically unstable patients acute management of Torsades de pointes in Romano-Ward syndrome patients are with the following:
  • Electrical cardioversion or defibrillation
  • If ventricular tachycardia is suspected or diagnosed treat the patient with cardiopulmonary resuscitation and the advanced cardiac life support (ACLS) protocol has to be initiated.
• If the patient is hemodynamically stable or cardioversion fails then treat the patient with following:
  • Preferred regimen (1): Magnesium sulfate 20–50 mg/kg intravenously initially up to 2 grams max

Interventions

• The feasibility of interventions depends on the severity of Romano-Ward syndrome patients at the time of diagnosis which include:
  • Implantable cardioverter-defibrillators (ICDs)
    • ICDs are reserved for the patients who undergone cardiac arrest resuscitation
    • ICDs are good alternative choice of treatment for the patients who are resistant to beta blockers

Surgery

• Surgery is not the first-line treatment option for patients with Romano-Ward syndrome which is stellectomy. Stellectomy is usually reserved for patients with either high-risk patients with long QT syndrome (LQTS), recurrent cardiac problems despite using beta-blocker treatment, and patients who have several ICD discharges.
  • Stellectomy: Stellectomy (Left cardiac sympathetic denervation) usally involves excision of the stellate ganglion

Primary Prevention

• There are no established measures for the primary prevention of Romano-Ward syndrome.

Secondary Prevention

• Effective measures for the secondary prevention of Romano-Ward syndrome include:
  • Taking special care while giving the anesthesia due to the risk of cardiac arrhythmias
  • Avoiding intense or sudden emotions which are trigger for syncope

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