Short QT syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]

Synonyms and keywords: SQTS; short QT; short QTc; QT interval shortening

Short QT syndrome is a rare autosomal dominant inherited disease of the electrical conduction system of the heart. It is defined by short QT intervals (≤ 360 ms) that increases an individual propensity to atrial and ventricular tachyarrhythmias.^[1] It occurs due to gain-of-function mutations in genes encoding for cardiac potassium channels KCNH2, KCNQ1 and KCNJ2. The shortened QT interval does not significantly change with heart rate, and there are tall and peaked T waves in the right precordium. It is associated with an increased risk of atrial fibrillation, syncope and sudden death.

The syndrome was first described by Dr. Prebe Bjerregaard MD, DMSc in 1999, who wrote the first clinical report of three members of one family who presented with persistently short QT interval.^[2][3]

• Short QT syndrome type 1 (SQT1): This variant is due to a gain-of-function mutation of the rapid component of the delayed rectifier potassium current HERG (KCNH2) channel(IKr)^[4]. The variant is a result of missense mutations which increase IKr. It is associated with sudden death and sudden infant death syndrome.
• Short QT syndrome type 2 (SQT2): Caused by a mutation in the KCNQ1 gene^[5]. In the first patient, a g919c substitution in the KCNQ1 gene encoding for the K+ channel KvLQT1 was identified. The mutation led to a gain of function in in the KvLQT1 (I(Ks)) channel. This variant is associated with ventricular fibrillation.
• Short QT syndrome type 3 (SQT3): This variant results from a G514A substitution in the KCNJ2 gene ( a change from aspartic acid to asparagine at position 172 (D172N))^[6]. This causes a defect in the gene coding for the inwardly rectifying Kir2.1 (I(K1)) channel. The ECG shows asymmetrical T waves. These patients have an increased risk for re-entry arrhythmias.
• Short QT syndrome type 4 (SQT4): A loss of function mutation in the CACNA1C gene alters the encoding for the α1- and β2b-subunits of the L-type calcium channel. The phenotype is similar to Brugada syndrome combined with a short QT interval. There is an increased risk of sudden cardiac death.
• Short QT syndrome type 5 (SQT5): A loss of function mutation in the CACNB2B gene alters the encoding for the α1- and β2b-subunits of the L-type calcium channel. The phenotype is similar to Brugada syndrome combined with a short QT interval. There is an increased risk of sudden cardiac death.
• Short QT syndrome type 6 (SQT6): A loss of function mutation in the CACNAD2D1 coding for the Cavα2δ-1 subunit of the L-type calcium channel. ^[7]

Short QT syndrome types 1-3 are due to increased activity of outward potassium currents in phase 2 and 3 of the cardiac action potential due to mutations in potassium channels. This causes a shortening of the plateau phase of the action potential (phase 2), causing a shortening of the overall action potential, leading to an overall shortening of refractory periods and the QT interval. In the families afflicted by short QT syndrome, two different missense mutations have been described in the human ether-a-go-go gene (HERG). These mutations result in expression of the same amino acid change in the cardiac I_Kr ion channel. This mutated I_Kr has increased activity compared to the normal ion channel, and would theoretically explain the above hypothesis. Short QT syndrome types 4 and 5 and 6 are due to mutations in the calcium channel and consequent reduction in L-type Ca-channel current.^[8]

In the families afflicted by short QT syndrome, mutations have been described in three genes, KvLQT1, the human ether-a-go-go gene (HERG), and KCNJ2. Mutations in the KCNH2, KCNJ2, and KCNQ1 genes cause short QT syndrome. These genes provide instructions for making proteins that act as channels across the cell membrane. These channels transport positively charged atoms (ions) of potassium into and out of cells. In cardiac muscle, these ion channels play critical roles in maintaining the heart’s normal rhythm. Mutations in the KCNH2, KCNJ2, or KCNQ1 gene increase the activity of the channels, which changes the flow of potassium ions between cells. This disruption in ion transport alters the way the heart beats, leading to the abnormal heart rhythm characteristic of short QT syndrome. Short QT syndrome appears to have an autosomal dominant pattern of inheritance.

Due to the autosomal dominant inheritance pattern, individuals may have family members with a history of unexplained or sudden death at a young age (even in infancy), palpitations, or atrial fibrillation. The penetrance of symptoms is high in affected family members. It is also interesting to note that while mutations involving potassium channel genes associated with the long QT syndrome are loss-of-function mutations, the mutations that cause short QT syndrome are gain-of-function mutations.^[9]

The calcium channels’ dysfunction are mostly due to CACNA1C and CACNB2b genes mutation which caused Brugada-like ECG changes with short QT interval. Lastly, a novel mutation of the CACNA2D1 gene was reported in a 17-year-old female who presented with short QT interval and ventricular fibrillation.^[9]

The causes of shortening of the QT interval can be divided into primary causes (Short QT syndrome types 1-5) and secondary causes such as drugs and electrolyte disturbances.

• Hypercalcemia
• Digoxin

• Acidosis
• Altered autonomic tone
• Digoxin
• Hypercalcaemia
• Hyperkalemia
• Hyperthermia
• Lanatoside C
• Rufinamide
• Short QT syndrome type 1
• Short QT syndrome type 2
• Short QT syndrome type 3
• Short QT syndrome type 4
• Short QT syndrome type 5
• Short QT syndrome type 6

Short QT may have secondary causes that must be ruled out, since the short QT syndrome is by definition a primary, congenital disease of the heart. Such causes include: hyperkalemia, hypercalcemia, acidosis, hyperthermia – caused by the use of drugs like digitalis, effect of acetylcholine or catecholamine and activation of Katp or Kach current.^[1] Only after ruling out such causes is that the diagnosis of short QT syndrome may be made.

European studies have estimated a prevalence of 0.02% to 0.1% among adults. A paper from 2015 which tried to assess the prevalence among pediatric population in the U.S. estimated a prevalence of 0.05% at this population.^[10] Sudden cardiac arrest has a peak incidence between the second and fourth decades of life, which might indicate an association with testosterone levels in males.^[9]

The disease can have clinical manifestations from the first year of life until as late as 80 years old, and most cases are symptomatic.^[9] Its most frequent symptoms include cardiac arrest (which was the first symptom in 28% of the patients), followed by palpitations, and syncope. Patients may also present with atrial fibrillation and ventricular extrasystoles. They remain at high risk for sudden death during their lifetime and may present with a strong family history for this occurence.^[9] Sudden cardiac death presents with two high-risk peaks, one in the first year of life, and another one from 20 to 40 years old.^[11] Even though familial association is present in the majority of patients, the yields for genetic tests is low.^[9]

Since the disease is so rare, no screening for the general population is advised. Individuals with short QT interval detected on the ECG must first rule out other causes. Genetic screening is performed if a patient presents with: sudden cardiac arrest, history of polymorphic ventricular tachycardia or ventricular fibrillation without a known cause, history of unexplained syncope, young individuals with atrial fibrillation, family members diagnosed with short QT syndrome, family members who died from sudden cardiac arrest.^[12]

The first step for diagnosing short QT syndrome is ruling out secondary causes, such as the ones cited above.^[1] Once them are ruled out, there are two suggested diagnostic approaches in the medical literature: one proposed by GOLLOB, and another one proposed by PRIORI:

– Scoring type of diagnostic criteria, as proposed by the Arrhythmia Research Laboratory at the University of Ottawa Heart Institute from Drs. Michael H Gollob and Jason D Roberts.^[13]

Diagnostic Criteria for Short QT Syndrome from UoO Heart Institute

QTc in milliseconds <370 = 1 point <350 = 2 points <330 = 3 points

J point – T peak interval in milliseconds <120 = 1 point

Clinical History Sudden cardiac arrest = 2 points Polymorphic VT or VF = 2 points Unexplained syncope = 1 point Atrial fibrillation = 1 point

Family History 1st or 2nd degree relative with SQTS = 2 points 1st or 2nd degree relative with sudden death = 1 point Sudden infant death syndrome = 1 point

Genotype Genotype positive = 2 points Mutation of undetermined significance in a culprit gene = 1 point

The points are summed and interpreted as follows:

• > or equal to 4 points: High-probability of SQTS
• 3 Points: Intermediate probability of SQTS
• 2 points or less: Low probability of SQTS

– Diagnostic criteria suggested by PRIORI, 2015 for the European Society of Cardiology:

• QTc <340ms or QTc <360ms and one or more of the following:
  • Confirmed pathogenic mutation;
  • Family history of SQTS;
  • Family history of sudden death at 40 years of age;
  • Survival from a VT/VF episode at the absence of heart diseases.^[14]
    

While the QT interval is generally short, the QT interval alone cannot be used to distinguish the patient with short QT syndrome from a normal patient (similar to long QT syndrome).^[15] In general though, if the QTc is < 330 msec in a male, and <340 msec in a female, then short QT syndrome can be diagnosed even in the absence of symptoms as these QT intervals are much shorter than in the rest of the population. On the other hand, if the QTc is moderately shortened to < 360 msec in a male or < 370 msec in a female, the short QT syndrome should only be diagnosed in the presence of symptoms or a family history according to the guidelines above. ^[14][13]

The QTc is usually < 300-320 msec.^[4][5][6]

The QTc is usually just under 360 msec ^[16]

The short QT interval does not vary significantly with the heart rate. Normally the QT will become longer at slow heart rates and this does not occur among patients with short QT syndrome. The Bazett formula may overcorrect (i.e. shorten) the QT interval in the patient with bradycardia, and it is therefore important to use treadmill testing to increase the heart rate and confirm the absence of QT interval variation.^[17]

• There is a high prevalence of early depolarization patterns on SQTS.^[8]
• QRS complex is followed by T wave without any ST segment.^[9]

• Prominent U wave separated by isoelectric T-U segment.^[9]
• Longer Tpeak – Tend interval.^[9]
• Prolongation of the QT interval at slower heart rates is suppressed, remaining below the lower limit.^[9]
• Depressed PQ segment commonly observed in the inferior and anterior leads.^[9]

• In a very limited number of patients it has been observed that early repolarization (which is present in 65% of patients with SQTS) and a longer T wave peak to T wave end period is associated with the occurrence of arrhythmic events.^[18]

70% of patients with short QT have a history of either paroxysmal atrial fibrillation or permanent atrial fibrillation, and atrial fibrillation is the first sign of short QT syndrome in 50% of patients. In young patients with lone atrial fibrillation, the patient should be screened for short QT syndrome.

Among patients with SQTS, the atrial and ventricular refractory periods are shortened (ranging from 120 to 180 ms). Ventricular fibrillation can be induced on programmed stimulation in 90% of patients with short QT syndrome. Despite the high rate of VF inducibility, the risk of sudden death in an individual patient is difficult to predict given the genetic and clinical heterogeneity of short QT syndrome and the limited number of patients with short follow-up to date. The limitations of electrophysiologic testing are highlighted by a study of Giustetto et al in which the sensitivity of electrophysiologic testing in relation to the clinical occurrence of ventricular fibrillation was only 50% (3 of 6 cases)^[19]. Importantly, lack of inducibility does not exclude a future episode of ventricular fibrillation^[20]. Thus, the role of electrophysiologic testing in risk stratification of the patient with SQTS is not clear at present.

Because new genetic variants of SQTS are still being identified, a negative genetic test for existing variants does not exclude the presence of SQTS. A negative genetic test for existing variants could mean that a patient with a short QT interval does not have a heretofore unidentified variant of SQTS.

However, among family members of an affected patient, genetic testing may identify the syndrome in an asymptomatic patient, and may also rule out the presence of the syndrome in asymptomatic patients.

Mutations in the KCNH2, KCNJ2, and KCNQ1 genes cause short QT syndrome. These genes provide instructions for making proteins that act as channels across the cell membrane. These channels transport positively charged atoms (ions) of potassium into and out of cells. In cardiac muscle, these ion channels play critical roles in maintaining the heart’s normal rhythm. Mutations in the KCNH2, KCNJ2, or KCNQ1 gene increase the activity of the channels, which changes the flow of potassium ions between cells. This disruption in ion transport alters the way the heart beats, leading to the abnormal heart rhythm characteristic of short QT syndrome. Short QT syndrome appears to have an autosomal dominant pattern of inheritance.

• Gene Tests: Short QT Syndrome 1
• Gene Tests: Short QT Syndrome 2
• Gene Tests: Short QT Syndrome 3

An implantable cardioverter-defibrillator (ICD) is indicated in symptomatic patients who have either survived a sudden cardiac arrest and/or have had documented episodes of spontaneous sustained ventricular tachyarrhythmias with or without syncope. There’s a problem with ICD in such patients though, because the tall and peaked T wave can be interpreted as a short R-R interval provoking inappropriate shock.^[9]

Generally accepted criteria for implantation of an AICD also include:

• Inducibility on electrophysiologic testing;
• Positive genetic test, although a negative result does not exclude the presence of a previously unreported mutation or the occurrence of a future arrhythmic event.

Inappropriate shocks may be delivered due to^[21]:

• The occurence of tachycardias such as sinus tachycardia and atrial fibrillation.
• Oversensing of the tall, narrow peaked T wave.

The efficacy of pharmacotherapy in preventing ventricular fibrillation has only been studies in patients with SQT1. Given the limited number of patients studied, and the limited duration of follow-up, pharmacotherapy as primary or secondary preventive therapy for patients with SQT1 cannot be recommended at this time. AICD implantation remains the mainstay of therapy in these patients. Pharmacotherapy may play an adjunctive role in reducing the risk of events in patients with an AICD as described below in the indications section.

Patients with Short QT Syndrome 1 (SQT1) have a mutation in KCNH2 (HERG). Class IC and III antiarrhythmic drugs do not produce any significant QT interval prolongation ^[22][23] . Flecainide has not been shown to consistently reduce the inducibility of ventricular fibrillation.^[24] Although it does not prolong the QT interval in SQT1 patients, propafenone reduces the risk of recurrent atrial fibrillation in SQT1 patients.^[25]

Quinidine in contrast may be effective in patients with SQT1 in so far as it blocks both potassium channels (IKr, IKs, Ito, IKATP and IK1) and the inward sodium and calcium channels. In four out of four patients, Quinidine prolonged the QT interval from 263 +/- 12 msec to 362 +/-25 msec, most likely due to its effects on prolonging the action potential and by virtue of its action on the I_K channels. Although Quinidine was successful in preventing the inducibility of ventricular fibrillation in 4 out of 4 patients, it is unclear if the prolongation of the QT interval by quinidine would reduce the risk of sudden cardiac death. It also prolonged the ST interval and T wave durations, restored the heart rate dependent variability in the QT interval and decreased depolarization dispersion in patients with SQT1.

There is a report which states that disopyramide was also effectively used in two patients with SQT-1, increasing their QT interval and ventricular refractory period while also abbreviating the Tpeak-Tend interval.

As atrial fibrillation is also very commonly found on those patients propafenone has also been successfully used to prevent its paroxysms, without having any effect on QT interval.^[9]

Although pharmacotherapy can be used to suppress the occurrence of atrial fibrillation in patients with SQT1, AICD implantation is the mainstay of therapy, and pharmacotherapy to prevent sudden death should is only indicated if AICD implantation is not possible.

The following are indications for pharmacologic therapy of SQTS^[26]:

• In children as an alternate to AICD implantation;
• In patients with a contraindications AICD implantation;
• In patients who decline AICD implantation;
• In patients with appropriate AICD discharges to reduce the frequency of discharges;
• In patients with atrial fibrillation to reduce the frequency of symptomatic episodes.

it:Sindrome del QT breve

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Sumanth Khadke, MD[2]}

The first evidence of Sudden cardiac death relating to decreased QT interval surfaced in year 1993^[1]. The Short QT syndrome (SQTS) was first described by Dr. Prebe Bjerregaard MD, DMSc in 1999^[2][3]. It was first identified in 1999 in a 17-year old patient who underwent laparoscopic cholecystectomy in Maryville,Illinois^[2].In 2004, Among the first families to report SQTS, among them the German family and the Italian family had substitution mutation in the KCNH2 gene which substituted arginine for lysine at codon 588 in KCNH2 protein which coded for S5-P loop region of cardiac IKr channel HERG^[4]. In 2004, Quinidine was found to be effective in treating SQTS syndrome and was used as first-line treatment in SQTS while Flecainide provides partial relief^[5].In 2004, the first patient with Ventricular fibrillation with SQTS was treated with ICD placement^[6]. In 2005, first evidence of fetal bradycardia due to SQTS was reported^[7]. In 2007 and 2008 studies linked SQTS to SIDS^[8].In 2011, the clinical guideline on diagnosing SQTS was established ^[9][10]. A “Schwartz score” was proposed to be instrumental in diagnosis SQTS ^[11].

• Shalon Hill, a 17-year-old white female, underwent laparoscopic cholecystectomy at Anderson Hospital, Maryville, Illinois in 1999 which was complicated by atrial fibrillation with a rapid ventricular response (RVR) at 150-200 beats/min along with acute pulmonary edema^[2][12]. The atrial fibrillation with RVR was treated with DC cardioversion and she was discharged to home in normal sinus rhythm on digoxin. The atrial fibrillation recurred 6 weeks later and she was found at that time to have a short QT interval of 225 mseconds unrelated to hypercalcemia, was treated with prophylactic therapy with propafenone^[13]. She then remained asymptomatic for 6 months and the propafenone was discontinued. However, the atrial fibrillation recurred 2 months after the propafenone was discontinued, and it was therefore resumed. She remained asymptomatic on propafenone, but an AICD was implanted given reports from around the world of sudden cardiac death.

• EKGs of the first patient’s family members were analyzed. The QT intervals of her 21 year old brother and her 84 year old maternal grandfather were 240 msecs each, and the QT interval of her 51 year old mother was 230 msec. The EKG of here father was normal^[2][14].
• Her brother was asymptomatic, and on August 13, 2003 was found to have inducible ventricular fibrillation on programmed electrical stimulation. This was treated with implantation of an implantable cardioverter defibrillator. Subsequently, he complained of occasional palpitations and paroxysmal atrial fibrillation with a rapid ventricular response was noted on the interrogation of the ICD.
• Her mother is a 51-year-old healthy white female with a history of 3 episodes of sustained palpitations and paroxysmal atrial fibrillation. She has remained asymptomatic on propafenone since April 2003. Programmed electrical stimulation on September 29, 2003, induced both atrial and ventricular fibrillation and an AICD was implanted.
• Her maternal grandfather was an 84-year-old white male who had chronic atrial fibrillation, coronary artery disease and hypertension who died following an embolic stroke.The then cardiologists waited for a few years for another family to show such symptoms to investigate if this was a unique syndrome. The second case showed up after 3 years in 2003.

• In the year 2003, the suspicion of a life-threatening cardiac syndrome grew when Dr. Fiorenzo Gaita presented a paper at the American College of Cardiology (ACC) originally written by Ospedale Mauriziano Umberto I from Torino, Italy. The research paper described 16 members from 5 generations with 6 sudden cardiac death victims including one and the other 2 additional family members with Short QT syndrome in an Italian family^[15]. Dr. Gaita et. al publish a paper in Circulation journal describing 2 unrelated families having symptomatic Short QT syndrome. Family 1 with 2 adults and 1 child presented with a past medical history of syncope with palpitations. One case had resuscitated sudden death. The family history documented a series of sudden cardiac death pertinent to the past 4 generations. All of them revealed to have a Short QT interval never exceeding 280 msec (QTc- 290msec). An Electrophysiological study was performed with Flecainide administration to prolong the Effective refractory period and to rule out Brugada syndrome. Patient 1, a 35-year-old white man showed frequent isolated monomorphic ventricular extrasystoles with Left Axis Deviation morphology and Right Bundle Branch Block.QT interval was recorded in between 240-280 msec and QTc <280msec^[16]. Patient 2, sister of patient 1, 31-year-old woman, also had Left axis deviation and QT interval between 220 to 250msec (QTc <290msec). Her Holter revealed isolated and monomorphic ventricular extra-systoles with the Right bundle branch block and left-axis deviation with variable coupling^[16]. Patient 3 was the child of patient 2 who had a cardiac arrest at the age of 8 months after a loud noise-induced adrenergic stress. He was successfully resuscitated with DC shock but had severe cerebral hypoxia. The child QT interval ranged between 240-260msec, QTc <290msec. Structural heart disease was ruled out in all these 3 patients prior to Electrophysiological studies. An Automated Defibrillator (ICD) was implanted in both patients 1 and 2 ^[16]. The second family reported with syncope and palpitations with strong family history sudden cardiac death present in 3 generations. Three of the family members had a short QT interval from 270 msec (QTc- 300msec). The patients underwent electrophysiological studies using Flecainide and Holter studies as in the case of family 1. Patient 4, a 67-year-old woman with palpitations had ventricular and supra-ventricular extrasystoles and one episode of paroxysmal atrial fibrillation. ECG showed a QT interval of 270msec (QTc-295msec). Patient 5 was a 15-year-old nephew of patient 4 with syncopal episodes. He had a QT of 260msec (QTc-300msec). Patient 6 was a 40-year-old daughter of patient 4 was asymptomatic with a QT interval of 240 msec(QTc-268msec) on ECG.

• In 1999, Short QT syndrome was first discovered by a United States-based doctor Dr.Preben Bjerregaard, MD, DMSc^[17].
• In 2004, the Masonic medical research laboratory, Utica, New York was the first lab to report a genetic mutation linked to SQTS in the year 2004 ^[18].
• In 2004, Among the first families to report SQTS, The german family and the Italian family had substitution mutation in the KCNH2 gene which substituted arginine for lysine at codon 588 in KCNH2 protein which coded for S5-P loop region cardiac IKr channel HERG^[19].
• In 2004, the first experimental model on SQTS which proved it is the cause of the life-threatening arrhythmia was conducted at the Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan^[20].
• In 2005, the first report of SQTS presenting in a subset of patients as bradycardia in utero was documented^[7].
• In 2007 and 2008, the first studies appeared which linked SQTS to Sudden Infant death syndrome ^[8][21].
• In 2011, first clinical guideline on diagnosing SQTS came into existence ^[9][10]. A “Schwartz score” was proposed to be instrumental in diagnosis SQTS ^[11].

• In 2004, Quinidine was found to be effective in treating SQTS syndrome and was deemed the first-line treatment in SQTS while Flecainide provides partial relief^[5].
• In 2004, the First patient with Ventricular fibrillation with SQTS was treated with ICD placement^[6].

The following are a few famous cases of [disease name]:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2]

Five variants of short QT syndrome have been characterized based upon the underlying genetic mutation, the electrocardiographic phenotype, and the clinical manifestations of the variant. The different genes which are mutated are KCNH 2 gene for SQTS 1 which causes upregulation of Ikr channel, KCNQ 1 for SQT 2 which upregulates IKs, KCNJ 2 gene for SQTS 3 which causes upregulation of alpha subunit of IK1, CACNA1C for SQTS 4 which causes downregulation of ICa and CACNB2b, for SQTS 5 which also causes downregulation of Ica.

	Type	OMIM	Gene	Gene Location	Mutation	Protein	Notes
1	SQTS 1[1][2]	609620	KCNH2 HERG[3]	7q 36.1	Mutation in the KCNH2 gene causing gain of function of α-subunit Ikr	Kv11.1
2	SQTS 2[1][4]	609621	KCNQ1, KvLQT1[3]	11p15.5-p15.4	Mutation in KCNQ1 causing gain of function of α-subunit Iks	Kv7.1
3	SQTS 3[1][5]	609622	KCNJ2, Kir2.1[3]	17q24.3	Mutation in KCNJ2 gene causing gain of function of α-subunit IK1	Kir2.1
4	SQTS 4[1][6]		CACNA1C, Cav1.2[3]	12p13.3	Mutation in CACNB2b causing loss of function of α-subunit ICa (L-channel)	Cav1.2
5	SQTS 5[1][6]		CACNB2b, Cavβ2b[3]	10p12	Mutation in CACNA1c causing loss of function of β2-subunit ICa (L-channel)	Cavβ2

Type 1 SQTS is caused by a missense mutation in KCNH2 gene. It is the most common familial variety of SQTS occurring in autosomal dominant pattern. The KCNH2 gene is located on chromosome 7q 36.1. The KCNH2 gene is often referred as HERG gene. HERG stands for the human ether-a-go-go-related gene which expresses a protein Kv11.1. This protein forms the alpha subunit of potassium channel responsible for rapidly activating rectifier outwards current (Ikr) ^[7].The genetic analysis reveal missense mutation with cytosine to guanine substitution at nucleotide 1764 resulting in change in the amino acid (N588K) in KCNH2 gene. The N588K mutation appears to be the main reason for occurrence of SQTS syndrome^[1]. The Bio-physical analysis reveal a gain of function mutation in IKr currents causing shortening of action potential duration and refractoriness making patients prone to re-entrant type of arrythmias ^[8]. The N588K mutations cause large outward currents in the ventricles sparing the Purkinje fiber system. There is a selective shortening of action potentials and shortening of the refractory periods in ventricles with sparing of the Purkinje fibers. This differential change promotes favorable factors for reentrant arrhythmia^[9]. The functional studies reveal N588K mutation leads to loss of normal correction of IKr at the normal range of voltages. This causes a voltage-dependent inactivation of the channel by +90mV which explains the gain of function of the channel during the plateau phase of the action potential.

Type 2 SQTS is caused by a mutation in the KCNQ1 gene which codes for Kv7.1 protein. This protein forms a part of slowly activating delayed outward potassium current (IKs). Bellocq and colleagues first identified this mutation where Valine was substituted by Leucine at position 307 (V307L). The biophysical analysis showed that KCNQ1 mutation produced physiological outward potassium current but caused a significant shift in the half-activation potential. The mutated channel now got activated at more negative potentials with accelerated activation kinetics. This led to the gain of function of the outward current. The functional studies reveal a shift of -20mV in the half-activation potential and caused enhanced activation or gain of function of IKs channel^[9][10].

Type 3 SQTS is caused by a mutation in the KCNJ2 gene which normally codes for protein Kir 2.1. This protein is believed to form a part of alpha subunit of the inward rectifier IK1 channel. The genetic studies revealed the substitution of aspartic acid by asparagine at position 172 (D172N). The net effect is the gain of function in outward potassium channel IK1 and shortening of the action potential^[9][10].

Type 4 SQTS is caused by a loss of function mutation in the CACNA1C gene. The L-type cardiac calcium channel is the association of α1, β, and α2δ subunits. The pore-forming Cav1.2 α1-subunit is encoded by CACNA1C and the β-subunit is encoded by CACNB2b (mutated in SQT5). CACNA1c codes for pore-forming protein Cav1.2. A missense mutation causing substitution of Alanine by valine at position 39 (A39V) or substitution of Glycine by arginine at position 490 (G490R) is seen in STQS4.

Type 5 SQTS is caused by a loss of function mutation in CACNB2b which codes for protein Cavβ2 which is a part of pore-forming proteins. A missense mutation causing substitution of serine by leucine at position 481 (S481L) is seen in SQTS5.

Both STQS 4 and STQS 5 cause a loss of function of Ica.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2]

Short QT syndrome types 1-3 are due to increased activity of outward potassium currents in phases 2 and 3 of the cardiac action potential. This causes a shortening of the plateau phase of the action potential (phase 2), causing a shortening of the overall action potential, leading to an overall shortening of refractory periods and the QT interval. In the families afflicted by short QT syndrome, two different missense mutations have been described in the human ether-a-go-go gene (HERG). These mutations result in the expression of the same amino acid change in the cardiac I_Kr ion channel. This mutated I_Kr has increased activity compared to the normal ion channel, and would theoretically explain the above hypothesis. Short QT syndrome types 4 and 5 are due to abnormalities in the calcium channel.

In the families afflicted by short QT syndrome, mutations have been described in three genes, KvLQT1, the human ether-a-go-go gene (HERG), and KCNJ2. Mutations in the KCNH2, KCNJ2, and KCNQ1 genes cause short QT syndrome. These genes provide instructions for making proteins that act as channels across the cell membrane. These channels transport positively charged atoms (ions) of potassium into and out of cells. In cardiac muscle, these ion channels play critical roles in maintaining the heart’s normal rhythm. Mutations in the KCNH2, KCNJ2, or KCNQ1 gene increase the activity of the channels, which changes the flow of potassium ions between cells. This disruption in ion transport alters the way the heartbeats, leading to the abnormal heart rhythm characteristic of short QT syndrome. Short QT syndrome appears to have an autosomal dominant pattern of inheritance.

Due to the autosomal dominant inheritance pattern, individuals may have family members with a history of unexplained or sudden death at a young age (even in infancy), palpitations, or atrial fibrillation. The penetrance of symptoms is high in affected family members.

In general, the action potential duration with normal repolarization depends on a delicate balance between the repolarizing currents acting on the myocardium. A decrease in inward depolarizing current like INa or ICa and an increase in the outward repolarizing current like Ito, IK1, IK-ATP, IACh, IKr, or IKs will lead to early repolarization of cardiac ventricles. This decreases the action potential duration and hence QT interval. The genetic studies reveal the cause of arrhythmia to be due to transmural dispersion of repolarization. Dispersion of repolarization and loss of refractoriness which serves as a substrate to initiate re-entry by promoting unidirectional block. Abrupt shortening of wavelength (calculated as a product of the refractory period and conduction velocity) of cardiac impulse helps in the maintenance of reentry. Present data on SQTS suggests shortening of action potentials is heterogeneous in epicardium or endocardial cells in comparison to subendocardial M cells. This eventually translates as an increase in transmural dispersion of repolarization and tall, positive T waves on ECG.

Conditions associated with [disease name] include:

• [Condition 1]
• [Condition 2]
• [Condition 3]

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2]

The causes of shortening of the QT interval can be divided into primary genetic causes (Short QT syndrome types 1-5) and secondary causes such as drugs and electrolyte disturbances like Hypercalcemia and digoxin respectively. A few causes to list are acidosis, altered autonomic tone,Digoxin, hypercalcemia, hyperkalemia, hyperthermia, lanatoside C and rufinamide.

• Hypercalcemia
• Digoxin

• Acidosis
• Altered autonomic tone
• Digoxin
• Hypercalcaemia
• Hyperkalemia
• Hyperthermia
• Lanatoside C
• Rufinamide
• Short QT syndrome type 1
• Short QT syndrome type 2
• Short QT syndrome type 3
• Short QT syndrome type 4
• Short QT syndrome type 5

• Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. There are no life-threatening causes of disease name, however complications resulting from untreated disease name is common.
• Life-threatening causes of [symptom/manifestation] include [cause1], [cause2], and [cause3].
• [Cause] is a life-threatening cause of [disease].

Common causes of [disease name] may include:

• [Cause1]
• [Cause2]
• [Cause3]

OR

• [Disease name] is caused by an infection with [pathogen name].
• [Pathogen name] is caused by [pathogen name].

Less common causes of [disease name] include:

• [Cause1]
• [Cause2]
• [Cause3]

• [Disease name] is caused by a mutation in the [gene name] gene.

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	No underlying causes
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	No underlying causes
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

List the causes of the disease in alphabetical order:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

In contrast to Long QT Syndrome (LQTS), there is often no specific trigger (such as a loud noise or exercise) for an episode of arrhythmia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2]

In contrast to Long QT Syndrome (LQTS), there is often no specific trigger (such as a loud noise or exercise) for an episode of arrhythmia. Short QT syndrome must be differentiated from the normal variant, secondary causes of QT prolongation, and deceleration dependent shortening of QT interval.

Short QT syndrome must be differentiated from normal variant, secondary causes of QT prolongation, and deceleration dependent shortening of QT interval.

• Normal variant: The presence of shorter QT interval does not automatically qualify for a diagnosis of SQTS. It may also represent a normal variant in the general population. Up to 2 % population has QT interval of ≤ 360 msec. This highlights the importance of using the diagnostic criteria for a final diagnosis of SQTS.
• Acquired causes of SQT interval: Conditions like hyperkalemia, acidosis, hyperthermia, hypercalcemia, digitalis, Acetylcholine, and catecholamines are a few causes of SQT interval. For more acquired causes click here.
• Deceleration dependent shortening of QT interval: This is a paradoxical ECG phenomenon termed as a deceleration-dependent shortening of QT interval. A strong parasympathetic stimulation not only leads to bradycardia but also leads to the activation of acetylcholine-sensitive K+ channels (KACh).In this case, the QT interval shortens paradoxically with bradycardia instead of prolongation. This change is a transient one and shall revert when the parasympathetic stimulus is decreased^[1].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2]

Since the syndrome was first described in 2000, < 30 cases have been identified. The median age of presentation in adults is 30 years. The overall prevalence of SQTS is is 0.02 to 0.1% in adults and 0.05% in the pediatric population. In Japanese cohort study of 114,334 patients, prevalence was found to be 0.37 %. In an American cohort of 46,129 prevalence was nearly 2 percent. The Swiss cohort of 1767 patients and Finnish cohort of 10,822 patients had a prevalence of 1 and 0.4 percent respectively.There is a higher male predominance with higher penetrance despite it being autosomal dominant. The mean age of presentation in 30 years.

According to a few studies prevalence of Short QT interval is 0.02 to 0.1% in adults and it is believed to be 0.05% in the pediatric population^[1].

• Inability to identify the risks associated with short QT interval has led to failure in knowing precise prevalence in adults but it appears to be less than 2 percent if a cut off of 360 milliseconds is used. Studies with large cohorts have made attempts to identify how frequently could SQTS occur in the general population.
• In a Japanese cohort of 114,334 patients with ECGs stored in an electronic database, 0.37 percent were found to have short QTc intervals (≤357 milliseconds in males, ≤364 milliseconds in females) ^[2].
• In an American cohort of 46,129 healthy volunteers (53 percent female), nearly 2 percent had a QTc interval ≤360 milliseconds ^[3].
• In a Swiss cohort of 41,767 army conscripts (99.6 percent male, mean age 19 years), 1 percent had a short QTc interval (<347 milliseconds), and 0.02 percent had a very short QTc interval (<320 milliseconds) ^[4].
• In a Finnish cohort of 10,822 middle-aged (mean 44 years) patients, 0.4 percent had a short QTc interval (<340 milliseconds), and 0.1 percent had a very short QTc interval (<320 milliseconds) ^[5]

The median age of presentation is 30 years but ranges from just weeks to the sixth decade of life.

SQTS is believed to affect both males and females equally due to the autosomal dominant nature of the disease. Although, A few studies believe it affects males more than females with high penetrance in males^[6].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2]

Short QT syndrome is an autosomal dominant inherited disease, and having a family member with the disease places an individual at risk for the disease. Family members of affected individuals should, therefore, be screened. New-onset lone atrial fibrillation may be a marker of the disease, and young patients with lone atrial fibrillation should be screened as well. Short QT syndrome should be excluded in patients without structural heart disease presenting with sudden cardiac death.

There is insufficient evidence to recommend routine screening for Short QT syndrome. In the year 2011, The Heart Rhythm Society and the European Heart Rhythm Association have produced an expert consensus statement on genetic testing of channelopathies including SQTS. They recommend genetic testing to be conducted by a cardiologist who has a strong clinical suspicion of SQTS based on history, physical examination, family history, and electrocardiographic findings (grade IIb). Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the SQTS-causative mutation in an index case (grade I)^[1].New-onset lone atrial fibrillation may be a marker of the disease, and young patients with lone atrial fibrillation should be screened as well. Short QT syndrome should be excluded in patients without structural heart disease presenting with sudden cardiac death.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2]

Short QT syndrome(SQTS) is associated with an increased risk of atrial fibrillation, syncope and sudden death due to ventricular fibrillation. The disease symptoms develop in between the second and fourth decade of life . The most common presentation is syncope and palpitations. Most of the pediatric patients remain asymptomatic and get diagnosed only when they have an index case in the family prompting a genetic testing. Without treatment most of the pediatric patients who present within first decade of life succumb to Sudden cardiac death and younger patients with QTc of 285 msec and adults with QT less than 300 msec have increased risk of sudden cardiac death.

The symptoms of SQTS usually develop between the second and fourth decade of life and start with symptoms such as syncope and palpitations. The primary manifestations of SQTS are palpitations, syncope, atrial fibrillation, and cardiac arrest. Without treatment, the patient will develop a worsening of arrhythmia, which may eventually lead to cardiac arrest. It is believed that most of the pediatric patients remain asymptomatic and get diagnosed only when they have an index case in the family prompting a genetic testing. The circumstances in which symptoms arise in SQTS patients are highly variable. According to a few studies, SQTS patients can be asymptomatic in a significant proportion of the study population and get diagnosed only with a strong familial predisposition^[1].

Complications can result due to SQTS.

• atrial fibrillation
• ventricular fibrillation
• Sudden cardiac death

Long term prognosis has not been assessed due to the unavailability of data. Severe shortening of QT values in adults ≤300 msec and in young patients with median QTc of 285 msec have increased risk of SCD either at rest or in sleep^[2].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2]

In general, diagnosis (plural diagnoses) has two distinct dictionary definitions. The first definition is “the recognition of a disease or condition by its outward signs and symptoms”, while the second definition is “the analysis of the underlying physiological/biochemical cause(s) of a disease or condition”.

Diagnosis covers a broad spectrum, or spectra, of testing in some form of analysis; collective reasoning using such tests is called the method of diagnostics, leading then to the results of those tests by ideal (ethics) would then be considered a diagnosis, but not necessarily the correct one.

In medicine, diagnosis or diagnostics is the process of identifying a medical condition or disease by its signs, symptoms, and from the results of various diagnostic procedures. The conclusion reached through this process is called a diagnosis. The term “diagnostic criteria” designates the combination of symptoms which allows the doctor to ascertain the diagnosis of the respective disease.

Typically, someone with abnormal symptoms will consult a physician, who will then obtain a history of the patient‘s illness and examine him for signs of disease. The physician will formulate a hypothesis of likely diagnoses and in many cases will obtain further testing to confirm or clarify the diagnosis before providing treatment.

Medical tests commonly performed are measuring blood pressure, checking the pulse rate, listening to the heart with a stethoscope, urine tests, fecal tests, saliva tests, blood tests, medical imaging, electrocardiogram, hydrogen breath test and occasionally biopsy.

The word diagnosis is derived from the Greek words dia which means “by”, and gnosis which means “knowledge”. The verb is diagnose and a person diagnosing could be considered a diagnostician.

A physician‘s job is to know the human body and its functions in terms of normality (homeostasis). The four cornerstones of diagnostic medicine, each essential for understanding homeostasis, are: anatomy (the structure of the human body), physiology (how the body works), pathology (what can go wrong with the anatomy and physiology) and psychology (thought and behavior). Once the doctor knows what is normal and can measure the patient’s current condition against those norms, she or he can then determine the patient’s particular departure from homeostasis and the degree of departure. This is called the diagnosis. Once a diagnosis has been reached, the doctor is able to propose a management plan, which will include treatment as well as plans for follow-up. From this point on, in addition to treating the patient’s condition, the doctor educates the patient about the causes, progression, outcomes, and possible treatments of his ailments, as well as providing advice for maintaining health.

It should be noted however, that medical diagnosis in psychology or psychiatry is problematic. Apart from the fact that there are differing theoretical views toward mental conditions and that there are few “lab” tests available for various major disorders (e.g., clinical depression), a causal analysis with respect to symptomatology and disorder/disease is not always possible. As a result, most if not all mental conditions, function as both symptoms as well as disorders. There are often functional descriptions provided for psychological disorders and these are vulnerable to circular reasoning due to the etiological fuzziness inherent of these diagnostic categories. (BDG, 2006)

Diagnosis is a fluid process in which the physician responds to information garnered from the patient and others, from a physical examination of the patient, and from medical tests performed upon the patient.

The doctor should consider the patient in his ‘well’ context rather than simply as a walking medical condition. This entails assessing the socio-political context of the patient (family, work, stress, beliefs), in addition to the patient’s physical body, as this often offers vital clues to the patient’s condition and its management.

The process of diagnosis begins when the patient consults the doctor and presents a set of complaints (the symptoms). If the patient is unconscious, this condition is the de facto complaint. The doctor then obtains further information from the patient himself (and from those who know him, if present) about the patient’s symptoms, his previous state of health, living conditions, and so forth.

Rather than consider the myriad diseases that could afflict the patient, the physician narrows down the possibilities to the illnesses likely to account for the apparent symptoms, making a list of only those conditions that could account for what is wrong with the patient. These are generally ranked in order of probability.

The doctor then conducts a physical examination of the patient, studies the patient’s medical record, and asks further questions as he goes, in an effort to rule out as many of the potential conditions as possible. When the list is narrowed down to a single condition, this is called the differential diagnosis, and provides the basis for a hypothesis of what is ailing the patient.

Unless the physician is certain of the condition present, further medical tests are performed or scheduled (such as medical imaging), in part to confirm or disprove the diagnosis but also to document the patient’s status to keep the patient’s medical history up to date. Consultations with other physicians and specialists in the field may be sought. If unexpected findings are made during this process, the initial hypothesis may be ruled out and the physician must then consider other hypotheses.

Despite all of these complexities, most patient consultations are relatively brief, because many diseases are obvious, or the physician’s experience may enable him to recognize the condition quickly. Another factor is that the decision trees used for most diagnostic hypothesis testing are relatively short.

Once the physician has completed the diagnosis, he explains the prognosis to the patient and proposes a treatment plan which includes therapy and follow-up (further consultations and tests to monitor the condition and the progress of the treatment, if needed), usually according to the guideline provided by the medical field on the treatment of the particular illness.

Treatment itself may indicate a need for review of the diagnosis if there is a failure to respond to treatments that would normally work.

The history of medical diagnosis began in earnest from the enlightened days of Hippocrates in ancient Greece but is far from perfect despite the enormous bounty of information made available by medical research including the sequencing of the human genome. The practice of diagnosis continues to be dominated by theories set down in the early 1900s.

Over two thousand years ago, Hippocrates recorded the association between disease and heredity. In similar fashion, Pythagoras noted the association between metabolism and heredity (allergy to Fava beans). The medical community, however, has only recently acknowledged the importance of genetics and its relevance to mainstream medicine.

The ideals of William Osler who transformed the practice of medicine in the early 1900s were based on the principles of the diagnosis and treatment of disease. According to Osler, the functions of a physician were to be able to identify disease and its manifestations, understand its mechanisms, how it may be prevented and how it may be cured. For his medical students he believed that the best textbook was the patient himself – analysis of morbid anatomy and pathology were the keys. The Oslerian ideal continues today, as the basis of the Doctor’s strategy is, “What disease does this patient have and what is the best way for treatment?” The emphasis is on the classification of the disease in order to use the remedies available for its effects to be reversed or ameliorated. The human being in question is representative of a class of people with this type of disease whereas the biological individuality of this person is not given any great weight.

The successor to William Osler as Regius Professor at Oxford was Archibald Garrod. Garrod echoed the observations of his Greek counterparts of two millennia ago, …our chemical individualities are due to our chemical merits as well as our chemical shortcomings; and it is more nearly true to say that the factors which confer upon us our predispositions to and immunities from various mishaps which are spoken of as diseases, are inherent in our very chemical structure; and even in the molecular groupings which confer upon us our individualities, and which went into the making of the chromosomes from which we sprang. Considering that the time that he formulated these ideas were the early 1900’s, and the knowledge of DNA encoding genes that in turn encoded proteins responsible for bodily structure and functions not being discovered until some fifty years later it took some time before medicine could fully appreciate the fundamental importance of his concept of diagnosis.

Whereas Osler laid the founding principles by which medicine should be practiced, Garrod placed these principles in a greater context of a chemical individuality that is inherited and is subject to the mechanisms of evolutionary selection. The Oslerian ideal of medical practice continues to dominate medical philosophy today. The patient is a collective of symptoms to be characterized and analyzed algorithmically in order to draw a diagnosis and subsequently produce a strategy of treatment. Medicine is about problems based solutions. In keeping with this philosophy, today’s pathology reports provide a momentary snapshot of the patient’s biochemical profile, highlighting the end result of the disease process.

Garrod’s conception of biological individuality was confirmed with the advent of the sequencing of the human genome. Finally the subtle relationship between inheritance, individuality and environment became apparent via the variations detected in DNA. In each patient’s DNA lies a script for how their bodies will change and become ill as well as how they will handle the assaults of the environment from the beginning of their life to its end. It is hoped that by knowing a patient’s genes that the biological strengths and weaknesses in respect to these assaults will be revealed and disease processes can be predicted before they have the opportunity to manifest. Although knowledge in this area is far from complete, there are already medical interventions based on this. More importantly, the physician, forewarned with this knowledge can guide the patient towards appropriate lifestyle changes to anticipate and mitigate disease processes.

• GPnotebook web site GPnotebook is a British medical database for GPs that provides an immediate reference resource for clinicians worldwide. The database consists of over 30,000 pages of information.
• Free 24/7 DRG & ICD-9-CM lookup powered by Flash Code at icd9coding.com
• Differential Diagnosis
• Merck Manual of Diagnosis and Therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2], Ogechukwu Hannah Nnabude, MD

Compliance with avoidance is important. The key to avoidance is proper evaluation and detection of causative allergen. Wear appropriate clothing to protect against irritants at home and in a work environment. ^{[1] [2]}

High-potency topical corticosteroids, e.g. clobetasol propionate 0.05% cream, may be used to reduce the inflammation. ^[3] As a general rule, high-potency corticosteroids should not be used on thin skin, e.g. face, genitals, intertriginous areas, to avoid the risk of skin atrophy. Antihistamines such as hydroxyzine and cetirizine are recommended to control pruritus. Systemic steroids are advised in severe cases but should be tapered gradually to prevent recurrences. Friction should be avoided as well as the use of soaps, perfumes, and dyes. Emollients are used for hydrating the skin. Tacrolimus ointment and pimecrolimus cream are immunomodulating drugs that inhibit calcineurin and are helpful in allergic contact dermatitis.