Andersen Syndrome

KCNJ2

Clinical synopsis: Andersen Syndrome

In 1971 Andersen et al. (Andersen ED 1971) reported the case of a 8-years old with short stature, hypertelorism, broad nasal root, and defect of soft and hard palate. The definition of Andersen syndrome (AS) was used for the first time in 1994 by Tawil et al. (Tawil R et al, 1994) to describe a clinical disorder consisting of three major features: potassium-sensitive periodic paralysis, ventricular arrhythmias and dysmorphic features (similar to those described by Andersen in 1971).
An additional peculiar feature of AS is the presence of a variable degree of QT interval prolongation and abnormal T wave morphology often presenting with very prominent U waves (Tawil R et al, 1994; Sansone V et al. 1997). Life threatening ventricular arrhythmias are probably be rare in AS although sudden death has been reported (Levitt LP et al. 1972; Sansone V et al. 1997; Gutmann L 2000).

The peculiar T wave morphology and the recognition of the characteristic face are the landmarks of diagnosis.

In 2001 Plaster et al successfully mapped the disease to the locus 17q in a large family. A candidate gene screening was carried out in the critical region and a heterozygous missense mutation was identified in the KCNJ2 gene. Additional mutations were subsequently identified in 8 unrelated individuals, thus providing the proof that KCNJ2 is the cause of at least some of AS (Plaster NM et al. 2001). KCNJ2 encodes an inwardly rectifier potassium channel, Kir2.1, the ionic channel conducting the IK1 current. It is highly expressed in the heart where it appears to act as a determinant factor of phase 4 repolarization and of resting membrane potential. Interestingly, since dysmorphic facial appearance constitutes a distinctive trait of AS, the data provided by Plaster et al. also strongly suggest that Kir2.1 plays a major role in developmental signaling. More recently the functional consequences of AS mutations have been assessed by Tristani-Firouzi by mean of in vitro expression of the mutated protein. Severe, functional impairment of IK1 current has been observed for all AS mutations so far studied with a variable degree of dominant negative effect when co-expression with wild type subunit (Tristani-Firouzi M et al 2002).

Only limited experience exists for the clinical management of AS (Gutmann L 2000). In a young woman with Andersen syndrome and an R218W mutation in the KCNJ2 gene (Junker J et al 2002) observed that amiodarone and acetazolamide treatment resulted in marked and long-lasting improvement of cardiac and muscular symptoms. The periodic paralysis may be prevented in the majority of cases by oral potassium administration. On the other hand, despite the frequent development of ventricular arrhythmias (premature ventricular beats and runs of nonsustained ventricular tachycardia often with a bidirectional morphology of QRS complexes), the risk of sudden cardiac death appears to be low as compared with long QT syndrome and other inherited channelopathies.

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