Cluster Headache, Familial

Description

The classification for headache disorders of the International Headache Society (1988) listed the following criteria for cluster headache (CH): at least 5 attacks of severe unilateral orbital, supraorbital, and/or temporal pain, lasting 15 to 180 minutes, associated with at least 1 of 8 local autonomic signs, and occurring once every other day to 8 per day. Approximately 85% of CH patients have the episodic subtype, in which the headaches occur in cluster periods lasting from 7 days to 1 year and separated by attack-free intervals of 1 month or more. The remainder of patients have the chronic subtype, in which attacks recur for greater than 1 year without remission or with remissions lasting less than 1 month (Lipton et al., 2004).

Clinical Features

Spierings and Vincent (1992) described 3 males, an 8-year-old boy, his father, and his paternal grandfather, with seemingly typical cluster headaches. The headaches responded to oxygen inhalation and to treatment with verapamil but were not prevented by propranolol and amitriptyline, which are effective medications in migraine. The 8-year-old boy suffered from headaches from the age of 4 years. He had pain in the right eye occurring 3 times a week, usually between 12:30 and 1:00 p.m., and lasting 30 to 60 minutes. His father had onset at 37 years of age, with headaches located around and behind the right eye lasting 30 to 90 minutes. They were associated with tearing of that eye and running of the right nostril. The paternal grandfather had had 3 episodes of headache, each occurring daily for 4 to 7 weeks, when he was 51, 58, and 67 years of age. They were located in the left eye and were associated with tearing of that eye and running of the left nostril.

Schuh-Hofer et al. (2003) reported monozygotic twin sisters with cluster headache. Symptoms began at ages 24 and 31 years, and consisted of severe attacks located behind the left eye and radiating to the left mandible. In addition, both sisters had migraine without aura since childhood. Their mother and a child of each sister had migraine without aura.

Inheritance

Russell et al. (1995) investigated the mode of inheritance of cluster headache in 370 families in Denmark. Of the 370 probands, 25 had 36 relatives with cluster headache. The segregation analysis suggested to the authors that cluster headache has an autosomal dominant gene with a penetrance of 0.3. to 0.34 in males and 0.17 to 0.21 in females. The gene was thought to be present in 3 to 4% of males and 7 to 10% of females with cluster headache.

Among 220 Italian patients with cluster headache, Leone et al. (2001) found a positive family history in 44 families (20%), strongly supporting a genetic component. Compared with the general population, first-degree relatives had a 39-fold increased risk of cluster headache, and second-degree relatives had an 8-fold increased risk.

De Simone et al. (2003) reported a pedigree of 4 related families from southern Italy in which 8 members over 2 generations were affected with cluster headache. Two of the 4 families were linked by a double marriage (2 sibs of 1 family married 2 sibs of another family). The overall prevalence of cluster headache in the 127 living family members was 6.29%, 91-fold higher than expected in the general population. De Simone et al. (2003) postulated autosomal recessive inheritance.

Molecular Genetics

Rainero et al. (2004) found an association between a 1246G-A polymorphism (rs2653349) in the HCRTR2 gene (602393) and cluster headache. The frequency of the G allele was 0.96 and 0.87 among 109 patients with cluster headache and 211 controls, respectively. Homozygosity for the G allele conferred a 5-fold increased risk for the disorder, compared to G/A and A/A. Rainero et al. (2004) noted that the hypocretin system modulates neuroendocrine functions and is involved in narcolepsy (161400). Alternatively, the association may represent a nearby locus on chromosome 6 in linkage disequilibrium with cluster headache.

Among 226 German patients with cluster headaches and 266 German controls, Schurks et al. (2006) found a significant association between cluster headache and the 1246G-A polymorphism in the HCRTR2 gene. The frequency of the G allele was 0.87 and 0.80 in patients and controls, respectively. Homozygous carriers of the 1246G allele had a 2-fold increased risk for cluster headache. In contrast, Baumber et al. (2006) found no association between cluster headache and the HCRTR2 gene in a cohort of 259 patients originating from Northern Europe. Linkage analysis of families and direct examination of polymorphisms (rs3122169 and rs2653349) in the HCRTR2 gene both failed to support an association.