Hhhh Syndrome

Clinical Features

Haar and Dyken (1977) described a family with many affected members in a pattern consistent with X-linked recessive inheritance with variable expression in heterozygous females. The disorder consisted of congenital left hemiparesis with subsequent development of left hemihypoplasia and athetoid posturing of the left hand. They referred to an unpublished family in which a young male proband, his brother, his sister and a maternal uncle were born with right hemiparesis with subsequent development of hemiatrophy, involuntary movements, and seizures. The authors labeled the disorder autosomal dominant, but X-linked inheritance seems equally or more likely. An instance of parental consanguinity in the family raises a question also of autosomal recessive inheritance. Others have interpreted this kindred as representing the same disorder as infantile hemiplegia with porencephaly (see 175780).

Reese et al. (2010) reported a family in which 3 males, related through clinically unaffected females, had right-sided hemiplegia and associated neurologic abnormalities. The proband was a 13-year-old boy in whom right-sided weakness was first noticed at 4 months of age. He only began to speak at 3 years of age, but at age 13 years was cooperative and articulate and was in regular classes at school. Examination revealed mild right hemiplegia with subtle flattening of the right nasolabial fold, mildly increased tone in his right arm, abnormally brisk tendon reflexes and decreased bulk in his right arm and leg, and contractures of his right arm and ankle. His maternal uncle also had right hemiplegia, which was first noticed at 3 years of age, and normal cognition; neurologic examination showed mild flattening of his right nasolabial fold, 4+ strength of his right hand with normal strength elsewhere on the right, mild right arm drift, increased tone in his right arm and leg, and brisk tendon reflexes with 5 to 7 beats of clonus at the right ankle. Brain imaging in these 2 patients revealed small porencephalies in the region of the left internal capsule. In addition, a maternal great-uncle had right hemiplegia and a cognitive deficit. He was noted to have developmental delay and abnormal movements around 6 months of age, had limited walking skills, and subsequently loss the ability to walk. All of his extremities were spastic, and he could only move his head. Reese et al. (2010) noted that the phenotype in this family resembled that of the family with HHHH reported by Haar and Dyken (1977).

Mapping

In a 3-generation pedigree in which 3 males, related through clinically unaffected females, had right-sided hemiplegia and associated neurologic abnormalities, Reese et al. (2010) performed genomewide linkage analysis and found nominal evidence for linkage across a 42-cM region of chromosome X (43-85 cM) with a lod score of 1.2 (of a possible maximum of approximately 1.5 in this family). With the inclusion of additional SNPs, the region was narrowed to 56 Mb on Xp21.1-q21.31, between SNPs rs2031554 and rs5940773.