Eiken Syndrome

A number sign (#) is used with this entry because of evidence that Eiken syndrome is caused by homozygous mutation in the PTHR1 gene (168468) on chromosome 3p21.

Clinical Features

In a consanguineous Turkish family living in Denmark, Eiken et al. (1984) described 3 brothers with a skeletal dysplasia characterized by severely retarded ossification, principally of the epiphyses, pelvis, hands, and feet. In the hands and feet, the retarded ossification was combined with a strikingly abnormal modeling of the bones. All the children appeared normal at birth. There was no mental retardation. The possibility of recessive inheritance was increased by the report of a maternal aunt, married to a cousin of both parents, who had a son and a daughter with dwarfism and characteristics similar to those in the 3 brothers. Eiken et al. (1984) concluded that the disorder in this kindred was quite different from any previously described disorder.

Duchatelet et al. (2005) noted that the skeletal features of Eiken syndrome are opposite to those in Blomstrand chondrodysplasia (215045), in which patients have advanced skeletal maturation.

Moirangthem et al. (2018) reported a 7-year-old boy, born to first-cousin parents, with several features consistent with Eiken syndrome, including type A1 brachydactyly, coarse bone trabeculae in the tubular bones, and delayed ossification of the pubic symphysis, carpal bones, and the epiphyses of the hands. In addition, the patient had failure of eruption of primary teeth and supernumerary epiphyses of the tubular bones of the hands. He had an elevated PTH with normal serum calcium levels; nutritional vitamin D deficiency was also present in the patient and may have been responsible for some of the findings. His parents were unaffected and did not have delayed tooth eruption or any tooth impaction.

Mapping

By linkage analysis with the original pedigree, Duchatelet et al. (2005) mapped Eiken syndrome to an approximately 50-cM region of chromosome 3p, between markers D3S2338 and D3S1285.

Molecular Genetics

Because of its implication in forms of chondrodysplasia and its role in bone development, Duchatelet et al. (2005) examined the PTHR1 gene as a candidate for Eiken syndrome. They identified a nonsense mutation in the C-terminal cytoplasmic tail of the PTHR1 gene (168468.0009) in homozygosity in affected individuals. Eiken syndrome is clinically distinct from Jansen (156400) and Blomstrand (215045) chondrodysplasias and from enchondromatosis (166000), which are also caused by PTHR1 mutations.

In a 7-year-old boy with Eiken syndrome, who was born to unaffected first-cousin parents, Moirangthem et al. (2018) identified a homozygous missense mutation at a conserved residue in the PTHR1 gene (E35K; 168468.0015). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in his parents. The variant was not found in several public databases (ExAC, gnomAD, and 1000 Genomes Project) or in an in-house exome database of 417 families. Protein modeling predicted that the mutation would disrupt normal protein function.