Larsen syndrome is characterized by joint hypermobility, multiple joint dislocations, especially of the knees, and talipes equinovarus. The midface is hypoplastic with a depressed nasal bridge. Cleft palate may be present. Radiographs reveal under-mineralisation and over-tubulation of the long bones, a bifid calcaneus and advanced bone age in the carpal, or extra carpal bones. Scoliosis, coronal clefts of the vertebrae and subluxation of the vertebra may be found. Scientists emphasized the importance of differentiating Larsen syndrome from other conditions in which arthrogryposis is the presumed diagnosis. The latter is, however, a symptom complex and not a diagnosis.
Missense mutations were identified in the gene encoding filamin B (FLNB gene) in individuals with autosomal dominant Larsen syndrome. The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are organized.
Sadat-Ali et al. (1997) reported four patients from three generations of a Saudi family with Larsen’s syndrome. All affected members presented with the classic features of Larsen’s syndrome, except the spinal involvement.
Patel et al. (2017) described two consanguineous Saudi families with a Larsen syndrome phenotype. The index patient of family 1, a 16-year-old girl, suffered from severe myopia, hips and knees dislocation, talipes, kyphoscoliosis with compromised lung function, progressive hearing loss and short stature. She had a 2.5-year-old brother with a similar presentation. Family 2 consisted of three brothers (ages 20, 16 and 7 years) exhibiting hyper-extensibility of large joints, severe myopia and short stature. Combined autozygome and exome analysis helped identify the GZF1 mutation c.865G>T (pGlu289*) in patients from family 1 and the GZF1 mutation c.1054dup (p.Thr352Asnfs*50) in patients from family 2. Both homozygous truncating mutations fully segregated with the phenotype and were absent from 2379 Saudi exomes and the ExAC browser. Further, by conducting a global transcriptional profiling of cells from affected individuals, the authors revealed a pattern of gene dysregulation. Several matrix remodeling genes were found to be significantly dysregulated, including P3H2, a gene implicated in a Mendelian form of severe myopia. Based on these findings, it was suggested that GZF1 mutations cause Larsen syndrome with myopia and articular involvement.
Al-Kaissi et al. (2003) reported eight distantly related family members of a Tunisian family, who over three generations had variable clinical manifestations, ranging from full clinical diagnostic criteria for Larsen syndrome in four subjects, to less apparent skeletal, oral, and mental manifestations in the rest of the family members. Al-Kaissi et al. (2003) noted the presence of the syndrome in three generations of the same family, which is suggestive of inheritance consistent with single-gene autosomal dominance. They also noted that the multiple neonatal deaths in the family might represent the extreme of expression of the syndrome.