Paula and Bobby
Parents of Lillie
Larsen syndrome (LRS)
What is Larsen syndrome (LRS)?
Larsen syndrome is a rare genetic condition that affects the development of the bones. It may also be referred to as LRS syndrome.
Symptoms may vary between individuals and even between those in the same family.
The main symptom of the syndrome is dislocations of the hips, knees or elbows. It is currently believed to occur in one in every 100,000 newborns, but it is possible that many cases are misdiagnosed or missed.
What gene changes cause Larsen syndrome (LRS)?
Mutations in the FLNB gene are responsible for causing the syndrome. It is inherited in an autosomal dominant pattern.
In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
What are the main symptoms of Larsen syndrome (LRS)?
Clubfeet are a common feature of the syndrome in affected individuals. An X-ray may also show the presence of small extra bones in the wrists and ankles.
Another syndrome is the tips of fingers, usually the thumbs, are blunt and square shaped.
Unique facial features associated with the syndrome are frontal bossing (prominent forehead), wide-set eyes and a flattened bridge of the nose and middle of the face.
Other symptoms involving the affected development of the bones includes a cleft palate, and abnormalities in tiny bones within the ear which can cause hearing loss.
Other physical symptoms of the syndrome include a short stature, and scoliosis.
It is not uncommon for individuals with the syndrome to also experience respiratory problems, and heart and kidney issues.
Possible clinical traits/features:
Cognitive impairment, Beaking of vertebral bodies, Depressed nasal bridge, Hypodontia, Hypoplastic cervical vertebrae, Short stature, Opacification of the corneal stroma, Hypertelorism, Brachydactyly, Dislocated wrist, Knee dislocation, Hip dislocation, Cleft upper lip, Cleft palate, Finger syndactyly, Malar flattening, Craniosynostosis, Cryptorchidism, Elbow dislocation, Conductive hearing impairment, Abnormality of thumb phalanx, Abnormality of the wrist, Bronchomalacia, Anonychia, Aortic dilatation, Arachnodactyly, Cervical kyphosis, Atrial septal defect, Bipartite calcaneus, Accessory carpal bones, Abnormality of the cardiovascular system, Abnormality of epiphysis morphology, Multiple carpal ossification centers, Pectus excavatum, Intellectual disability, Intrauterine growth retardation, Laryngomalacia, Joint laxity, Joint hypermobility, Shallow orbits, Spatulate thumbs, Pectus carinatum, Autosomal dominant inheritance, Respiratory failure, Talipes equinovalgus, Short nail, Spinal cord compression, Talipe
How does someone get tested for Larsen syndrome (LRS)?
The initial testing for Larsen syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Larsen syndrome (LRS)
This autosomal dominant syndrome is characterized by large joint dislocations and craniofacial abnormalities.
Joint hypermobility, multiple joint dislocations, especially of the knees, and talipes equinovarus are typical features. The mid-face is hypoplastic with a depressed nasal bridge. Cleft palate may be present. Radiographs reveal undermineralisation and overtubulation of the long bones, a bifid calcaneus and advanced bone age in the carpals, or extra carpal bones. Scoliosis, coronal clefts of the vertebrae and subluxation of the vertebrae may be found. Hoeve et al., (1996) reported three cases with subglottic stenosis, possible due to lack of ridigity of the laryngeal and tracheal cartilages. Frints et al., (2000) reported a case with evidence of somatic mosaicism and Debeer showed another case of asymmetric Larsen's suggesting mosacism. An aneurysm of the ductus arteriosus was reported by Je et al., (2006). Cardiovascular anomalies are discussed by Liang and Hand (2001).
There is an autosomal dominant form and a more severe autosomal recessive form.
Petrella et al., (1993) reported an affected adult brother and sister pair with apparently normal parents. The sister gave birth to an affected girl, suggesting germinal mosaicism in the parents of the affected sibs. Both sibs in this report had central cataracts. Laville et al., (1994) reported 38 cases from the island of Reunion (presumed to be autosomal recessive because of the high incidence of consanguinity in the population). Amongst this group cervical spine fusion, radio-ulnar synostosis, and bifid thumbs appeared to be additional features. Becker et al., (2000) reported a family where a severely affected fetus was picked up at 16 weeks by ultrasound examination and the father was found to be mildly affected. Baspinar et al., (2005) reported a case with a dilated, elongated aorta.
Pierquin et al., (1991) reported two unrelated patients with partial trisomy 1q and monosomy 6p with features of Larsen syndrome. Type I collagen abnormalities were suggested. Klenn and Iozzo (1991) reported a female infant with features of Larsen syndrome who also had anal atresia and a bifid uterus. Bonaventure et al., (1992) performed linkage analysis in three recessive pedigrees, from La Reunion Island in the Indian Ocean, segregating for a Larsen-like syndrome. There was no linkage to COL1A1, COL1A2, COL3A1 or COL5A2. Vujic et al., (1995) mapped the gene to 3p21.1-14.1 in a large dominant pedigree. This was close to the COL7A1 locus but this gene was excluded by linkage.
The gene has now been located - it is filamin B (Krakow et al., 2004). The same gene is mutated in atelosteogenesis types I and III, and in spondylocarpotarsal syndromes. Mutations seem to cluster in about 5 of the 46 exons (Zhang et al., 2006). In thecohort of 20 patients reported by Bicknell et al., (2007), 6 had a 5071G to A mutation.
Eight CHST3 mutations in 6 unrelated individuals, who presented at birth with joint dislocations were reported by Hermanns et al., (2008). Three had been diagnosed as having Larsen syndrome (recessive) and 3 as having 'humero-spinal dysostosis'. Note that this is the same gene that is involved in 'spondyloepiphyseal dysplasia - type Omani' and all 3 conditions are probably allelic. A patient with a recessive CHST3 mutation and features of recessive Larsen syndrome had craniosynostosis (Searle et al., 2014).
Yang et al. (2016) identified missense mutations in the FLNB gene in three unrelated cases (one familial and two sporadic) with congenital talipes equinovarus.
Patel et al. (2017) described five individuals (2.5-20 years old) from two unrelated consanguineous families with Larsen syndrome and homozygous truncating mutations in the GZF1 gene. All patients presented with short stature, hyperextensibility of joints and severe myopia. Skeletal findings included scoliosis, talipes equinovarus and pectus carinatum. Additional eye findings were glaucoma, retinal detachment, iris and chorioretinal coloboma. Hearing loss was noted in two patients from different families. Other findings, including inguinal and umbilical hernia, and hypothyroidism, were seen in one patient.
* This information is courtesy of the L M D.
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