Spondyloepimetaphyseal Dysplasia With Joint Laxity, Type 2

A number sign (#) is used with this entry because of evidence that spondyloepimetaphyseal dysplasia with joint laxity type 2 (SEMDJL2) is caused by heterozygous mutation in the KIF22 gene (603213) on chromosome 16p11.

Description

Spondyloepimetaphyseal dysplasia with joint laxity type 2 (SEMDJL2) is characterized by short stature, distinctive midface retrusion, progressive knee malalignment (genu valgum and/or varum), generalized ligamentous laxity, and mild spinal deformity. Intellectual development is not impaired. Radiographic characteristics include significantly retarded epiphyseal ossification that evolves into epiphyseal dysplasia and precocious osteoarthritis, metaphyseal irregularities and vertical striations, constricted femoral neck, slender metacarpals and metatarsals, and mild thoracolumbar kyphosis or scoliosis with normal or mild platyspondyly (summary by Min et al., 2011).

For a discussion of genetic heterogeneity of SEMD with joint laxity, see SEMDJL1 (271640).

Nomenclature

The International Nosology and Classification of Constitutional Disorder of Bone initially described two disorders of SEMD with dislocation and joint laxity: SEMDJL (Beighton type) and SEMD with multiple dislocations, the Hall or leptodactylic type (Hall et al., 1998). However, in the 2006 revision of Nosology and Classification of Genetic Skeletal Disorders, the Nosology Group of the International Skeletal Dysplasia Society proposed the use of the united term 'joint laxity' instead of the term 'multiple dislocations' (Superti-Furga et al., 2007). These included 2 conditions: SEMDJL-Beighton type (designated SEMDJL1 (271640) in OMIM) and SEMDJL-leptodactylic or Hall type (designated SEMDJL2 in OMIM).

Clinical Features

Hall et al. (1998) described 3 children from unrelated families who presented in infancy with hip dislocation and joint laxity and developed progressive deformity, particularly involving the knees, spine, and hips. Clinically, the facial appearance was normal in 2 of the 3 cases; in the third case, there was mild midface hypoplasia. Cleft palate and ocular or auditory abnormalities were not present. Cognitive development was normal. Height measurements were available for only 1 individual, who was below the 3rd centile at age 5.5 years. Radiographically, the epiphyses were small, flattened, irregular, and fragmented. The metaphyses showed widening, irregularity, and streaky sclerosis. The dorsal vertebral bodies showed posterior decrease in height with scalloping of the posterior aspects of the lumbar vertebral bodies, vertebral endplate irregularity, and progressive chordal narrowing of the interpedicular distances. Scoliosis was not present at birth, but developed in the first years of life. Hall et al. (1998) regarded the hand changes as being particularly characteristic. The metacarpals were gracile, the phalanges were long and slender with squared ends, and the distal phalangeal tufts were prominent. Carpal bones were individually small, irregular, and flattened, and the overall size of the carpals was reduced. There was gross delay in the appearance of the phalangeal epiphyses. All 3 cases showed absent or severely delayed ossification of the patellae.

Hall et al. (1998) noted that 2 cases with virtually identical findings, one reported by Camera et al. (1994) and one (case 5) by Langer et al. (1997), had been considered examples of sponastrime dysplasia (271510). Hall et al. (1998) argued, however, that the striking epiphyseal changes, specific hand findings, and joint laxity with dislocations, in addition to narrow interpedicular distances and posterior scalloping of the vertebrae, allowed differentiation of this condition from sponastrime dysplasia. Hall et al. (1998) also differentiated this condition from the form of spondyloepimetaphyseal dysplasia with joint laxity described by Beighton and Kozlowski (1980) (SEMDJL1; 271640), since SEMDJL1 is associated with kyphoscoliosis at birth, progressing to severe deformity and talipes equinovarus, cleft palate, congenital heart disease, and a specific facial dysmorphism. In addition, the particular radiographic findings in the spine and hands described by Hall et al. (1998) are absent in SEMDJL1.

Hall et al. (2002) reported 3 additional patients with spondyloepimetaphyseal dysplasia with multiple dislocations, including a father with mild manifestations and his daughter who was severely affected. All of the patients showed facial dysmorphism with a short, broad, upturned nose. There were striking epiphyseal and metaphyseal changes of the long bones and joint laxity with multiple dislocations of the large joints, which were particularly incapacitating at the knees.

Megarbane et al. (2003) reported a 6-year-old male with congenital hip dislocation, short stature, macrocephaly, low-set ears, short neck, and hyperlaxity of the wrists and fingers. A broad thorax and limitation of extension of the elbow were seen. X-rays showed severe delay of ossification of the epiphyses and carpal bones and a generalized osteoporosis. There was thoracic scoliosis, mild changes of vertebral endplates, right hip dislocation, and subluxation of the elbows. The epiphyses were small, flattened, and irregular. The femoral neck was slender with flattened femoral epiphyses. Metaphyses of the knees were irregular, squared with vertical striations. Tarsal bones were normally ossified. Delay in early development was noted in this case, as in those reported by Camera et al. (1994) and Hall et al. (2002). Macrocephaly, frontal bossing, midface hypoplasia with saddle-nose, low-set ears, and short neck were thought to be common findings.

Holder-Espinasse et al. (2004) reported a patient with a mild form of spondyloepimetaphyseal dysplasia with persistent inspiratory stridor secondary to laryngeal stenosis.

Nishimura et al. (2003) described 4 patients with spondyloepimetaphyseal dysplasia with multiple dislocations, 2 of whom had previously been diagnosed with sponastrime dysplasia by Masuno et al. (1996) and Nishimura et al. (1998). Clinical findings included midface hypoplasia, micromelic short stature, and generalized joint laxity leading to thoracolumbar scoliosis and multiple joint subluxations. Laryngotracheomalacia was present in 2 patients, an increased serum creatine kinase with transient, mild muscle weakness was noted in another, and pronounced developmental delay was present in 1 patient. Radiologic findings included mild platyspondyly and stellar ossification of the calcaneus (both notable in infancy), narrow interpediculate distances and posterior scalloping of the lumbar spine, constriction of the femoral neck, delayed epiphyseal ossification that evolved to epiphyseal dysplasia and degenerative joint disease, metaphyseal irregularities and striations, and slender, short tubular bones of the hands.

Rossi et al. (2005) reported a father and son with the Hall type of spondyloepimetaphyseal dysplasia with multiple dislocations. The father had short stature and marked joint laxity, including multiple severe joint dislocations. The son had a milder phenotype.

Park et al. (2007) reported a mother and son with the Hall type of SEMD. The son had persistent inspiratory stridor beginning at 4 months of age. Microlaryngoscopy at 22 months revealed laryngeal stenosis secondary to failure of abduction of the vocal cords. A tracheostomy was performed to provide an adequate airway. Park et al. (2007) noted that 5 of the 13 published cases of Hall-type SEMD had upper airway obstruction. They suggested that this is a clinically important diagnostic feature of the disorder.

Kim et al. (2009) reported the clinical and radiologic findings in a Korean mother, daughter, and son with Hall-type SEMDJL and in 3 unrelated Korean patients and 1 Japanese patient. The major clinical features were short stature, midface hypoplasia, and multiple dislocations and/or ligamentous laxity of the large joints, particularly at the knees with genu valgum or varum deformity. One patient had mild mental retardation. No cleft palate was found, and there were no neurologic, ophthalmologic, or auditory abnormalities. One patient had undergone surgical correction of an atrial septal defect, and another had a tracheostomy for tracheomalacia. The main radiologic features included small, irregular epiphyses, metaphyseal irregularity with vertical striations that was a consistent finding at the knees, constricted femoral necks, delayed ossification of the carpal bones, and slender metacarpals. Progressive thoracolumbar scoliosis was evident with aging; however, the vertebral bodies appeared normal in height or showed mild platyspondyly. Kim et al. (2009) stated that the slender appearance of the metacarpals ('leptodactyly') is distinctive enough for a definitive diagnosis.

Boyden et al. (2011) stated that the most distinctive features of leptodactylic SEMD are the slender metacarpals and phalanges and the progressive degeneration of carpal bones; however, these 2 features are evident only in older children and young adults. The soft consistency of cartilage in the airways leads to laryngotracheomalacia with proneness to respiratory obstruction and inspiratory stridor in infancy and childhood.

Inheritance

Hall et al. (2002) reported variable intrafamilial expressivity of the disorder and suggested autosomal dominant inheritance with the majority of cases being new mutations. Nishimura et al. (2003) and Megarbane et al. (2003) concurred, noting that all of the other cases had been sporadic, with no clinical differences between males and females, and none of the families had been consanguineous. Rossi et al. (2005) reported father-to-son transmission.

Molecular Genetics

In affected members of a Korean family and 2 unrelated Korean patients with Hall-type spondyloepimetaphyseal dysplasia and joint laxity, previously studied by Kim et al. (2009), as well as 3 additional unrelated Korean patients, Min et al. (2011) performed exome sequencing and identified sequence variants in the KIF22 gene (603213) in 7 of the 8 affected individuals. Sanger sequencing confirmed 3 heterozygous missense mutations in the 7 patients (603213.0001-603213.0003). The patient in whom no KIF22 mutation was found showed a relatively mild clinical phenotype, with moderate short stature and equivocal midface retrusion, suggesting the possibility of genetic heterogeneity.