Spondylometaphyseal Dysplasia, Axial

A number sign (#) is used with this entry because of evidence that axial spondylometaphyseal dysplasia (SMDAX) is caused by homozygous or compound heterozygous mutation in the C21ORF2 gene (CFAP410; 603191) on chromosome 21q22.

Biallelic mutations in C21ORF2 have also been reported in patients with isolated retinal dystrophy (RDMS; 617547).

Description

Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on electroretinogram. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora (summary by Suzuki et al., 2011).

Clinical Features

Ehara et al. (1997) presented a previously undescribed, probably autosomal recessive skeletal dysplasia characterized by mild platyspondyly, small thorax with cupping of the anterior ends of the ribs, irregular proximal femoral metaphyses, and lacy appearance of the iliac wings. The 3 patients were a Korean brother and sister and an unrelated 5-year-old Japanese girl. Retinitis pigmentosa (RP) and optic atrophy were associated findings. The lacy appearance of the iliac crest is a feature also of Dyggve-Melchior-Claussen syndrome (223800), but Ehara et al. (1997) pointed out that the severe epiphyseal dysplasia of the proximal femurs and marked platyspondyly with particular double-hump appearance of the vertebral bodies seen in DMC syndrome were not present in their patients. The parents in both cases were nonconsanguineous. The authors excluded other rare forms of SMD. Because the metaphyseal abnormalities were almost exclusively confined to the thorax, spine, and pelvis, they proposed the designation 'axial SMD' for this disorder.

Isidor et al. (2010) reported 2 unrelated French boys with short stature, femoral metaphyseal abnormalities, platyspondyly, and RP. The first boy, born of consanguineous parents, was evaluated at 7.5 years of age for short stature and found to have frontal bossing, a narrow bell-shaped thorax with prominent sternum, and rhizomelic shortening of the limbs. Radiologic examination showed moderate platyspondyly with ovoid vertebral bodies and enlarged short ribs, irregular iliac crest, and very abnormal femoral metaphyses with short and enlarged femoral neck. Bone age was moderately delayed. By 14.8 years of age, he had developed photophobia; ophthalmoscopy showed bilateral pale papillae, normal maculae, and diffuse atrophy of the pigmentary epithelium. Goldman visual fields were normal, whereas electroretinography (ERG) showed a 50% decrease in scotopic white and red waves. Cerebral MRI showed slight bilateral optic nerve atrophy. The other boy, born of healthy nonconsanguineous parents, was evaluated at 6.5 years of age for growth failure and noted to have delayed bone age, telecanthus and hypertelorism with antimongoloid palpebral fissures, slight eversion of the inferior eyelids, and short nose with anteverted nares. The thorax was very narrow with a bell-shaped thoracic cage, and he had rhizomelic shortening of the limbs; radiography showed spondylometaphyseal dysplasia, predominating in the pelvis and femoral neck, with lacy iliac wings. Ophthalmologic examination revealed bilateral symmetric cone-rod dystrophy without optic atrophy, and ERG showed a very severe defect of cone function and a small defect of the rods. Optical coherence tomography (OCT) was normal. At 15 years of age, the visual fields remained stable, but his facial features were unusual, with proptosis, hypertelorism, and frontal bossing. Radiography showed platyspondyly with 'codfish' appearance in the thoracic region, but disappearance of the irregularities of the iliac crest. Isidor et al. (2010) proposed that these 2 patients and the 3 patients described by Ehara et al. (1997) shared a distinctive phenotype, with major features consisting of postnatal growth deficiency, mild short stature, rhizomelic shortening of the limbs without bowing of the long bones of the legs, axial metaphyseal abnormalities with progressive mild platyspondyly, progressive femoral metaphyseal changes, decreased anteroposterior diameter of the thorax with markedly flared anterior ends of the ribs, normal tubular bones, and early onset and progressive visual impairment, with cone-rod dystrophy and/or optic atrophy.

Taniai et al. (2001) reported a Japanese sister and brother with 'osteochondrodysplasia' and RP. The 9-year-old sister had low height (-2 SD for age) and weight as well as progressive deformation of the thorax from the age of 8 months, with pneumonia at age 3 years due to reduced respiratory function. She also exhibited night blindness, and funduscopy was consistent with early RP. Her 3-year-old brother was similarly affected with low height and weight, thorax deformation from 1 year of age that was associated with bronchitis and pneumonia, and retinal degeneration. Examination showed precordial stenosis in both sibs, with protruding breastbone and concave thorax. X-rays showed lack of physiologic thoracic kyphosis with flat thoracic vertebrae, and distal metaphyseal bone trabeculae of the femur were obscure. Dark-adapted ERGs showed severe reduction of both a- and b-waves, which were more reduced in the sister than her brother. Suga et al. (2016) restudied these sibs and noted bilateral shortening of the metacarpals in the sister, involving the fifth metacarpal on the right and the third and fifth metacarpals on the left. Ocular findings were similar in both sibs, including funduscopy that showed salt-and-pepper appearance of the peripheral retina and narrowing of retinal vessels, with visual field tests showing loss of the middle peripheral area and decreased sensitivity in the central area in both eyes. Flash ERGs of the combined rod and cone response were nonrecordable, and OCT showed thinning and disorganization of the photoreceptor layer outside the macular area.

Suzuki et al. (2011) described clinical and radiologic findings in 7 affected individuals with SMDAX from 5 families of varying ethnicities, including Japanese, Korean, and Saudi Arabian, and tabulated the findings from all reported patients. The clinical hallmarks were postnatal growth deficiency, thoracic hypoplasia, and retinal abnormalities. Birth lengths were in the normal range, but short stature with rhizomelic limb shortening became apparent during childhood, with ultimate stature in adulthood sometimes less than -5 SD. Progressive shortening of the trunk resulted in short-trunk body proportion. Thoracic hypoplasia was present in all patients, associated with mild to moderate neonatal respiratory distress and susceptibility to airway infections in some patients. Pigmentary retinal degeneration was detectable in childhood, with RP diagnosed by 8 years of age; visual acuity worsened and vision was severely impaired within the first decade of life, with low to no night vision. Suzuki et al. (2011) stated that the patient reported by Megarbane et al. (2004) with rhizomelic skeletal dysplasia and RP (see 609047) might represent the same disorder.

Wang et al. (2016) studied 13 patients from 9 families, including the Korean sibs and Japanese girl originally reported by Ehara et al. (1997); a French boy previously reported by Isidor et al. (2010); and 2 Saudi Arabian sibs (patients 2 and 3), a Korean boy (patient 4), and a Japanese boy (patient 5) previously reported by Suzuki et al. (2011). The common clinical findings among the patients included mild postnatal growth failure and severe thoracic deformity, as well as impaired visual acuity and retinal dystrophy, diagnosed as RP or cone-rod dystrophy. In all patients, impaired visual acuity came to medical attention early in life, and retinal function deteriorated rapidly. Thoracic hypoplasia, due to severe shortening of the ribs, was also observed in all patients. Radiologic features of the patients included cupped and flared anterior ends of ribs and lacy ilia (serrated iliac crests). Mild platyspondyly was common, but the height of vertebral bodies was sometimes normal. Proximal femoral metaphyses were irregular and enchondroma-like, and there was often progressive shortening of the femoral neck, resulting in mild coxa vara in older patients; however, metaphyseal dysplasia was rarely seen in other long tubular bones.

McInerney-Leo et al. (2017) reported a 30-year-old woman who exhibited features of both Jeune asphyxiating thoracic dysplasia (JATD; see 208500) and SMDAX, including short stature with shortened limbs, narrowing of the thorax that required chest expansion surgery, severe scoliosis, and retinal dystrophy. Eye findings included reduced visual acuity (20/200), pigment displacement, and significantly reduced responses on electroretinography. In addition, she had delayed puberty, with menarche occurring at age 18 years.

Inheritance

Suzuki et al. (2011) noted that equally affected sib pairs of opposite genders and parental consanguinity were strongly suggestive of autosomal recessive inheritance of SMDAX.

Molecular Genetics

Wheway et al. (2015) cross-compared validated ciliogenesis candidate genes with whole-exome data from a cohort of patients with shortened limbs and ribs, narrow chest, and retinal degeneration, who had been clinically diagnosed as having JATD, and identified homozygous or compound heterozygous mutations in the C21ORF2 gene in affected individuals from 3 unrelated families (see, e.g., 603191.0001 and 603191.0002). In addition, homozygosity for a 1-bp deletion in C21ORF2 (603191.0003) was detected in a patient (CR-F024.1) previously reported by Abu-Safieh et al. (2013) as having isolated cone-rod dystrophy (see 617547), but in whom later reassessment showed deformation of the thorax and very short stature.

Wang et al. (2016) performed whole-exome sequencing in 8 families with axial SMD and identified biallelic mutations in the C21ORF2 gene in patients from 5 of the families, including a French boy originally described by Isidor et al. (2010) (603191.0006); 2 Saudi Arabian sibs (patients 2 and 3; 603191.0007) and a Korean boy (patient 4; 603191.0008-603191.0009) previously studied by Suzuki et al. (2011); and a Swedish woman and affected members of a Turkish family with the recurrent R73P mutation (603191.0001). Wang et al. (2016) stated that the skeletal phenotypes of the patients reported by Wheway et al. (2015) with the R73P mutation, who were studied as part of a Jeune syndrome (see 208500) cohort, were similar to their own axial SMD patients carrying the R73P variant.

In 147 Japanese families with inherited retinal diseases, Suga et al. (2016) performed whole-exome sequencing and identified compound heterozygosity for missense mutations in the C21ORF2 gene (603191.0008; 603191.0010) in a Japanese sister and brother with SMDAX originally reported by Taniai et al. (2001). From the same cohort, Suga et al. (2016) also detected biallelic C21ORF2 mutations in 2 Japanese sibs with isolated retinal dystrophy (see 617547).

In a 30-year-old woman with short stature, extremely narrow thorax, severe scoliosis, and retinal dystrophy, McInerney-Leo et al. (2017) identified homozygosity for the recurrent R73P mutation in the C21ORF2 gene. The authors noted that the R73P variant had been associated with patients with clinical diagnoses of JATD, SMDAX, and isolated retinal dystrophy, and stated that in this patient, who exhibited features of both JATD and SMDAX, the severity of thoracic restriction added to the phenotypic spectrum attributable to C21ORF2 mutations. McInerney-Leo et al. (2017) tabulated the clinical findings in reported patients with C21ORF2 mutations and noted that all cases had retinal disease, none had renal disease, and the skeletal phenotype was variable.

Exclusion Studies

Wang et al. (2016) did not find C21ORF2 mutations in the Korean sibs or Japanese girl described by Ehara et al. (1997), or in the Japanese boy (patient 5) reported by Suzuki et al. (2011). Haplotype analysis excluded C21ORF2 as the causative gene in the Korean sibs, and Sanger sequencing, RT-PCR, and SNP analysis showed that C21ORF2 was unlikely to be the disease gene in the Japanese families. Wang et al. (2016) concluded that there was genetic heterogeneity in axial SMD.