Spondylometaphyseal Dysplasia With Cone-Rod Dystrophy
A number sign (#) is used with this entry because of evidence that spondylometaphyseal dysplasia with cone-rod dystrophy is caused by homozygous or compound heterozygous mutation in the PCYT1A gene (123695) on chromosome 3q29.
DescriptionSpondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) is characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction (summary by Hoover-Fong et al., 2014).
Yamamoto et al. (2014) reviewed 16 reported cases of SMDCRD, noting that all affected individuals presented uniform skeletal findings, with rhizomelia and bowed lower limbs observed in the first year of life, whereas retinal dystrophy had a more variable age of onset. There was severe disproportionate short stature, with a final height of less than 100 cm; scoliosis was usually mild. Visual loss was progressive, with stabilization in adolescence.
Clinical FeaturesWalters et al. (2004) described 8 cases (4 female and 4 male) of an apparently unique form of spondylometaphyseal dysplasia (SMD) characterized by concomitant cone-rod dystrophy (CRD). Three of the 8 cases were sibs. One of the 8 cases was the product of a first-cousin union. Walters et al. (2004) stated that 3 sets of clinical features, in addition to autosomal recessive inheritance, allowed for definition of SMDCRD as distinct from previously described conditions: (1) postnatal growth deficiency, profound short stature, rhizomelic foreshortening of the limbs, and early bowing of the long bones of the legs; (2) platyspondyly and characteristic vertebral body shape, progressive metaphyseal irregularity and cupping, and shortening of all the tubular bones; and (3) early onset and progressive visual impairment (perhaps with stabilization in adolescence), clinical evidence for pigmentary maculopathy, and electrophysiologic demonstration of cone-rod dystrophy. Distinguishing SMDCRD from other forms of SMD were the absence of corner fractures, vertebral bodies that were ovoid and distinctively abnormal, severity that was far less than in the Sedaghatian form of SMD (250220), and absence of enchondromatous changes. Walters et al. (2004) suggested that SMDCRD is probably not rare.
Sousa et al. (2008) reported 3 patients with SMDCRD: a 16-year-old boy, born of healthy, unrelated parents, and 4-year-old female African American twins, born of a consanguineous union. They found that the boy had low alpha-neuraminidase activity levels in fibroblasts (residual activity of about 5%), but normal levels in leukocytes. They suggested that SMDCRD may be a metabolic disorder in which lowered neuraminidase levels are a secondary phenomenon.
Kitoh et al. (2011) described a 16-year-old Japanese boy with a skeletal phenotype identical to that of previously reported patients with SMDCRD. Profound short stature with rhizomelic shortening of the limbs was observed early in infancy. There was increased bowing deformity of the long bones of the legs with progressive metaphyseal flaring, cupping, fragmentation, and sclerosis. Platyspondyly was associated with ovoid-shaped vertebral bodies, and anterior wedging of the vertebrae was found in adolescence. In addition, he had prominent joints with limited mobility in knees and elbows and mild thoracic scoliosis. Vision impairment was first recognized at 11 years of age; funduscopy revealed bilateral macular chorioretinal atrophic lesions of variable sizes. Optical coherence tomography demonstrated bilateral retinal thinning, and full-field electroretinography (ERG) showed marked reduction of the cone response, although the rod response was relatively preserved, consistent with a mild form of cone dystrophy. Kitoh et al. (2011) noted that the ophthalmologic findings in this patient were relatively milder than those in previously reported patients.
Hoover-Fong et al. (2014) described 2 previously unreported patients with SMDCRD. The first was a 61-year-old woman of Greek origin who had a typical skeletal presentation but a later onset of the retinal phenotype. ERG at age 43 years was normal; however, ERG at age 51 showed evidence of cone-rod dysfunction, and she had limited vision. Examination at 54 years of age showed short stature (adult height, 108.3 cm), rhizomelic limb shortening, brachydactyly, stiffness of large joints, and internal tibial torsion. She had an affected brother who died at 45 years of age with short stature and confirmed CRD. The second patient was a Korean boy who presented at 23 months of age with short stature, increased anteroposterior thoracic diameter, rhizomelic shortening of the extremities, bilateral bowing of the legs, and mildly limited elbow and knee extension and hip abduction, with typical findings on radiography. At 2 years of age, he had frequent pneumonias requiring oxygen therapy that were thought to be related to chest wall deformity, and he had a waddling gait because of coxa vara deformity. The radiographic abnormalities were more severe at 3.75 years of age, with development of mild scoliosis. No visual impairment was noted at 23 months, but at 3.75 years of age, fundus examination showed hypopigmented macular atrophy in both eyes with markedly decreased photopic and moderately decreased scotopic ERGs.
Yamamoto et al. (2014) reported 2 consanguineous Brazilian pedigrees with SMDCRD. In the first family, a 17-year-old boy and his 2-year-old sister both presented in infancy with visual impairment that progressed to hand movements-only visual acuity, as well as short stature and bowing of the legs. Radiologic evaluation of the sibs showed platyspondyly, with scoliosis in the older sib, shortened long bones, generalized metaphyseal flaring, cupping and spurs in the lateral and medial distal femur, and mild involvement of the tubular bones of the hands. Ophthalmologic evaluation revealed similar findings in both sibs, including microphthalmia, nystagmus, strabismus, inferior corectopia, subluxated lenses, optic nerve coloboma, severe macular atrophy, and areas of choroidal and retinal atrophy. ERG in the brother detected no electrical activity. Their cognitive development was adequate and there was no facial dysmorphism. In the second family, 2 distant female cousins presented with progressive lower limb bowing starting at 1 year of age, severe short stature, normal cognitive development, no facial dysmorphisms, and no visual complaints, with normal funduscopic examinations initially. Skeletal survey at 14 and 11 years of age showed abnormalities similar to those of the first Brazilian family, highly suggestive of SMDCRD. Ophthalmologic reevaluation showed thinning of the macular retina in the older cousin by optical coherence tomography (OCT), and ERG revealed a scotopic response at the lower limit of normal and markedly reduced waves in the photopic phase, consistent with cone dysfunction. Both cousins and the brother in the first family had mildly reduced plasma lipids. Abdominal ultrasound was normal in the sibs in the first family, whereas the younger cousin of the second family showed hyperechogenic liver compatible with increased lipid content, and the older cousin had gallbladder stones.
InheritanceWalters et al. (2004) noted that parental consanguinity and affected sibs support autosomal recessive inheritance of SMDCRD.
Molecular GeneticsHoover-Fong et al. (2014) performed whole-exome sequencing in 3 patients with SMDCRD, 2 of whom had been described by Walters et al. (2004), and identified homozygosity or compound heterozygosity for missense mutations in the PCYT1A gene (123695.0001-123695.0003). Analysis of PCYT1A in 5 more affected individuals from 3 families, including 3 sibs from a family previously reported by Walters et al. (2004) and a Japanese boy previously described by Kitoh et al. (2011), revealed compound heterozygous mutations in all (123695.0004-123695.0008). Segregation of the variants with disease was confirmed in the 4 families in which family members were available for testing, and the mutations were not found in the Exome Variant Server or 1000 Genomes Project databases.
By whole-exome sequencing in 2 consanguineous Brazilian families with SMDCRD, Yamamoto et al. (2014) identified homozygosity for a missense mutation (E129K; 123695.0007) and a 1-bp duplication (123695.0009) that segregated with disease in the respective families.