A number sign (#) is used with this entry because of evidence that the Stanescu type of spondyloepiphyseal dysplasia (SEDSTN) is caused by heterozygous mutation in the COL2A1 gene (120140) on chromosome 12q13.

Spondyloepiphyseal dysplasia with accumulation of glycoprotein in chondrocytes has been designated the 'Stanescu type.' Clinical hallmarks include progressive joint contracture with premature degenerative joint disease, particularly in the knee, hip, and finger joints. Interphalangeal joints of the hands are swollen due to osseous distention of the metaphyseal ends of the phalanges. Affected individuals may be relatively tall despite the presence of a short trunk. Radiologically, there is generalized platyspondyly with mild modification of the endplates, hypoplastic pelvis, epiphyseal flattening with metaphyseal splaying of the long bones, and enlarged phalangeal epimetaphyses of the hands. In addition, the proximal femora are characteristically broad and elongated with striking coxa valga (summary by Nishimura et al., 1998).

Stanescu et al. (1984) reported a French boy who presented with difficulty in walking. Examination at 10.5 years of age showed normal height with mild genu valgum. Joints were enlarged, especially the elbows and knees, hip flexion was limited except on external rotation, and he had a waddling gait. Other features included hearing loss, which required hearing aids by age 20 years, and mild myopia. His parents were nonconsanguineous, and he had 2 healthy brothers. X-rays showed massive enlargement of long bone epiphyses with enlargement of the adjacent metaphyses as well. The most striking finding, however, involved the femoral necks, which were very enlarged, particularly distally, and showed valgus deformation. The iliac wings appeared small in comparison, with poor coverage of the femoral heads. The metacarpal metaphyses were also enlarged, with epiphyses that were increased in size and mildly flattened. The height of all vertebral bodies was slightly reduced. Tibial growth cartilage biopsy showed significant cellularity and irregularly arranged chondrocytes, with moderate hypertrophy along the ossification line. Histochemical analysis revealed metachromasia in the growth zone, which was reduced in the resting zone. Cells in all zones were larger than normal and contained what appeared to be glycoprotein inclusions. Electrophoretic analysis of proteoglycans was normal, but analysis of noncollagenous protein bands showed some alterations, with significant reduction in P1 and a mild decrease in P4 and P5. Stanescu et al. (1984) concluded that the disorder in this patient represented an unusual form of spondyloepiphyseal dysplasia with normal stature.

Nishimura et al. (1998) examined 3 affected individuals from 2 unrelated Japanese families segregating a bone dysplasia in an autosomal dominant fashion. The proband of the first family had an unsteady gait from 2 years of age, with a tendency to fall on ambulation; he was referred for evaluation of knee deformity and back pain at age 10 years. His father reported flexion contractures of the fingers and knees in childhood that gradually worsened. The proband in the second family noted painful knees and ankles after athletic activity at 7 years of age, and at age 14 presented for evaluation of left hip pain while walking. All 3 patients had painful large joints with joint restriction, progressive contracture of the finger joints with osseous expansion, and normal height despite the presence of a short trunk. Moderate platyspondyly, hypoplastic ilia, epiphyseal flattening with metaphyseal splaying of the tubular bones, and characteristically broad elongated femoral necks were identical in all 3 patients. However, the proband from the second family exhibited severe brachydactyly, which was not seen in the father and son from the first family. Histologic examination of an iliac crest biopsy showed PAS-positive, amylase-resistant intracytoplasmic inclusion bodies in the chondrocytes, corresponding to dilated rough endoplasmic reticulum filled with moderately electron-dense material on electron microscopy. Nishimura et al. (1998) stated that the clinical and radiologic features in these patients were identical to those seen in the spondyloepiphyseal dysplasia reported by Stanescu et al. (1984).

Jurgens et al. (2015) studied 3 affected individuals from 2 unrelated families with spondyloepiphyseal dysplasia of the Stanescu type. The 38-year-old proband of the first family was originally reported by Hurvitz et al. (1999) as having progressive pseudorheumatoid dysplasia (208230), but was negative for mutation in the WISP3 gene (603400). She had a daughter who was also affected. The proband of the second family was a Korean boy born of unaffected nonconsanguineous parents. All 3 patients were noted to have a waddling gait in early childhood. They developed progressive joint stiffness and pain with flexion contractures of the hips and knees resulting in difficulty with mobility and a 'Z' posture upon standing. Spine radiographs showed platyspondyly and anterior wedging, as well as generalized joint space narrowing and metaphyseal irregularity. The mother underwent bilateral hip and knee replacements at ages 25 and 26, respectively. She developed progressive thoracolumbar kyphosis with severe spinal stenosis by age 35 requiring laminectomy and spinal fusion, after which she remained ambulatory. Her daughter, who developed kyphosis and progressive scoliosis in adolescence, had severe pain with ambulation and could only walk short distances with crutches by her third decade of life. At 10.5 years of age, the Korean boy could walk only with assistance due to joint pain and limb muscle weakness from prolonged disuse, and had 20-degree flexion contractures at the hips and knees. Jurgens et al. (2015) noted phenotypic overlap between their patients and previously reported patients with Stanescu SED; however, because they did not have access to the patients' chondrocytes, they were unable to test for the characteristic cytoplasmic inclusions.

Hammarsjo et al. (2015) examined 6 affected members of a 3-generation family with the Stanescu type of spondyloepiphyseal dysplasia. All affected individuals presented with progressive joint disease of varying severity, with age of onset ranging from 1 to 20 years. The most prominent sign was early onset of pain and deformities, particularly involving the knee, hip, and finger joints. Skeletal survey of the 25-year-old male proband revealed features consistent with SEDSTN, including moderate platyspondyly with elongated vertebral bodies and endplate irregularities, mild iliac hypoplasia, mild epiphyseal flattening of hip and knee, and bulbous ends of short tubular bones. Hammarsjo et al. (2015) noted that elongation of the femoral neck, seen on x-ray of the proband at age 15 years, was not observed in pelvic films from 4 affected adults, indicating that this is an age-dependent feature.

In a mother and daughter with the Stanescu type of spondyloepiphyseal dysplasia, Jurgens et al. (2015) performed whole-exome sequencing and identified a heterozygous missense mutation in the COL2A1 gene (G207R; 120140.0055). The mutation was not present in the unaffected maternal grandmother; DNA from the maternal grandfather was unavailable. Jurgens et al. (2015) sequenced COL2A1 in a similarly affected Korean boy and identified heterozygosity for the same missense mutation. The mutation was not present in either of his unaffected parents, indicating de novo occurrence in the proband.

In an affected member of a 3-generation family with SEDSTN, Hammarsjo et al. (2015) analyzed a skeletal gene panel including 347 genes, and identified heterozygosity for a missense mutation in the COL2A1 gene (D1219H; 120140.0056). Sanger sequencing confirmed that the mutation segregated with disease in the family, and the mutation was not found in 249 exomes from a local ethnically mixed population or in public variant databases.