Spondyloepimetaphyseal Dysplasia, Sponastrime Type

A number sign (#) is used with this entry because of evidence that the sponastrime type of spondyloepimetaphyseal dysplasia (SEMDSP) is caused by homozygous or compound heterozygous mutation in the TONSL gene (604546) on chromosome 8q24.

Description

Sponastrime dysplasia is an autosomal recessive spondyloepimetaphyseal dysplasia (SEMD) named for characteristic clinical and radiographic findings, including spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, and striation of the metaphyses. Additional features include disproportionate short stature with exaggerated lumbar lordosis, scoliosis, coxa vara, limited elbow extension, small dysplastic epiphyses, childhood cataracts, short dental roots, and hypogammaglobulinemia. Radiographically, the abnormalities of the lumbar vertebral bodies are suggested to be the most specific finding because the characteristic metaphyseal striations may not be apparent at young ages. Striking clinical variability in presentation, severity, and associated features has been observed (summary by Burrage et al., 2019).

Clinical Features

Fanconi et al. (1983) described 4 sisters with short-limb dwarfism, moderate deformity of the vertebral bodies, mildly striated metaphyses, saddle nose, frontal bossing, relatively large head, and normal intelligence. The parents were not related. The paternal grandmother and 1 of her sisters, as well as the maternal grandmother and a maternal aunt, showed short stature (height, 148-156 cm). One of the illustrations showed a 13-year-old girl who appears to have a somewhat shortened trunk. The designation proposed by the authors, sponastrime dysplasia, was derived from 'spondylar and nasal alterations with striated metaphyses.'

Lachman et al. (1989) reported a second family with affected brother and sister. The midface hypoplasia and saddle nose created an 'Oriental look.' There was no history of consanguinity. The father and mother were 176 and 170 cm tall, respectively. The maternal grandfather and grandmother were 172 and 165 cm tall, respectively.

Langer et al. (1996) reviewed 9 published cases and described 5 new cases. Of the 9 previous cases, Langer et al. (1996) believed that 3 did not have sponastrime dysplasia. They summarized the clinical findings as including mild to moderate short stature with the lower limbs more severely affected than the upper limbs. Birth length is usually reduced but may be in the normal range. The tallest adult male was 154 cm and the tallest female 145 cm. All patients have a depressed nasal bridge with midface hypoplasia, epicanthal folds, and frontal bossing; most have a short broad anteverted nose and mild prognathism. Most affected persons had an increased lumbar lordosis and generalized joint laxity. Several had limitation in elbow extension or rotation. Scoliosis was found in 2 sibs. Two patients had progressive infantile coxa vara. Avascular necrosis of the hip was seen in 2 patients. One patient had subglottic stenosis and bronchotracheomalacia. One patient had a human growth hormone (139250) deficiency that did not have a typical response to therapy with growth hormone. Langer et al. (1996) stated that the diagnosis depends on characteristic radiographic changes. The shape of the lumbar vertebral bodies is characteristically abnormal from birth through mid-adolescence. Characteristic changes of the distal tibia, fibula, radius, and ulna, and the proximal humerus and femur are described.

Cooper et al. (2000) stated that 12 patients from 6 families had been reported. They reported a new case in an 11-year-old boy.

Offiah et al. (2001) reported a case of sponastrime dysplasia. Routine ultrasound scanning of the patient in utero revealed extreme limb shortening. At birth, the baby had midface hypoplasia with an upturned saddle nose with rhizomelic and mesomelic shortening of the upper and lower limbs. The hands and feet were short and broad, and there was marked joint laxity. At 4 months of age the child developed severe eczema and hypogammaglobulinemia, which was transient. Skeletal survey showed characteristic changes of the vertebral bodies, as previously described by Langer et al. (1996), along with a spannerlike appearance of the proximal femora, becoming less marked with time, and progressive development of coxa vara. The distal humeral metaphyses were flared, giving a bulbous appearance becoming more pronounced with time. The proximal humerus diaphyses also had an unusual appearance reminiscent of focal fibrocartilaginous dysplasia. The vertical metaphyseal striations present around the knee and in the distal radius did not appear until 5 years of age, prior to which Slaney et al. (1999) had diagnosed the child with a new syndrome of spondyloepimetaphyseal dysplasia, eczema, and hypogammaglobulinemia. Offiah et al. (2001) noted that only 1 previously reported case (Langer et al., 1996) had been diagnosed in infancy, but suggested that the association of midface hypoplasia, saddle nose, short stature due to short limbs, and radiographic features including the spannerlike appearance of the proximal femora, short curved femoral necks, and loss of the normal metaphyseal flare along with characteristic platyspondyly allowed this diagnosis to be made in infancy. Offiah et al. (2001) suggested the designation 'spondyloepimetaphyseal dysplasia (SEMD), sponastrime type' for the disorder.

Jeong et al. (2016) reported a 36-year-old Korean man with sponastrime dysplasia, who also exhibited Arnold-Chiari malformation. Features consistent with SEMDSP included short-limbed dwarfism, relative macrocephaly, frontal bossing, midface hypoplasia, saddle nose, and normal intelligence. Radiographic findings included marked delay of epiphyseal ossification, metaphyseal dysplasia, and metaphyseal striation of the long bones. Jeong et al. (2016) stated that the radiographic finding most specific to SEMDSP was the characteristic ovoid configuration of the vertebral bodies.

Gripp et al. (2008) noted additional findings in 3 patients with sponastrime dysplasia; 2 brothers (cases 3 and 4) previously reported by Langer et al. (1996) and an unrelated case reported by Cooper et al. (2000). All 3 patients had short dental roots. One brother was diagnosed with bilateral posterior subcapsular cataracts at age 11. In addition, like the patient reported by Slaney et al. (1999) and Offiah et al. (2001), the 2 brothers had hypogammaglobulinemia.

Burrage et al. (2019) reported 9 patients from 8 families with SEMDSP and mutations in the TONSL gene (see MOLECULAR GENETICS), including the girl previously studied by Slaney et al. (1999) and Offiah et al. (2001) (P4) and the boy originally reported by Cooper et al. (2000) (P15). All had significant disproportionate short stature, spine abnormalities, and characteristic facial features, including midface hypoplasia with a depressed nasal bridge, and all but the youngest patient also exhibited metaphyseal striations. Other features included bilateral cataracts in 3 patients, subglottic stenosis in 3, shallow dental roots in 4, and a history of hypogammaglobulinemia in 2. The authors also found biallelic TONSL variants in 4 patients from 3 families (P6, P7-1 and -2, and P8) without a clinical diagnosis of sponastrime dysplasia. These patients exhibited platyspondyly and biconcave vertebrae as well as metaphyseal irregularities and striations; other features included hypogammaglobulinemia (family 7), neutropenia (P8), and primary aphakia with absent pupils (P6).

Chang et al. (2019) studied 13 patients with SEMDSP from 12 families of 4 different ethnicities (Korean, Indian, Finnish, and Brazilian), including the Korean man (P07) previously reported by Jeong et al. (2016), who all had mutations in the TONSL gene (see MOLECULAR GENETICS). The patients exhibited a wide range of heights, from mild to severe short stature. All shared similar facial dysmorphism, including midface hypoplasia, depressed nasal root, short upturned nose, prognathism, and a relatively large head size with prominent forehead. Other clinical findings shared by more than 1 individual included short dental roots, airway narrowing, cataracts, joint laxity, and congenital hypothyroidism. X-rays revealed distinct changes in the vertebrae as well as long bone metaphyseal irregularities and vertical striations, and 8 of the 13 patients were also reported to show small dysplastic epiphyses. The authors noted that the radiographic features changed and became more conspicuous with age.

Pathogenesis

In a case of sponastrime dysplasia, Umpaichitra et al. (2002) found elevated urinary glycosaminoglycans and a lack of response to growth hormone. They suggested that the disorder may be caused by a defect in the synthesis of collagen.

Molecular Genetics

In 8 probands clinically diagnosed with the sponastrime type of SEMD, including the girl previously studied by Slaney et al. (1999) and Offiah et al. (2001) and the boy originally reported by Cooper et al. (2000), Burrage et al. (2019) identified compound heterozygosity for mutations in the TONSL gene (see, e.g., 604546.0001-604546.0007). In 2 more SEMDSP probands, they identified only 1 TONSL mutation, and in 2 others, they did not detect any mutation. The authors suggested that SEMDSP might be genetically heterogeneous, but noted that they could not exclude the possibility of deep intronic or promoter variants, large intragenic rearrangements, or large intragenic deletions in the TONSL gene in the latter patients. In addition, 3 unrelated patients who exhibited overlapping features but were not clinically diagnosed with SEMDSP were found to be compound heterozygous for mutations in TONSL (see, e.g., 604546.0008 and 604546.0009).

In 10 patients from 9 families with SEMDSP, including the Korean man originally reported by Jeong et al. (2016), Chang et al. (2019) identified homozygous or compound heterozygous mutations in the TONSL gene (see, e.g., 604546.0001, 604546.0004, 604546.0010, and 604546.0011). In 3 more probands, only 1 TONSL mutation was detected; the authors suggested that these individuals likely carried a cryptic structural variation or noncoding variation in the second TONSL allele. All TONSL variants were either not found in the ExAC database (5 of 9) or were present at low frequency, and no significant variation was detected in other skeletal dysplasia-associated genes in the affected individuals.