Calvarial Doughnut Lesions With Bone Fragility

A number sign (#) is used with this entry because of evidence that calvarial doughnut lesions with bone fragility (CDL) and CDL with spondylometaphyseal dysplasia (CDLSMD) are caused by heterozygous mutation in the SGMS2 gene (611574) on chromosome 4q25.

Description

Calvarial doughnut lesions with bone fragility (CDL) is characterized by low bone mineral density, multiple spinal and peripheral fractures beginning in childhood, and sclerotic doughnut-shaped lesions in the cranial bones. Some more severely affected individuals exhibit neonatal onset of fractures, severe short stature, marked cranial sclerosis, and spondylometaphyseal dysplasia (CDLSMD) (Pekkinen et al., 2019).

Clinical Features

Bartlett and Kishore (1976) described multiple hyperostotic or osteosclerotic lesions of the calvaria in a man and 3 of his sons, each by a different mother. One of the affected sons also experienced recurrent facial nerve palsy. Two other sons and a daughter were presumed unaffected. The authors mistakenly interpreted the genetics as 'incompletely dominant sex-linked.'

Baumgartner et al. (2001) reported the sporadic case of a 16-year-old boy with this rare autosomal disorder. They emphasized that many pathologic fractures, lumps on the head, elevated serum alkaline phosphatase levels, and dental caries are the main characteristics of the disorder. Their patient had had 10 pathologic fractures between age 6 weeks and 15 years. An elevated serum alkaline phosphatase was found at age 11 and skull lumps at age 15. Radiography showed frontal and parietal round radiolucencies surrounded by sclerotic bone resembling doughnuts. Because the findings were reminiscent of osteogenesis imperfecta (see 166200), collagen types I, III, and V were analyzed in fibroblasts and shown to be normal. They found that MRI of the skull could detect skull lesions at an early stage, even before palpable lesions appeared.

Patients reported by Colavita et al. (1984) and Nishimura et al. (1996) had clinical features suggestive of CDL or gnathodiaphyseal dysplasia (GDD; 166260).

Jaakkola et al. (2009) studied a Finnish family in which a 13-year-old girl, her father, and paternal grandmother had vertebral and peripheral fractures as well as multiple doughnut lesions, hyperostosis, or sclerosis in the skull. The proband sustained low-energy fractures of the right radius and humerus at age 6 and 11 years. Lumbar spine BMD Z-score was -1.9 at age 11, and x-rays showed a compression fracture at T12 and sclerotic lesions in the skull. Plasma alkaline phosphatase was elevated, consistent with increased bone turnover. Transiliac bone biopsy revealed thin and structurally abnormal cortical bone and thin trabeculae, and osteoclast activity was increased. Her father sustained multiple fractures beginning at age 4 years, involving the skull, clavicle, radius, ulna, metacarpal and carpal bones, tibia, and fibula. He also experienced peripheral facial nerve palsies, and transient episodes of oculomotor and trochlear nerve paresis beginning in the fifth decade of life. MRI and CT showed no narrowing of the bony cranial nerve canals. Skull x-rays revealed CDL. The proband's 85-year-old paternal grandmother had severe osteoporosis and had sustained at least 14 nonvertebral fractures as well as multiple vertebral compression fractures. Skull x-rays showed irregular diffuse thickening but no clear doughnut lesions. She also experienced transient peripheral facial nerve beginning in the sixth decade of life, and abducens nerve palsies at age 82 years. The proband was diagnosed with glaucoma at age 3 years and had secondary uveitis and cataracts, and the grandmother was diagnosed with chronic congestive glaucoma at age 58, but the father had normal intraocular pressures. The authors concluded that CDL with osteoporosis segregated in this family with dominant inheritance and high penetrance, although they noted that the severity of the condition varied between family members.

Pekkinen et al. (2019) described 10 patients from 4 unrelated families with CDL (families 1 to 4), including the Finnish family reported by Jaakkola et al. (2009), who exhibited low bone mineral density combined with multiple childhood-onset peripheral and/or vertebral fractures, often but not always associated with the mild cranial sclerotic lesions characteristic of CDL. Several patients experienced recurrent peripheral facial nerve palsy or other neurologic manifestations. Pekkinen et al. (2019) reviewed transiliac bone biopsies from 2 unrelated Finnish patients (families 1 and 2), which showed reduced mineral content, increased heterogeneity in matrix mineralization, and a highly increased proportion of low-mineralized bone compared to controls. Polarized light microscopy showed bone matrix predominantly formed by haphazard arrangement of collagen fibrils.

Clinical Variability

Pekkinen et al. (2019) studied a 43-year-old Dutch mother and her 7-year-old son (family 5), as well as an 11-year-old boy of Hispanic ancestry (family 6), who had multiple spinal and long-bone fractures of neonatal onset, severe short stature, and metaphyseal changes associated with marked platyspondyly and scoliosis on x-ray, consistent with spondylometaphyseal dysplasia. In addition, these patients showed a more severe degree of cranial sclerosis than others with CDL. All 3 had episodes of facial paresis, and the Dutch woman experienced other neurologic symptoms, including diplopia, sensory neuropathy, ataxia, absent patellar and Achilles reflexes, and decreased arm reflexes. The Dutch woman and the Hispanic boy also had mixed hearing loss. The authors reviewed a femoral bone biopsy from the Dutch boy, in which polarized light microscopy showed bone matrix predominantly formed by haphazard arrangement of collagen fibrils.

Molecular Genetics

Calvarial Doughnut Lesions with Bone Fragility

In 10 patients from 4 unrelated families with CDL (families 1 to 4), including the Finnish family reported by Jaakkola et al. (2009), Pekkinen et al. (2019) identified heterozygosity for the same nonsense mutation in the SGMS2 gene (R50X; 611574.0001). Functional analysis suggested that the underlying cause of osteoporosis and skeletal dysplasia in these patients involved perturbation in sphingomyelin metabolism at the plasma membrane due to a catalytically nonfunctional enzyme.

Calvarial Doughnut Lesions with Bone Fragility and Spondylometaphyseal Dysplasia

In a Dutch mother and son and a Hispanic boy with CDLSMD (families 5 and 6), Pekkinen et al. (2019) identified heterozygosity for 2 different missense mutations in SGMS2: I62S (611574.0002) in the Dutch patients, and M64R (611574.0003) in the Hispanic boy. Functional analysis suggested that the underlying cause of osteoporosis and skeletal dysplasia in these patients involved perturbation in sphingomyelin metabolism at the plasma membrane due to a retention of enzymatically active protein in the endoplasmic reticulum.

Exclusion Studies

In the proband from a 3-generation Finnish family with CDL and bone fragility, Jaakkola et al. (2009) screened the COL1A1 (120150), COL1A2 (120160), and LRP5 (603506) genes but did not detect any disease-causing mutations.