Calvarial “doughnut lesions”: Clinical spectrum of the syndrome, report on a case, and review of the literature

Abstract

Many pathologic fractures, lumps on the head, elevated serum alkaline phosphatase (ALP) levels, and dental caries are the main characteristics of the rare autosomal dominantly inherited calvarial "doughnut lesions" (MIM 126550). We report the sporadic case of a 16-year-old patient who has had 10 pathologic fractures between age 6 weeks and 15 years. An elevated serum ALP level was found at age 11 and skull lumps at age 15; radiography showed frontal and parietal round radiolucencies surrounded by sclerotic bone comparable to doughnuts. Magnetic resonance imaging (MRI) showed skull lesions at an early stage. Because the findings are reminiscent of osteogenesis imperfecta (OI), collagen types I, III, and V were analyzed in fibroblasts and shown to be normal in terms of quantities, proportions, electrophoretic mobility, and thermostability. Thus, this rare syndrome can be distinguished from OI by collagen analysis and MRI of the skull at an early stage, even before palpable skull lesions appear.

Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2

“…One patient with p.Ile62Ser was also diagnosed with progressive ataxia due to sensory neuronopathy. Recurrent facial nerve palsy has been reported in one patient with CDL (41), while several other publications on CDL (6, 42–44) lack information on potential neurological symptoms. There are several plausible mechanistic explanations: compression due to cranial sclerosis, as previously suggested (5); basilar invagination due to compromised bone strength, as in OI (45), although no evidence for that was noted in our patients; and neurotoxicity induced by aberrant sphingomyelin metabolism, similar to neuronal damage with incidental cranial nerve palsies in acid sphingomyelinase deficiency (Niemann-Pick disease) (46).…”

Calvarial doughnut lesions and osteoporosis: A new three‐generation family and review

“…In addition to the original report of 24 sporadic cases affected with CDL [Keats and Holt, 1969], 5 other sporadic individuals affected with CDL have been described [Royen and Ozonoff, 1974; Canigiani and Salomonowitz, 1984; Colavita et al, 1984; Nishimura et al, 1996; Baumgartner et al, 2001]. Some of the sporadic cases presented with a systemic disorder affecting not only the calvarial bones but also causing osteopenia and increased tendency to fractures [Royen and Ozonoff, 1974; Colavita et al, 1984; Nishimura et al, 1996; Baumgartner et al, 2001].…”

“…Five years later, a sporadic male patient with multiple CDLs and a history of fractures, elevated serum alkaline phosphatase values, and mild radiologic changes in metacarpal and metatarsal bones was reported [Royen and Ozonoff, 1974]. Thereafter, only four sporadic cases and three families with similar symptoms were described [Bartlett and Kishore, 1976; Aube et al, 1988; Baumgartner et al, 2001]. Based on these reports a specific autosomal dominant disorder of familial doughnut lesions of the skull (OMIM 126550) was defined, characterized by osteopenia, multiple pathologic fractures, elevated serum alkaline phosphatase levels, and dental caries.…”

“…The pathophysiology and genetic cause of the disorder remain unknown and biochemical, histologic, and genetic studies thus far published are scarce. Collagen I, III, and V defects have been excluded in one affected patient and it has been concluded that this disorder can be distinguished from OI by collagen analysis and by MRI of the skull [Baumgartner et al, 2001].…”

Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2

“…One patient with p.Ile62Ser was also diagnosed with progressive ataxia due to sensory neuronopathy. Recurrent facial nerve palsy has been reported in one patient with CDL (41), while several other publications on CDL (6,(42)(43)(44) lack information on potential neurological symptoms. There are several plausible mechanistic explanations: compression due to cranial sclerosis, as previously suggested (5); basilar invagination due to compromised bone strength, as in OI (45), although no evidence for that was noted in our patients; and neurotoxicity induced by aberrant sphingomyelin metabolism, similar to neuronal damage with incidental cranial nerve palsies in acid sphingomyelinase deficiency (Niemann-Pick disease) (46).…”