A number sign (#) is used with this entry because of evidence that brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) is caused by homozygous or compound heterozygous mutation in the CSF1R gene (164770) on chromosome 5q32.

Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) is an autosomal recessive disorder characterized by brain abnormalities, progressive neurologic deterioration, and sclerotic bone dysplasia similar to dysosteosclerosis (DOS). The age at onset is highly variable: some patients may present in infancy with hydrocephalus, global developmental delay, and hypotonia, whereas others may have onset of symptoms in the late teens or early twenties after normal development. Neurologic features include loss of previous motor and language skills, cognitive impairment, spasticity, and focal seizures. Brain imaging shows periventricular white matter abnormalities and calcifications, large cisterna magna or Dandy-Walker malformation, and sometimes agenesis of the corpus callosum (summary by Guo et al., 2019).

Guo et al. (2019) reported 6 patients from 3 unrelated families with variable manifestations of BANDDOS. The first affected patient was a 4-year-old Brazilian boy who had congenital hydrocephalus, hypotonia, focal seizures, and global developmental delay. He had his first steps at age 20 months, but regressed and was unable to sit without support by age 4.5 years. Brain imaging showed Dandy-Walker malformation, periventricular calcifications, agenesis of the corpus callosum, and abnormal signals in the periventricular white matter. Dysmorphic features included long eyelashes, epicanthus, bulbous nose, dysplastic ears, narrow, bell-shaped thorax, pectus carinatum, joint restrictions, and kyphosis. He also had poor vision with nystagmus secondary to optic nerve atrophy and narrowing of the optic canal in the skull. The second patient was a 37-year-old Japanese woman who was diagnosed with osteopetrosis in childhood, but apparently did not manifest major features until her late twenties after graduating from college. She developed decreased visual acuity associated with optic canal narrowing and a type 1 Chiari malformation, progressive difficulty speaking, severely impaired walking, and mildly impaired cognition. She was severely hypophonic and had generalized spastic rigidity. The third family was a highly consanguineous Chaldean family in which 5 patients were affected, although only 2, a 14-year-old boy and a 23-year-old woman, were described in detail. The boy had symptoms from infancy, including hydrocephalus, hypotonia, focal seizures, developmental delay, and impaired intellectual development (IQ of 50), whereas the woman had slightly less impaired cognitive function (IQ of 73). Both patients showed progressive cognitive decline, deterioration in vocalization, rigidity, and spasticity with hyperreflexia. Brain imaging showed dilated ventricles, multiple punctate or periventricular calcifications, white matter abnormalities, and large cysterna magna. Other affected members in this family had a similar, if variable, disorder characterized as a rapidly progressive encephalopathy with intellectual decline, pyramidal, extrapyramidal, and cerebellar features, ataxia, dysarthria, seizures, and psychiatric symptoms culminating in spastic paraplegia, mutism, and a persistent vegetative state. The age at onset of symptoms was variable. Three patients were able to attend special education schools, 2 had delayed walking and language milestones, 1 completed college, and another completed a year of college prior to symptom onset. Skeletal survey in all patients from the 3 families showed diffuse osteosclerosis of the craniofacial bones and skull, as well as platyspondyly and abnormalities of the long bones, including undermodeling, widened metaphyses, and constricted and sclerotic diaphyses. Two patients also had optic canal narrowing and pelvic and vertebral sclerosis. The radiographic findings were consistent with DOS.

Oosterhof et al. (2019) reported 2 unrelated patients with highly variable phenotypic expression of BANDDOS. The first patient, born of consanguineous Native Alaskan parents, presented at birth with multiple congenital brain anomalies first detected in prenatal ultrasound and associated with increased alpha-fetoprotein (104150). He had macrocephaly (+5 SD) and dysmorphic features, including cranial asymmetry, flattened midface, depressed nasal bridge, and bony prominences in the parietal skull. Skeletal survey showed a dense skeleton with irregular metaphyses. He also had hearing loss, respiratory difficulties, feeding difficulties, intractable seizures, and persistent hypocalcemia. He died of bacteremia at age 10 months. Postmortem examination of the brain showed Dandy-Walker malformation, small pyramidal tracts with no definite decussation, small cerebellum with loss of Purkinje cells, and complete absence of the corpus callosum. Other abnormalities included periventricular and brainstem calcifications, periventricular heterotopia, white matter abnormalities, malformed hippocampi, and enlarged cisterna magna. There were subcortical axonal spheroids and reactive astrocytes, as well as a severe deficiency of microglial cells associated with decreased CUX1 (116896) immunostaining. None of the patient's parents or grandparents reported neurologic symptoms, but all were under 40 years of age. The second patient was a 24-year-old man, born of consanguineous Arab parents, who presented with refractory seizures and severe developmental regression at age 12 years after normal development. At age 24 years, he was no longer able to walk, speak, read, or feed himself, and had spasticity with hyperreflexia. Brain imaging showed ventriculomegaly, hypoplasia of the corpus callosum, periventricular calcifications, leukodystrophy, atrophy of the cerebellar vermis, and mega cisterna magna. He did not have osteopetrosis or hypocalcemia. He had 1 similarly affected brother who died at age 21; the parents were unaffected. Oosterhof et al. (2019) noted that Monies et al. (2017) had reported 2 sibs, born of consanguineous Arab parents, with a perinatal lethal phenotype comprising osteopetrosis, hypocalcemia, and severe brain abnormalities, including agenesis of the corpus callosum, enlarged ventricles, periventricular calcifications, and cerebellar hypoplasia. Although DNA from these affected sibs was not available, a potentially pathogenic nonsense variant (Y540X) in the CSF1R gene was found in the heterozygous state in each unaffected parent and in unaffected sibs.

The transmission pattern of BANDDOS in the families reported by Guo et al. (2019) and Oosterhof et al. (2019) was consistent with autosomal recessive inheritance.

In 6 patients from 3 unrelated families with BANDDOS, Guo et al. (2019) identified homozygous or compound heterozygous mutations in the CSF1R gene (164770.0010-164770.0014). The mutations, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Five different mutations were identified, including a nonsense and a missense variant in compound heterozygosity (see 164770.0010), an in-frame deletion and a deep intronic mutation in compound heterozygosity (see 164770.0012), and a deep intronic mutation in homozygosity (164770.0014). In vitro functional expression studies of 3 of the variants showed that they were associated with decreased JNK (MAPK8; 601158) phosphorylation, consistent with impaired CSF1R function. The authors noted that the skeletal phenotype in these patients was not as severe as that observed in Csf1r-null mice, suggesting that some of the mutations likely result in hypomorphic alleles. However, the overall findings suggested that biallelic mutations that result in decreased CSF1R produce the skeletal phenotype, as heterozygous mutations that cause HDLS (221820) do not result in skeletal abnormalities. Moreover, Guo et al. (2019) noted that the heterozygous parental carriers in their study did not have manifestations, suggesting that HDLS mutations likely act via a dominant-negative effect.

In 2 unrelated patients with BANDDOS, Oosterhof et al. (2019) identified homozygous mutations in the CSF1R gene: the more severely affected patient who died at age 10 months carried a splice site mutation (164770.0015), likely resulting in a loss of function, whereas the other patient who had a less severe phenotype without obvious skeletal anomalies carried a missense mutation (H643Q; 164770.0016), which may have resulted in a hypomorphic effect. The mutations, which were found by exome sequencing, segregated with the disorder in both families. None of the carrier parents were affected.

Dai et al. (2004) found that Csf1r-null mice had frequent spontaneous fractures and decreased bone strength associated with an expanded epiphyseal chondrocyte region, poorly formed cortex with disorganized collagen fibrils, and a severely disturbed matrix structure. Since Csf1r is expressed in osteoclasts, the findings suggested that mutant mice had a deficiency of osteoclast-mediated regulation of osteoblasts during formation of lamellar bone.

Erblich et al. (2011) found that Csf1r-null mice had postnatal developmental brain abnormalities, including enlarged ventricles, periventricular changes, parenchymal volume loss, thinning of the cerebral cortex, and propensity to hydrocephalus. These changes were associated with severely decreased numbers of microglia in the brain. Mutant mice also died early.

Oosterhof et al. (2019) found that knockdown of the csf1r homologs in zebrafish resulted in lack of microglia in the brain. Vertebral arches in mutant animals were smaller compared to controls, which the authors suggested may recapitulate osteopetrosis. These abnormalities were associated with downregulation of cux1 (116896), a transcription factor present in neurons.

Elcioglu et al. (2002) described in detail the radiologic findings in 3 patients with dysosteosclerosis, 2 of whom were sibs. One patient presented in infancy with blindness, and brain CT scan showed thick, dense bones, and markedly narrowed optic foramina. She later showed severe delayed psychomotor development and lost language development. Radiographs at age 14 years showed sclerosis of the skull base, abnormal dentition, osteosclerosis of the thorax, and platyspondyly and other abnormalities of the vertebral bodies. The long bones of the upper and lower limbs had striking expansion of their metadiaphyses and irregular sclerosis. The patient's younger brother presented in infancy with blindness due to optic nerve compression, and showed diffuse generalized sclerosis with irregularity of the proximal humeral metaphyses and platyspondyly on radiography. He died at age 10 months due to complications of bone marrow transplant. The third patient was blind with developmental delay. Radiologic evaluation at 6 months of age showed sclerosis with slender ribs, platyspondyly, and flared femoral metaphyses. At age 1 year, there was sclerosis of the skull base and striking bone abnormalities in the ribs. Elcioglu et al. (2002) discussed the differentiation of dysosteosclerosis from childhood osteopetrosis (see OPTB1, 259700).