TY - JOUR
T1 - Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant
T2 - A report of three siblings
AU - Beerepoot, Shanice
AU - Verbeke, Jonathan I.M.L.
AU - Plantinga, Maud
AU - Nierkens, Stefan
AU - Pouwels, Petra J.W.
AU - Wolf, Nicole I.
AU - Simons, Cas
AU - van der Knaap, Marjo S.
N1 - Publisher Copyright:
© 2024 Wiley Periodicals LLC.
PY - 2024/11
Y1 - 2024/11
N2 - We report three siblings homozygous for CSF1R variant c.1969 + 115_1969 + 116del to expand the phenotype of “brain abnormalities, neurodegeneration, and dysosteosclerosis” (BANDDOS) and discuss its link with “adult leukoencephalopathy with axonal spheroids and pigmented glia” (ALSP), caused by heterozygous CSF1R variants. We evaluated medical, radiological, and laboratory findings and reviewed the literature. Patients presented with developmental delay, therapy-resistant epilepsy, dysmorphic features, and skeletal abnormalities. Secondary neurological decline occurred from 23 years in sibling one and from 20 years in sibling two. Brain imaging revealed multifocal white matter abnormalities and calcifications during initial disease in siblings two and three. Developmental brain anomalies, seen in all three, were most severe in sibling two. During neurological decline in siblings one and two, the leukoencephalopathy was progressive and had the MRI appearance of ALSP. Skeletal survey revealed osteosclerosis, most severe in sibling three. Blood markers, monocytes, dendritic cell subsets, and T-cell proliferation capacity were normal. Literature review revealed variable initial disease and secondary neurological decline. BANDDOS presents with variable dysmorphic features, skeletal dysplasia, developmental delay, and epilepsy with on neuro-imaging developmental brain anomalies, multifocal white matter abnormalities, and calcifications. Secondary neurological decline occurs with a progressive leukoencephalopathy, in line with early onset ALSP. Despite the role of CSF1R signaling in myeloid development, immune deficiency is absent. Phenotype varies within families; skeletal and neurological manifestations may be disparate.
AB - We report three siblings homozygous for CSF1R variant c.1969 + 115_1969 + 116del to expand the phenotype of “brain abnormalities, neurodegeneration, and dysosteosclerosis” (BANDDOS) and discuss its link with “adult leukoencephalopathy with axonal spheroids and pigmented glia” (ALSP), caused by heterozygous CSF1R variants. We evaluated medical, radiological, and laboratory findings and reviewed the literature. Patients presented with developmental delay, therapy-resistant epilepsy, dysmorphic features, and skeletal abnormalities. Secondary neurological decline occurred from 23 years in sibling one and from 20 years in sibling two. Brain imaging revealed multifocal white matter abnormalities and calcifications during initial disease in siblings two and three. Developmental brain anomalies, seen in all three, were most severe in sibling two. During neurological decline in siblings one and two, the leukoencephalopathy was progressive and had the MRI appearance of ALSP. Skeletal survey revealed osteosclerosis, most severe in sibling three. Blood markers, monocytes, dendritic cell subsets, and T-cell proliferation capacity were normal. Literature review revealed variable initial disease and secondary neurological decline. BANDDOS presents with variable dysmorphic features, skeletal dysplasia, developmental delay, and epilepsy with on neuro-imaging developmental brain anomalies, multifocal white matter abnormalities, and calcifications. Secondary neurological decline occurs with a progressive leukoencephalopathy, in line with early onset ALSP. Despite the role of CSF1R signaling in myeloid development, immune deficiency is absent. Phenotype varies within families; skeletal and neurological manifestations may be disparate.
KW - ALSP
KW - BANDDOS
KW - bi-allelic
KW - CSF1R
KW - leukoencephalopathy
KW - skeletal dysplasia
UR - http://www.scopus.com/inward/record.url?scp=85197188820&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.63800
DO - 10.1002/ajmg.a.63800
M3 - Article
AN - SCOPUS:85197188820
SN - 1552-4825
VL - 194
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 11
M1 - e63800
ER -