Microcephaly-micromelia syndrome phenotype and pedigrees. (A) Photographs of an affected individual (12601) illustrating the severe microcephaly, facial dysmorphisms, and limb anomalies characteristic of microcephaly-micromelia syndrome. (B) Photograph of a foot (individual 15204) and photograph and X-ray of a hand (individual 12601) showing both pre-axial (malformed toe and absent thumb) and post-axial (underdeveloped fifth metatarsal bone, and hypoplastic fifth digit arising from bifid fourth metacarpal bone) abnormalities. (C) Brain MRIs of two affected individuals showing the common structural brain abnormalities of MMS: profound microcephaly, simplified gyral pattern, markedly diminished white matter volume and myelination, hypoplastic or absent corpus callosum, aqueductal stenosis, and a small pons. Note the large dorsal interhemispheric cysts in both individuals, which was present in nearly every affected individual examined by MRI or autopsy to date. Cortical thickness is grossly normal and the cerebellar hemispheres are relatively large compared to the rest of the brain. Head circumferences (HC) and z-scores (number of standard deviations [SD] from the mean of newborns of the same gestational age at birth) are shown. MRI sequences were as follows: 12601: axial T2 (top left), mid-sagittal T1 (top right), left-sagittal T1 (bottom right), coronal T2-FIESTA (bottom left); 15204: axial T2 (top), coronal T2-HASTE (bottom). White scale bars = 1 cm. (D) Brain histology of MMS cases. (Left) Low-power Nissl-stained brain section of a child who died at 3 mo of age showing simplified gyral pattern and reduced white matter (CG) cingulate gyrus, (CC) corpus callosum, (LV) lateral ventricle, (Cd) caudate, (P) putamen, (GP) globus pallidus, (OT) optic tract). (Top right) Cresyl violet-stained brain section of a 35-wk-gestation newborn at the angle of the lateral ventricle (LV) showing decreased cells in the subventricular zone (SVZ; arrow). Bar = 100 μm. (Middle right) Hematoxylin- and eosin-stained section of the cerebral cortex of a 41-wk-gestation newborn demonstrating disorganized clusters of neurons (arrows) separated by cell-free zones in superficial layers. Bar = 100 μm. (Bottom right) Cresyl violet-stained section from a full-term newborn cerebral cortex demonstrating the persistence of radial columns of neurons separated by cell-sparse regions. Bar = 500 μm. (E) Pedigrees of the families with MMS profiled in this study. Individual IDs are labeled for individuals whose samples were profiled. The pedigree at the top left can be linked via individuals VII:7 and VIII:2 to the larger pedigree in the original description of the syndrome by Ives and Houston (Ives and Houston 1980). Gray symbol (top right pedigree) represents a child that died in infancy with limb anomalies, but the specific diagnosis of MMS was not confirmed. Deceased status is indicated with crossed-out symbols for affected individuals only and not for unaffected individuals. For simplicity, not all individuals of the pedigrees are illustrated. See Supplemental Data 1 for a list of all case samples in this study.
