microcephaly

Patients have multiple severe systemic abnormalities.  There is generalized developmental delay along with mild microcephaly and hypotonia.   The forehead is often broad while the face appears flattened with anteverted nares, a flat nasal bridge, a short philtrum, low-set and crumpled ears.  Infants may have an inadequate upper respiratory apparatus with atrophic vocal cords and some die of laryngeal obstruction in the first days of life.  Sialorrhea and difficulty swallowing have been noted.  Mild to moderate neurosensory hearing loss is often present but there may also be a conduction component to this. 

Brain imaging has revealed large ventricles, with subcortical hypomyelination, a thin corpus callosum, and prominent cortical sulci.  The vertebrae may have coronal clefts and scoliosis often develops. Generalized metaphyseal dysplasia and delayed bone age are usually present.  The anus may be imperforate and a rectovaginal fistula and cryptorchidism have been reported.  Long bones may be malformed as well and most patients are short in stature. Delayed dentition, enamel dysplasia, and abnormal cusp morphology are often present.  Cardiac septal defects may be seen.

Patients have mild to severe microcephaly (up to -15 SD) with psychomotor delays.  Profound intellectual disability is a consistent feature.  Physical growth is retarded and patients have shortness of stature.  Most patients are unable to sit, stand, or walk unassisted.  One patient died at 5.5 years of age while another was alive at 20 years of age.  Rare patients may have hearing loss and seizures.

Scoliosis, kyphosis, and lordosis may be seen while  other skeletal malformations seem to occur sporadically e.g., triphalangeal thumbs, brachydactyly, postaxial polydactyly, and restricted large joint motion.  

The forehead slopes markedly.  Neuroimaging shows a consistent reduction in cortex size with simple gyral folding while the cerebellum and the brain stem are also small.  Subarachnoid cysts have been noted in several patients and the corpus callosum may be short or otherwise malformed.

Infants are born with low birth weight due to intrauterine growth retardation and there is often a history of oligohydramnios.  Newborns are often floppy and hypotonic although spasticity may develop later.  A small midface and microcephaly (80%) with a sloping forehead and a flat occiput are frequently evident.  The ears are large, floppy, and low-set while the hard palate is highly arched and the degree of micrognathia can be severe.  The fists are often clenched and the digits can appear narrow and arachnodactylous.  Hiatal hernias may be present.

Many patients develop features of the nephrotic syndrome in the first year of life with proteinuria and hypoalbuminemia due to glomerular kidney disease and renal system malformations.  Renal biopsies show focal segmental glomerulosclerosis in the majority of glomeruli.

Evidence of abnormal neuronal migration with brain deformities such as cystic changes, porencephaly, encephalomalacia, and spinal canal anomalies have been reported.  MRI imaging shows diffuse cortical and cerebellar atrophy atrophic optic nerves, and thinning of the corpus callosum.  The normal striated layers of the lateral geniculate nuclei are obliterated.  The cerebellum shows severe cellular disorganization with profound depletion of granule cells and excessive Bergmann gliosis.  The vermis is shortened. 

Multifocal seizures are sometimes (40%) seen in infancy and early childhood and the EEG generally shows slowed and disorganized backgound and sometimes a high-voltage hypsarrhythmia.  The degree of psychomotor delay and intellectual disability is often severe.   Most patients are unable to sit independently (90%), ambulate (90%), or make purposeful hand movements (77%).  The majority (87%) of children have extrapyramidal movements and a combination of axial dystonia and limb chorea.  Mean age of death is about 11 years (2.7 to 28 years in one series) and most die from renal failure.

Intrauterine growth retardation is common and infants are born with significant deformities including microcephaly, limb malformations, flexion deformities, ichthyosis, and edema of the hands and feet.   Brain malformations may be present as well.

This is a lethal dysplasia-malformation syndrome in which some infants are stillborn while others do not live beyond a few days.  The placenta is often small and the umbilical cord is short.  Decreased fetal movements and polyhydramnios are often noted.  Microcephaly can be striking at birth but there is overall intrauterine growth retardation.  The skin is ichthyotic and dysplastic containing excess fatty tissue beneath the epidermis.  Digits are often small and may be fused (syndactyly).  There is generalized edema with ‘puffiness’ of the hands and feet.  The lungs are frequently underdeveloped and cardiac defects such as septal openings, patent ductus arteriosus and transposition of great vessels are common.  Males often have cryptorchidism while females have a bifid uterus and renal dysgenesis has been reported.

The face is dysmorphic with prominent globes (in spite of microphthalmia), the ears are large and malformed, the forehead is sloping, the nose is flattened and the jaw is small.  Some infants have a cleft lip and palate while the mouth is round and gaping.  The neck is usually short.

Severe brain malformations such as lissencephaly, cerebellar hypoplasia, and dysgenesis/agenesis of the corpus callosum are frequently present.

Head circumference ranges from the 10^th to the 25^th percentile at birth  Psychomotor development has been described as normal during the first 6 to 8 months but is followed by rapid deterioration in performance with spasticity, vomiting and continuous crying.  An MRI on one 3 day old patient was reported as normal while at 15 months of age there was atrophy of the vermis and corpus callosum and at 8 years of age the atrophy of these structures was even more extensive.  Similar atrophy patterns were seen in the two other patients and eventually all cerebral while matter is lost and there is atrophy of the brainstem as well. 

Microcephaly relative to age norms is evident usually by 2 months of age and there is little subsequent growth of the skull.  Regression of developmental milestones is noted by 4 months of age with signs of irritability, akathisia, spasticity, visual impairment, seizures, and increased startle responses.  Sucking responses and eye-to-eye contact are usually lost by 6 months of age.  Repetitive body stiffening and extension of arms in older individuals consistent with seizure activity has been confirmed by EEG in at least one infant.  Imaging consistently reveals cerebral atrophy with ventriculomegaly and general loss of brain volume. Progressive muscle weakness is evident after about 1 year of age and oral feeding is impaired. There is complete lack of responsive interaction beyond irritability and agitation while motor function is limited to involuntary responses.  Two individuals have lived into the second decade of life.