Polymicrogyria in chromosome 22 deletion syndrome

Clinical reports over the past decade highlight the role of prenatal circulatory injury in the pathogenesis of polymicrogyria. Genetic,¹ toxic,² metabolic,³ or other embryopathic syndromes⁴ of uncertain etiology have also been implicated in polymicrogyria. The current report describes polymicrogyria in two children with chromosome 22q11 deletion (del 22q11) syndrome. This relatively common haploinsufficiency syndrome (approximately 1/4,000)⁵ principally affects neural-crest cell-derived tissues of the third and fourth branchial arches. Individuals with del 22q11 syndrome are most often recognized because of conotruncal heart defects, cleft palate, or neonatal hypocalcemia. Manifestations are highly variable and include dysmorphism as well as cognitive, cardiologic, immunologic, and hormonal abnormalities. Facial dysmorphism (prominent nasal bridge/bulbous nose) and cognitive deficit are the most consistent del 22q11 syndrome abnormalities.⁶ Neuroradiologic abnormalities reported in association with this syndrome include holoprosencephaly, small vermis, pituitary abnormalities, and agenesis of the corpus callosum.⁷ Under-opercularization, prevalent among infants, may underlie bulbar dysfunction in del 22q1 syndrome.⁸ Polymicrogyria, as seen in two children with del 22q11 syndrome reported here, appears to be a relatively rare neuropathologic manifestation of this syndrome.

Case reports. Patient 1. This patient was the 6-pound 1-ounce product of a pregnancy complicated by decreased fetal movements at 32 weeks. Delivery was by cesarean section after unsuccessful induction at 38 weeks. Cranial ultrasound in the neonatal period revealed asymmetric ventricles, right smaller than left.

Difficulty with choking and gagging during feeding, as well as nasopharyngeal reflux during feeds, resolved during the first year of life. The parents noted a preference for use of the right hand at 4 months, and the pediatrician noted hemiparesis involving the left side at 6 months. The patient had her first tonic-clonic seizure at age 7 months and was treated with phenobarbital after onset of "staring spells" diagnosed as epileptic seizures at age 9 months. Developmental history was remarkable for moderate delay in motor, communications, and adaptive milestones. Medical history was notable for frequent otitis media requiring myringotomy/tympanostomy. Previous ophthalmologic evaluation noted myopia with a small optic disk on the right. Family history was unremarkable.

Physical examination at 27 months showed a head circumference in the 75th to 90th percentile, with commensurate length and weight. The palate was highly arched. Neurologic examination showed flattening of the left nasolabial fold, hyperreflexia and mild hypertonia on the left with decreased spontaneous use of the left arm, and a Babinski sign on the left. She performed at a 15-month level on the Bayley Scale.

Laboratory studies showed normal echocardiogram. Karyotype was normal, but fluorescent in situ hybridization (FISH) studies showed chromosome 22q11 deletion; neither parent showed a deletion by this test. Immunologic evaluation showed normal immunoglobulins, mitogen studies, and lymphocyte subsets (except for a low CD8 count).

Head MRI at 27 months (figure 1, A and B) showed a diffusely abnormal right cerebral hemisphere with effacement of normal sulci and fissures, dilated right lateral ventricle, and shift of the flax cerebri toward the right. Thickening of the cortex was most prominent in the perisylvian area and adjacent frontal cortex. On axial T2 sequences there were thin, linear areas consistent with neuronal heterotopia extending from cortex into the white matter. The rostal brainstem was asymmetric, smaller on the right. Spine MRI showed a syrinx in the low cervical/high thoracic area. EEG showed intermittent slowing in the right temporal/parietal area.

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Figure 1. Patient 1. (A) Parasagittal (right-hemisphere) T1-weighted image shows irregular thickening of the cortex. The sylvian fissure is unusually deep and wide, in part because of decrease in size of the frontal lobe at this level. (B) Axial T2-weighted image shows definite abnormalities of the right hemisphere (reader's left). There is severe thickening and irregularity of the cortex in the perisylvian area as well as the anterior frontal, posterior parietal, and occipital regions. The sulci are effaced, and the whole right hemisphere appears smaller than the left, with relative dilatation of the right lateral ventricle. The sylvian fissure appears as an irregular, shallow cleft, posterior to its usual location at this level. An anomalous fissure can be seen more posteriorly in the occipital lobe. The contrast between right thalamus and putamen and surrounding white matter is attenuated. (Cavum septum pellucidum; heterotopic gray matter; and linear, T2-bright areas extending from cortex into the white matter are better seen on adjacent slices.)

Patient 2. This patient was born to a 29-year-old G1PO well mother whose prenatal monitoring (including ultrasounds) was normal. Delivery at 42 weeks' gestation was by vacuum extraction after labor induction with oxytocin and prostaglandin. Birth weight was 2.92 kilograms, and length was 52 cm. Apgar scores were 7 at 1 minute and 9 at 5 minutes.

Hypocalcemia and symptoms of congestive heart failure developed in the first week of life. Calcium supplementation was eventually withdrawn, and calcium levels normalized. He was treated with digoxin and diuretics, and underwent repair of a ventriculo-septal defect/interrupted aortic arch at age 2 weeks. After the surgery, the infant developed vomiting that persisted throughout the first year of life, and weight gain was poor. He had feeding problems as well as gastroesophageal reflux, with particular difficulty swallowing solids at age 15 months. These problems led to a Nissen fundoplication and gastrostomy tube placement at age 18 months. Family history was significant for nonsyndromic cleft palate in the mother. The father had mild facial dysmorphism consistent with del 22q11 syndrome. This diagnosis was confirmed in him by FISH.

Physical examination at 45 months revealed hypertelorism, bulbous nasal tip with anteverted nares, micrognathia, prominent simple ears, and scars from prior cardiac surgery. Neurologic examination showed hypotonia with brisk reflexes. There was decreased facial expression and no spontaneous speech. There was a persistent asymmetric tonic neck reflex, grasp reflex, and bilateral Babinski reflexes. The child could sit independently but was unable to stand or walk. Developmental evaluation (Vineland Behavioral Scale) showed performance at the 6- to 9-month level.

Laboratory studies were remarkable for an echocardiogram showing truncus arteriosus type 1 with a ventricular septal defect. Brainstem auditory evoked response was normal. Karyotype was normal 46XY. An interstitial deletion at 22q11 was identified by FISH. T- and B-cell studies were normal, as was the calcium level.

MRI performed at 45 months (figure 2, A and B) showed prominent sylvian fissures and a thick, irregularly contoured, perisylvian cortex.

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Figure 2. Patient 2. (A) Parasagittal (right hemisphere) T1-weighted image shows abnormal width of the sylvian fissure. The cortex is abnormally thick and smooth. There is increase in the subarachnoid space particularly over the parietal lobe. (B) Axial T2-weighted image shows symmetric dilatation of the sylvian fissures. Prominent vessels lying free in the fissures are seen more clearly in the left fissure (reader's right). The entire insular cortex, from its junction with the inferior frontal gyrus anteriorly to the posterior sylvian fissure posteriorly, is abnormally thickened and smooth. There are some areas of cortical thickening in the frontal lobes.

Discussion. Neurodevelopmental abnormalities characteristic of del 22q11 syndrome include learning disabilities, mild mental retardation, attention deficit, and impairment of oromotor skills.⁶ Apart from their feeding difficulties, the children reported here had more severe neurodevelopmental and neuroradiologic abnormalities than are usually seen in patients with chromosome 22q11 deletion. We are aware of two other cases of chromosome 22 deletion syndrome associated with perisylvian polymicrogyria (S. Moniotte and H. Kawame, personal communication, 1998). This observation adds to the list of conditions associated with polymicrogyria and suggests that del 22q11 may be a genetic determinant of this pattern of cerebral dysgenesis.

Polymicrogyria on cranial MRI can be seen in patients with del 22q11 syndrome. Considering that neuroimaging of most children with del 22q11 syndrome does not reveal such severe cortical lesions, haploinsufficiency at this locus cannot fully account for these neuroradiologic findings. Other factors that may underlie polymicrogyria include the fetal cerebral vasculature, tendency toward thrombosis, regulation of energy metabolism, and postmigrational cortical maturation. Deletion of genes in del 22q11 syndrome thus may influence one or more of these aspects of fetal brain development.