Bilateral polymicrogyria: always think in chromosome 22q11.2 deletion syndromes

Abstract

Polymicrogyria (PMG) is a malformation of cortical development due to an abnormal organisation. It is a heterogeneous disorder associated with genetic and acquired events, namely 22q11.2 deletion syndrome also known as DiGeorge syndrome (DGS) /velocardiofacial syndrome (VCFS) among others. This association has been known since 1996 and more than 30 cases have been described. Neurological features include motor and cognitive impairment, epilepsy, microcephaly and spasticity. The authors present an 8-month old infant with minor dysmorphic features, microcephaly, global psychomotor retardation and epilepsy. Brain MRI revealed diffuse bilateral PMG. The 22q11.2 deletion was confirmed by fluorescent in situ hybridisation (FISH). The child had no other manifestation of DGS/VCFS. paediatricians, neuropaediatricians, development specialists and geneticists should be aware that in the presence of PMG, especially when bilateral, 22q11.2 deletion should be investigated, even in the absence of the typical features of DGS/VCFS. On the other hand, in children with 22q11.2 deletion, brain malformations should be ruled out.

Background

Germline deletion in 22q11.2 chromosome is reported in several overlaping phenotypes such as: velocardiofacial syndrome (VCFS) (OMIM 192430), DiGeorge syndrome (DGS) (OMIM 188400) and conotruncal heart malformations (OMIM 217095).¹ Additionally, some patients with CHARGE syndrome (OMIM 214800) also have the deletion.² It is seen in 1/3900–1/9700 children and they are born with conotruncal cardiac anomalies and mil-to-moderate immune deficiency. Development delay, facial dysmorphia, palatal dysfunction and feeding difficulties are seen in most infants with the syndrome.²

Several brain malformations have been described in association with 22q11.2 deletion syndrome, like polymicrogyria (PMG), cerebellar hypoplasia, megacisterna magna and corpus callosum agenesis.³

PMG refers to an abnormal cortical pattern characterised by an excess of small, irregular convolutions without intervening sulci due to fusion of the molecular layers or with intervening shallow sulci.⁴

Although brain malformations are a rare feature of 22q11.2 deletion syndrome, PMG is the most frequently reported in patients with this condition.⁵

We present a patient with diffuse bilateral PMG due to 22q11.2 delection, but without other manifestations of DGS/VCFS.

Case presentation

This male patient was the first child of unrelated healthy parents with uneventful family history. The pregnancy proceeded without complications and the delivery was at 41 weeks. Birth weight was 3410 g (50th percentile), length 50 cm (50th percentile) and head circumference 33 cm (10th percentile). He was born with polydactylya of the fifth fingers of both hands that was corrected in the neonatal period. Feeding difficulties were noted since birth. At 7-months-old, he was evaluated for global development delay. Clinical examination showed dysmorphic features (figure 1): microcephaly (head circumference below 5th percentile), frontal bossing, broad nasal bridge, large ears, small mouth with down turned corners, large philtrum and short neck. Weight and length below the 5th percentile. He had no cardiac murmur. Neurological examination showed poor cephalic control, spasticity of the four limbs, closed hands and feeding difficulties with poor suction/swallow control. At the age of 8 months, he started myoclonic focal seizures that were controlled with carbamazepine.

Figure 1.

Some of the dysmorphic features of the child.

Investigations

Brain MRI showed diffuse bilateral PMG predominantly fronto-parietal with cortico-subcortical atrophy (figure 2a,b and incomplete operculisation (figure 3). EEG showed frequently bilateral spike discharge, more often in the right hemisphere. Cardiac and renal ultrasound showed no abnormalities. Cytomegalovirus DNA in guthrie card was negative. Ig A, M and G titres, lynfocyte subsets, calcium and parathormone levels were normal. Auditory evoked potentials were normal. Kariotype showed 46, XY. Fluorescent in situ hybridisation (FISH) specific for the 22q11.2 region showed a monosomic microdeletion. None of the parents had the deletion.

Figure 2.

Axial (a) and coronal (b) T2 FSE: bilateral diffuse PMG, predominatly fronto-parietal, with irregular cortical surface and multiple shallow sulci. Global cortico-subcortical atrophy.

Figure 3.

Axial T1 3D FSPGR: incomplete opercularisation of both sylvian fissures and polymicrogyric perisylvian and temporo-occipital regions. Note the irregular interface between cortex and adjacent white matter.

Outcome and follow-up

During follow-up, at the age of 22 months he developed hypocalcemia and was evaluated by endocrinology, starting oral calcium and vitamin D supplements with improvement of calcium levels (parathormone levels were normal). In spite of early stimulation, at the age of 24 months, the boy maintained severe development delay with partial cephalic control, could not sit without support, did not speak any word, maintained spasticity of all limbs and feeding difficulties with failure to thrive. He restarted seizures and levetiracetam was added to carbamazepine with complete control.

Discussion

PMG can be caused by intrauterine infections, fetal vascular supply disruption and monogenic causes. PMG has also been described in chromosomal abnormalities such as 22q11.2 deletion syndromes and its pathogenesis is still unknown.³

In general, cognitive and behavioral dysfunction, cardiac defects and microcephaly are among the cardinal features of 22q11.2 deletion syndromes.² Development delay is more severe and always present in patients with associated PMG, unlike patients with deletion and no PMG (75%). Seizures are also more frequent (47% vs 21%).⁶

Our patient did not have cardiac abnormalities, wich are only present in about half of 22q11.2 deletion patients with PMG. Although PMG is a rare feature in 22q11.2 deletion, it can be the presenting sign of this syndrome, as illustrated by our patient.

Paediatricians, neuropaediatricians, development specialists and clinical geneticists should be aware that PMG should indicate the need for 22q11.2 deletion testing. If the result is positive, screening for cardiac abnormalities, velopharingeal dysfunction, hearing loss, immune-deficiencies, hypocalcemia and urogenital malformations should be conducted. Genetic counseling for the parents is also indicated.

Learning points.

• ▶Testing for 22q11.2 deletion is indicated in children with PMG even in the absence of other DGS/VCFS features.
• ▶Brain MRI should be performed to look for brain malformations, including PMG, in children with proven 22q11.2 deletion syndrome, especially those with neurological signs.