Abnormal Myelination in Ring Chromosome 18 Syndrome

Case Summary

The patient, a 12- year- old girl born to a French Canadian couple, was delivered via spontaneous breech vaginal delivery at 36 weeks of gestation to a healthy Gravida₃Para₃Abortus₀ mother. The pregnancy was unremarkable. The Apgar scores were 5 and 7 at 1 and 5 minutes, respectively. The child required transient oxygen supplementation but no other resuscitation measure was necessary. Her birth weight was 2.52 kg (5th percentile), and she was discharged home at 7 days of life.

The patient was admitted to the hospital at the age of 2 months for failure to thrive and feeding difficulties. During this first admission, she was found to have facial dysmorphic features, thereby prompting a karyotype analysis, which revealed a ring chromosome 18. Over the years she was found to have multiple medical issues including congenital cyanotic heart disease with aortic-pulmonary collaterals that was corrected by coiling, after which she acquired right pulmonary vein atresia. She was followed by cardiology and respirology for recurrent pulmonary hemorrhages and pulmonary hemosiderosis. The patient had recurrent oto-sino-pulmonary infections, pneumococcal bacteremias, and Clostridium difficile colitis which prompted an immunologic workup revealing hypogammaglobulinemia and polysaccharide antibody deficiency (normal immunoglobulin A, but low immunoglobulin G ± immunoglobulin M), normal T and B cell enumeration, normal lymphocyte proliferation studies, and normal complement studies. She was started on intravenous immunoglobulin at the age of 2 years but because of later side effects (mood disturbance and headaches) she was later switched to subcutaneous immunoglobulin at the age of 9 years. She was diagnosed with pauciarticular (antinuclear antibody positive) juvenile rheumatoid arthritis at the age of 2 years, which was initially managed with steroids and later subcutaneous methotrexate, which she continues to take. Her other medical issues include growth hormone deficiency, hypothyroidism, short stature, adrenal insufficiency secondary to chronic steroid use, bilateral conductive hearing loss secondary to aural stenosis, cervical spine anomaly (hypoplastic arch of C1 partially fused to a hypertrophic arch and spine process of C2), scoliosis, and bilateral subluxations of the hips. With respect to surgical procedures, she underwent myringotomies with bilateral tube placement at 1 year of age, bilateral inguinal hernia repair, blepharoptosis repair at 1 year of age, multiple botulinum toxin injections, and submandibular duct ligation for hypersalivation. Ophthalmologic assessments have been normal. Her current medications include losec, subcutaneous immunoglobulin on alternate days, oral prednisone, subcutaneous methotrexate once a week, leucovorin 24 hours post-methotrexate, l-thyroxine, Nutropin (somatropin [rDNA origin]; growth hormone), and Seroquel (quetiapine fumarate).

From the neurodevelopmental standpoint, she has global developmental delay. She produces no speech but is able to communicate with gestures. She was diagnosed with mild intellectual disability by formal neuropsychological assessments. She is able to feed herself with a spoon and fork, but with some difficulty. She is toilet trained during the day but not at night. She is unable to read and write but can however type using a computer. The patient demonstrates disruptive and self-injurious behaviors, including hyperactivity, inattention, food stealing, self-mutilation, and temper tantrums that have been worsening since the age of 11 years.

On physical examination, she weighs 29 kg (<5th percentile), her height is 120 cm (<5th percentile), and her head circumference is 50 cm (2nd percentile). She has multiple dysmorphic features including midface hypoplasia, epicanthal folds, broad nasal bridge, carp mouth, and stenotic ear canals. She produces no speech and communicates with gestures. She is agitated and is difficult to examine. However, her neurologic examination is nonfocal with normal cranial nerve examination, mildly increased tone in both the upper and lower extremities, no evidence of muscle weakness, a negative Gower sign, normal stretch reflexes, and bilateral Babinski reflexes. She has a very broad-based ataxic gait. Her sensory examination is grossly normal to touch. Spine examination reveals a sinus tract at the lower spine.

MRI was performed using a 1.5-Tesla superconducting magnet at 15 months of age and demonstrated mild symmetrical enlargement of the supratentorial lateral ventricles, with no deformity, no signs of increased intracranial pressure and no transependymal reabsorption. There were abnormal bilateral symmetrical areas of low T1 and high T2 signal intensities of deep and superficial white matter, more extensive in the posterior parietal and occipital lobes (Figure 2A). A repeat MRI at 11 years of age continued to demonstrate persistent enlargement of the supratentorial ventricles, which were thought to be slightly more prominent. There was evidence of improved myelination with overall increased fatty content and higher T1 and lower T2 signals of both subcortical and deep white matter tracts (Figure 2B). However, there was a diffuse decrease in gray-white matter differentiation, as well as persistently abnormal increased T2 and fluid-attenuated inversion recovery signal intensities of the periventricular white matter, patchier in appearance than on previous MRI with relative sparing of temporal lobes (Figure 2B). Furthermore, there were new cystic changes of the deepest white matter along the horns of the ventricles that did not enhance with gadolinium (Figure 2B, fluid-attenuated inversion recovery).

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Figure 2.

A, Initial MRI performed at 15 months of age using a 1.5-Tesla magnet. Axial T1 image demonstrating mild bilateral symmetric hyperintensity of the white matter compared with to gray matter structures and poor gray-white matter differentiation consistent with hypomyelination. Axial T2 image demonstrating mild hyperintensities of the white matter with relative preservation of the corpus callosum and optic radiations. B, Repeat MRI performed at 11 years of age using a 1.5-Tesla magnet. Axial T1 image demonstrating progression of myelination with higher T1 signal compared with gray matter structures and improved gray-white matter differentiation. Axial T2 image demonstrating lower T2 signals compared with to previous, but still abnormal, white matter signal. Cystic changes in the periventricular white matter evident on axial fluid-attenuated inversion recovery sequence.

A microarray comparative genomic hybridization revealed a deletion of approximately 565 kb at 13q12.12 (22442669-23007193), a second deletion of approximately 13.976 Mb at 18p11.32-18p11.21 (131491-14107537), and a third deletion of approximately 23.723 Mb at 18q21.31-18q23 (52392046-76114684). The latter starts at the centromere, consists of the long arm of chromosome 18 at 18q21.31 (r(18)(p10q21.31)), and results in a monosomy of the distal part of chromosome 18 from 18q21.31 until the telomere of 18q while the second deletion results in complete monosomy of the short arm of chromosome 18 (Figure 1).

Discussion

Although 18q- syndrome has an estimated incidence of 1 in 40 000 live births, ring chromosome 18 is relatively rarer. We report a case of ring chromosome 18 and deletions involving 18p11.32-11.21 and 18q21.31-18q23 (Figure 1). This patient presents with multiple medical problems including dysmorphic features, microcephaly, short stature, growth hormone deficiency, hypothyroidism, mild intellectual disability, behavioral abnormalities, cardiac malformation, immunodeficiency, musculoskeletal abnormalities, biaural stenosis with conductive hearing loss, and some pyramidal tract signs on neurologic examination. These clinical features have been well documented in 18q- syndrome ^{3 –11} but have also been reported in patients with ring chromosome 18. ^{26,28 –34}

Of interest, our patient also presents juvenile rheumatoid arthritis that has never been described in patients with either chromosome 18q- syndrome or ring chromosome 18. Although other autoimmune conditions such as autoimmune thyroiditis and insulin-dependent diabetes mellitus have been reported with ring chromosome 18 and have raised the speculation that a susceptibility locus may be present on this chromosome, no specific locus or gene has yet been implicated. ³⁵ Examination of the disease-causing genes identified on the short arm of chromosome 18 reveals a susceptibility locus (IBD21, OMIM 612354) at 18p11 for inflammatory bowel disease, another autoimmune-mediated disorder (Figure 1, upper insert). However, this specific locus is not deleted in our patient.

Neuroimaging studies have consistently shown that white matter abnormalities—mild hyperintensities in T2-weighted images being the most common findings—are seen in up to 75% of patients with chromosome 18q- syndrome. ^{5,17 –23} The typical pattern consists of greater involvement of the upper frontal, parietal, and occipital areas and less pronounced involvement of the lower frontal and temporal areas. ^19,20 Hyperintensities of the anterior and posterior limbs of the internal capsule, as well as the periventricular white matter, have also been described. Less commonly, porencephalic cysts or focal lesions have been reported. ^5,19 Similar white matter abnormalities were present in our patient where neuroimaging demonstrated enlarged ventricles as well as mild hypointensities on T1-weighted images and mild hyperintensities on T2-weighted images and fluid-attenuated inversion recovery sequences of both the superficial and deep white matter, more prominently seen in the parietooccipital regions with a relative sparing of the temporal lobes (Figure 2). To our knowledge, there has only been 1 previous report of similar white matter abnormalities described in a Japanese patient with ring chromosome 18. ²⁷

The temporal evolution of the white matter abnormalities seen in our patient was also similar to what has previously been described in chromosome 18q- syndrome. Specifically, within the 10-year span that elapsed between the 2 imaging studies (obtained at 15 months and 11 years, respectively), there was some evidence of progression but not completion of myelination. Overall, arcuate white matter fibers, centrum ovale, internal capsules, as well as the corpus callosum demonstrated higher T1 and lower T2 and fluid-attenuated inversion recovery signals compared with the initial imaging study. This interval progression in myelination, together with the persistently abnormal increased T2 signals especially in the periventricular region, probably explains the more patchy appearance seen on the second MRI (Figure 2). This temporal evolution has also been reported in chromosome 18q- syndrome where authors have demonstrated that with increasing age, there is a decrease in the T1 and T2 relaxation times. ^17,19 Despite this age-related maturation, T1 and T2 signals never approach a normal appearance in patients with 18q- syndrome, indicating that despite progression in myelination, this process is never actually completed. ^17,23,36

In spite of the above similarities in the pattern and evolution of the white matter abnormalities, the progressive or delayed cystic changes observed in the periventricular white matter was one notable difference. This raises the question as to whether the periventricular white matter is more severely involved or whether this pattern could be more specific for ring chromosome 18.

White matter abnormalities are not specific to chromosome 18 and have also been reported in partial deletions involving chromosomes 6, 11, 14, 22, and the sex chromosomes. ^{37 –40} Nevertheless, the consistent findings of hypomyelination in patients with partial deletions of chromosome 18 are interesting in the context of the presence of the gene coding for myelin basic protein (OMIM 159430) located on the distal segment of chromosome 18 at 18q23. Myelin basic protein is the second most abundant protein found in myelin and comprises approximately 30% of this insulating material. It is postulated to play a role in the adhesion of the cytosolic surfaces of the multilayered myelin sheath and thus in myelin compaction. ²⁵ Combined neuroimaging and molecular studies have demonstrated white matter abnormalities in patients with distal deletions in chromosome 18q- involving 18q23 and subsequent myelin basic protein hemizygosity as opposed to deletions sparing myelin basic protein. ^4,5,17,21 The results of these studies suggest that the absence of 1 copy of myelin basic protein may lead to a hypomyelination pattern through abnormal compaction of myelin (and thus the abnormal T2 signal hyperintensities) rather than the content of myelin itself. ⁴¹ Although in our patient we did not test for MBP haploinsufficiency, the array comparative genomic hybridization indicates deletion of this locus. Furthermore, there are no other putative genes on 18p11.32-11.21 nor on 13q12.12 that have been reported to cause white matter abnormalities nor are any apparently implicated in myelination. The latter deletion of 13q12.12 that was also reported in our patient is not linked with any known congenital anomalies but renders the patient a carrier for ARSACS or autosomal recessive spastic ataxia of Charlevoix-Saguenay (OMIM 270550) and limb-girdle muscular dystrophy type 2C (OMIM 253700).

In conclusion, we have described a case of ring chromosome 18 with clinical features similar to those seen in chromosome 18q- syndrome but with a more severe phenotype. The abnormal myelination seen in this patient is similar and indicates a hypomyelination process rather than a delayed myelination. One notable difference is the presence of periventricular cystic changes that, to our knowledge, have not been previously described in chromosome 18q- syndrome. Ring chromosome 18, although rare, is an important analogous syndrome to consider in 18q- deletion syndrome. Finally, our case underlines the importance of performing both a comparative genomic hybridization array and a karyotype in the evaluation of patients with documented white matter abnormalities.