18q Syndrome Chapter 35

(1)

35.1 Clinical Features

and Laboratory Investigations The 18q

^–

syndrome is an autosomal deletion disorder with variable phenotype. Most patients have a de no- vo deletion, but in some patients it is inherited. The most frequent disease characteristics include mental retardation, short stature, microcephaly, midface hypoplasia, hypertelorism, epicanthus, carp-shaped mouth, high or cleft palate, preauricular skin tags, narrow or atretic ear canals, sensorineural or conduc- tive hearing deficit, short neck, tapering fingers, clin- odactyly, proximally placed thumbs, prominent fin- ger whorls, widely spaced nipples, congenital heart disease, genital abnormalities, and foot deformities.

Mental capacities vary from borderline to severely deficient. Apart from mental retardation, neurologi- cal abnormalities include hypotonia, seizures, nystag- mus, poor coordination, tremor, and choreoathetosis.

Routine and metabolic laboratory investigations reveal no abnormalities. IgA deficiency and abnor- malities in growth hormone production are relatively frequent. Peripheral nerve conduction is normal.

Study of evoked potentials may reveal prolonged cen- tral conduction. Chromosomal analysis reveals a par- tial deletion of the long arm of chromosome 18, most often including the bands q22.3Æqter. Inversion of the long arm of chromosome 18 with loss of the 18q23 region, translocations involving 18q, ring chromo- some 18, and interstitial 18q23 deletions may also be seen.

35.2 Pathology

Reduction of cerebral white matter and delay of myelination are the main histopathological findings.

Ventricles and subarachnoid spaces may be mildly enlarged.

35.3 Pathogenetic Considerations

18q

^–

Syndrome is a contiguous gene syndrome. It is likely that haplo-insufficiency of genes located in the deleted region explains the clinical phenotype and that the variability of the phenotype depends on the exact genes deleted. However, whether there is a cor- relation between the size of the deletion and the phe-

notype or not is still controversial. The deletion in the 18q

^–

syndrome includes the locus for the myelin basic protein gene (18q22–23). It is likely that the impair- ment in myelination of the CNS is at least partially related to haplo-insufficiency of the myelin basic pro- tein gene. In patients with an interstitial deletion of chromosome 18, which retains the myelin basic pro- tein region, myelination is normal (Linnankivi et al.

2003). The two most important proteins of CNS myelin are proteolipid protein and myelin basic pro- tein. Myelin basic protein accounts for 30–40% of the total myelin protein, proteolipid protein for 40–50%.

The 18q

^–

syndrome could be considered to be the autosomal counterpart of X-linked Pelizaeus–Merz- bacher disease, which is caused by mutations of the proteolipid protein gene. However, an important dif- ference is that one normal myelin basic protein gene is present in the 18q

^–

syndrome, whereas no normal proteolipid protein gene at all is present in males suffering from Pelizaeus–Merzbacher disease. Peli- zaeus–Merzbacher disease is characterized by severe impairment of myelination of the CNS. The extent of impairment of myelin deposition is less severe and more variable in the 18q

^–

syndrome. The degree to which myelination is affected in the 18q

^–

syndrome has been found to correlate with the severity of the other features, whereas the myelin basic protein gene is included in the deletion in all patients. It is there- fore unlikely that the presence of only one copy of the myelin basic protein gene is solely responsible for producing the abnormalities in myelination.

The so-called shiverer mouse has an autosomal re- cessive disease related to a mutation of the myelin ba- sic protein gene. In this mouse a defect in CNS myeli- nation is found. Clinical disease is characterized by generalized action tremor, increasingly frequent con- vulsions, and premature death. Histopathological ex- amination reveals that CNS myelin is largely absent and, when present, appears as abnormal whorls of cy- toplasm-filled membranes, tightly compacted at the intraperiod line, but uncompacted at the major dense line. The so-called myelin-deficient mouse has a du- plication of the myelin basic protein gene and a low level of myelin basic protein mRNA. The phenotype of the myelin-deficient mouse is similar to that of the shiverer mouse, but less severe.

Myelin basic protein is also a component of PNS myelin. A curious feature is that absence or mutation of the gene has little effect on PNS myelin. PNS is on-

18q ^– Syndrome

Chapter 35

035_Valk_18q_Syndrome 08.04.2005 15:52 Uhr Seite 281

(2)

ly subtly altered and is functionally normal. It is sug- gested that some component specific to peripheral myelin is functionally equivalent to myelin basic pro- tein and capable of substituting for this protein in its absence.

35.4 Therapy

Supportive care is the only therapeutic option.

Chapter 35 18q^–Syndrome 282

Fig. 35.1. A 2.5-year-old girl with 18q- syndrome. Note the delay in myelination, leading to poor contrast between gray and white matter. There are additional spots of abnormal sig-

nal intensity in the periventricular region.The corpus callosum is relatively well myelinated. The gyri have a relatively thin, atrophic appearance

035_Valk_18q_Syndrome 08.04.2005 15:53 Uhr Seite 282

(3)

35.5 Magnetic Resonance Imaging

MR images show a variable myelin deficit. Initially, myelination is delayed (Fig. 35.1) but further ad- vanced at every follow-up MRI. In older patients a sta- ble picture of incomplete myelination is seen. The severity of the myelin deficit is variable. In some pa- tients, a near-total absence of myelin in cerebral and cerebellar white matter, internal capsule, and corti- cospinal tracts is seen with relatively normal myelina- tion of the corpus callosum. The cortical gyri are rel- atively thin and the sulci relatively deep due to reduc- tion in white matter volume. Other patients have bet- ter myelination. The partial hypomyelination often leads to poor differentiation on MRI between white

and gray matter (Fig. 35.1). The myelin deficiency in the cerebral hemispheric white matter is often patchy with focal white matter signal abnormalities (Fig.

35.2). In some patients, hypomyelination of the corti- cospinal tracts in the brain stem and posterior limb of the internal capsule is present, but in most other pa- tients these structures contain a considerable amount of myelin. The corpus callosum seems to have a rela- tively normal myelin content. Measurements of white matter T

1

and T

2

relaxation times show significant prolongation in patients with the 18q

^–

syndrome, even in structures that seem well myelinated such as the corpus callosum, compatible with incomplete myelination. In some patients the lateral ventricles are mildly enlarged.

35.5 Magnetic Resonance Imaging 283

Fig. 35.2. The transverse T2-weighted MRI series of this 3- year-old boy shows widespread patches of hypomyelination.

Myelination is delayed for the age of the child, most evidently

in the temporal lobes, where the white matter still has a high- er signal intensity than the cortex. Courtesy of Prof. Dr. U.

Stephani, Kiel and Prof. Dr. B. Terwey, Bremen, Germany 035_Valk_18q_Syndrome 08.04.2005 15:53 Uhr Seite 283