Article Text

Findings that shed new light on the possible pathogenesis of a disease or an adverse effect
Duplication of the Williams–Beuren critical region: case report and further delineation of the phenotypic spectrum
  1. C Orellana1,
  2. Jordi Bernabeu1,2,
  3. Sandra Monfort1,
  4. Monica Rosello1,
  5. Juan Silvestre Oltra1,
  6. Irene Ferrer1,
  7. Ramiro Quiroga1,
  8. Isabel Martinez-garay3,
  9. Francisco Martinez1
  1. 1
    Hospital Universitario La Fe, Unidad de Genetica, Avenida de Campanar 21, Valencia, 46009, Spain
  2. 2
    Universitat de Valencia, MIDE, Avda Blasco Ibañez, Valencia, 46010, Spain
  3. 3
    Universitat de Valencia, Genetica, Dr Moliner, Burjasot, 46120, Spain
  1. orellana_car{at}gva.es

Summary

Only 12 patients with a duplication of the Williams-Beuren critical region (WBCR) have been reported to date, with variable developmental, psychomotor and language delay, in the absence of marked dysmorphic features. In this paper we present a new WBCR microduplication case, which supports the wide variability displayed by this duplication in the phenotype. The WBCR microduplication may be associated with autistic spectrum disorder, but most reported cases do not show this behavioral disorder, or may even show a hypersociable personality, as with our patient. From the present case and a review of the 12 previously described,16 we conclude that the phenotype associated with duplication of WBCR can affect the same domains as WBCR deletion, but that they cluster near the polar ends of social relationship (autism-like v hypersociability), language (expressive language impairment v “cocktail party” speech), visuospatial (severe v normal), mental retardation (severe v mild) and dysmorphic (severe v mild) features.

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BACKGROUND

The Williams–Beuren critical region (WBCR), located in 7q11.23, is commonly deleted in Williams–Beuren syndrome (WBS), a microdeletion syndrome. However, only 12 patients with a duplication of the WBCR have been reported to date, with variable developmental, psychomotor and language delay, in the absence of marked dysmorphic features. In addition, this duplication has been found to be inherited from healthy parents in three cases.

In a recently published paper, Depienne et al1 included for the first time autistic spectrum disorder among the features associated with WBCR microduplication syndrome. More recently, a paper describing seven new cases with this alteration also reported autistic behaviour in two of them.2

In this paper we present a new WBCR microduplication case, which supports the wide variability displayed by this duplication in the phenotype. More specifically, the WBCR microduplication may be associated with autistic spectrum disorder, but most reported cases do not show this behavioral disorder, or may even show a hypersociable personality, as with our patient. From the present case and a review of the 12 previously described,16 we conclude that the phenotype associated with duplication of WBCR can affect the same domains as WBCR deletion, but that they cluster near the polar ends of social relationship (autism-like v hypersociability), language (expressive language impairment v “cocktail party” speech), visuospatial (severe v normal), mental retardation (severe v mild) and dysmorphic (severe v mild) features. They do not present a clear profile like that resulting from WBCR deletion.

CASE PRESENTATION

This male patient was initially referred at the age of 13 years with polymalformation syndrome and mental retardation. A karyotype performed at the 400–500-band level was normal, and molecular analysis for 22q11 deletion and the fragile X syndrome was negative.

The patient is the first child of consanguineous (second-degree cousins), healthy parents. A maternal uncle had died at birth with polymalformation syndrome and a cleft lip. The patient was born at week 36 of gestation by caesarean section because of maternal hypertension. The birth weight was 2400 g (3rd–10th centile), length was 50 cm (50th centile) and cranial circumference was 37 cm (90th centile). The neonate had low-set and dysmorphic ears, bilateral cleft lip, cleft palate, choanal atresia, bilateral cryptorchidism, hydrocephaly, brachycephaly, long and thin fingers and toes, and bradycardia. Cardiac ultrasonography showed supravalvular aortic stenosis with post-stenotic dilation.

According to the parental report, the patient walked at 18 months, but was only able to say monosyllabic words at 4 years, and sphincter control was achieved at 5 years.

Clinical examination at 33 months of age showed strabismus, astigmatism and bilateral inguinal hernia. Radiography of the thorax showed a horizontal heart with a slight prominence and elongated aorta ascendens. MRI of the brain revealed metopic craniosynostosis and discrete supratentorial ventriculomegaly with external benign hydrocephaly. Multiple hyperintense focal nodules in the frontal lobes and less intense nodules in the parietal and occipital lobes were seen (fig 1).

Figure 1 MRI of the brain (axial fluid-attenuated inversion recovery T2-weighted) showing cranial malformation and foci with altered signal intensity in the periventricular, predominantly frontal, white matter.

INVESTIGATIONS

The neuropsychological profile was obtained using the following tests: Wechsler Intelligence Scale for Children (WISC)-IV, Woodcock–Johnson III, Test of Memory and Learning (TOMAL), Children’s Auditory Verbal Learning Test (CAVLT)-2, Grooved Pegboard Test, Benton Judgment of Line Orientation, Benton Facial Recognition, Benton Visual Retention Test, Rey Complex Figure, Token Test for Children, Peabody Picture Vocabulary Test (PPVT)-III, Phonetic and Semantic Fluency, Stroop Colour–Word Task, Five-point Test, Children’s Color Trails Test (CCTT) and Conners Continuous Performance Test (CPT)-II. All the results were converted into Z scores. Psychopathological screening was performed with Achenbach scales (Child Behavior Checklist 6–18, Teacher Report Form 6–18 and Youth Self-Report 11–18).The most salient results of neuropsychological and psychopathological assessment performed at 15 years of age are as follows.

Moderate mental retardation (WISC-IV: total IQ=44) was found. Other WISC-IV dimensions were: verbal comprehension 49, perceptual reasoning 49, working memory 48, speed of processing 64. We found no significant discrepancies among dimensions.

The patient presented developmentally delayed speech and a deficit in both receptive and expressive language. His language is currently poor having more receptive than expressive impairments. Grammatical comprehension is the most affected function (z=–6.14). Denomination and fluency are normal or close to normal, but the pragmatics of language are not adequate, with perseverations.

Severe impairment in visuospatial abilities was found using the Rey Complex Figure (z=–5.06) and Object Assembly (z=–3).

Assessment was performed through direct observation and Achenbach scales. We found an agreement between school and family about these clinically significant problems: attention deficit hyperactivity disorder (ADHD) of a predominantly hyperactive–impulsive type (moreover Conners CPT-II gave 94.6% for ADHD classification: seven scores of attention deficit and two of impulsivity), aggressive behaviour, and somatic, social, anxiety and oppositional–defiant problems. We also observed hypersociability and obsessive–compulsive behaviours.

Molecular karyotyping was performed with array comparative genome hybridisation (array-CGH) with a microarray containing 6000 bacterial artificial chromosome clones, which allows genomewide survey and molecular profiling of genomic aberrations with a resolution of 0.5–1 Mb7,8 (Monfort et al, 2008) this paper has been published). Array-CGH results showed increased dosage for two consecutive clones (RP11-89A20 and RP11-137E8) located in the WBCR. The flanking clones RP11-107L23 and RP11-349P21 were not duplicated, suggesting that the duplication affected the classic WBCR. As the score obtained with one of these clones was just below the established threshold, multiplex ligation-dependent probe amplification analysis for a panel of syndromes with mental retardation (P064 probe set; MRC-Holland, Amsterdam, The Netherlands), including WBS, was used as described previously.9 The results confirmed an increased dosage for all seven probes corresponding to the WBS region. Fluorescent in situ hybridisation using the specific probe for the WBS region (VYSIS, Downers Grove, Illinois, USA), consistently yielded one hybridisation signal larger than the other, as expected in a tandem duplication in one of the chromosomes. Finally, segregation analysis with two microsatellite markers located in the ELN gene did not allow ascertainment of the parental origin of the duplication. However, one of these markers showed the presence of three different alleles in the patient, indicating that the duplication arose prezygotically de novo.

A reciprocal duplication of the region deleted in WBS was found in our patient. The presence of three different alleles with the ELN microsatellite marker clearly indicates that the mechanism involved in this rearrangement is unequal interchromatid exchange, and not an intrachromosomal recombination

DISCUSSION

The patient has marked dysmorphic features, in contrast to other patients with WBCR duplications. However, we cannot exclude the possibility that some of the phenotypic features in our patient are not caused by the 7q11 duplication. Consanguinity in the parents and a background of cleft lip in the family suggest that medial-line defects might be caused by a recessive gene that is unrelated to the 7q11 duplication. However, two other patients with WBS have also been reported previously with cleft lip.2

The major findings of all patients with the WBCR duplication reported to date are summarised in table 1. The phenotype associated with this duplication is highly variable, and language impairment and mental retardation are the only constant features found in all the patients reported to date. Other common findings are psychomotor delay, short stature, high and broad nose, dysplastic ears with abnormal helix, and attention deficit or hyperactivity. Less commonly, a cranial malformation due to premature obliteration of sutures or a high arched palate are found.

Table 1 Patients with Williams-Beuren critical region duplication

Three cases in which duplication was inherited from a healthy parent have been described. This fact does not exclude the pathological condition of duplication, but incomplete penetrance or multifactorial influences might cause a variability of the phenotype. In addition, a mosaic condition in the healthy parents may conceivably have profound consequences on the clinical presentation.

Four cases with autistic behaviour have been reported, and two other cases were reported with good social skills. Our patient presents hypersociability, which further confirms that autistic traits are only occasionally associated with WBSR duplication. On the other hand, a disturbance of perceptive language might conceivably predispose to autistic behaviour. Clear language and psychopathological assessments are necessary to differentiate between language impairment and autism.

Poor visuospatial skills have been noted in our patient and in two other patients,1,5 whereas four patients were reported with relative strength in visuospatial construction.2,3

In conclusion, the WBCR is related to specific cognitive and behaviour impairments. Deletion of 7q11.23 causes a consistent behavioural and cognitive phenotype in children. Conversely, the corresponding duplication does not show a clear phenotype. Various studies have reported impairments in the same domains as with WBCR deletion (language, social relationships, visuospatial, mental retardation), but they present degrees of impairment in opposite directions. These results confirm that WBCR is involved in the development of these features, and deletion or duplication produce different degrees of impairment in the same domains. Wider neuropsychological assessments are needed in order to delineate the WBCR duplication phenotype, in language, psychopathology and other domains. Well-known batteries and tests are recommended worldwide in order to compare results.

The wide spectrum of clinical phenotypes is possibly related to genetic, environmental and/or stochastic factors under a multifactorial model. The study of the gene expression of this chromosomal region can offer useful data on gene-related cognition and behaviour.

LEARNING POINTS

  • The phenotype associated with duplication of the WBCR is variable, with a spectrum of language and mental impairment and dysmorphism.

Acknowledgments

This article has been adapted with permission from in Orellana C, Bernabeu J, Monfort S, Roselló M, Oltra S, Ferrer I, Quiroga R, Martínez-Garay I, Martínez F. Duplication of the Williams–Beuren critical region: case report and further delineation of the phenotypic spectrum. J Med Genet 2008;45:187–9.

REFERENCES

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Footnotes

  • Competing interests: None.

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