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. 2004 Apr;74(4):715-20.
doi: 10.1086/383093. Epub 2004 Mar 1.

Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos syndrome

Geneviève Baujat  1 , Marlène Rio, Sylvie Rossignol, Damien Sanlaville, Stanislas Lyonnet, Martine Le Merrer, Arnold Munnich, Christine Gicquel, Valérie Cormier-Daire, Laurence Colleaux
Affiliations

Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos syndrome

Geneviève Baujat et al. Am J Hum Genet. 2004 Apr.

Abstract

Sotos syndrome is an overgrowth syndrome characterized by pre- and postnatal overgrowth, macrocephaly, advanced bone age, variable degrees of mental retardation, and typical facial features. Defects of the NSD1 gene account for >or=60% of cases of Sotos syndrome, whereas the disease-causing mechanism of other cases remains unknown. Beckwith-Wiedemann syndrome (BWS) is a distinct overgrowth condition characterized by macroglossia, abdominal-wall defects, visceromegaly, embryonic tumors, hemihyperplasia, ear anomalies, renal anomalies, and neonatal hypoglycemia. Deregulation of imprinted growth-regulatory genes within the 11p15 region is the major cause of BWS, whereas the molecular defect underlying a significant proportion of sporadic BWS cases remains unknown. Owing to clinical overlaps between the two syndromes, we investigated whether unexplained cases of Sotos syndrome could be related to 11p15 anomalies and, conversely, whether unexplained BWS cases could be related to NSD1 deletions or mutations. Two 11p15 anomalies were identified in a series of 20 patients with Sotos syndrome, and two NSD1 mutations were identified in a series of 52 patients with BWS. These results suggest that the two disorders may have more similarities than previously thought and that NSD1 could be involved in imprinting of the chromosome 11p15 region.

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Figures

Figure 1
Figure 1
Methylation analysis of H19 and KCNQ1OT genes in patients (RD and FD) and normal subjects (C). A, H19 methylation was assessed by digestion with Pst1 and SmaI. The 1.8-kb Pst1 fragment is cut with SmaI, resulting in a 1-kb fragment. The H19 methylation index was determined by scanning autoradiographs and calculating the ratio (1.8-kb fragment)/(1.8-kb fragment + 1-kb fragment) × 100. B, KCNQ1OT methylation was assessed by digestion with BamHI and NotI. The 6-kb BamHI fragment is cut with NotI, resulting in a 4.2-kb fragment. The KCNQ1OT methylation index was determined by scanning autoradiographs and calculating the ratio (4.2-kb fragment)/(4.2-kb fragment + 6-kb fragment) × 100.
Figure 2
Figure 2
Facial features of patients with BWS who have NSD1 mutations. A and B, Patient PB at age 1 year. Note that the craniostenosis may hide the classic facial gestalt of Sotos syndrome. Frontal bossing and antimongoloid slant of the palpebral fissure are not typical. C and D, Patient BA at age 4 years. Note the absence of typical facial characteristics of Sotos syndrome: normo-versed nares and absence of prominent forehead, dolichocephaly, and prominent chin.
Figure 3
Figure 3
Facial features in patients with Sotos who have 11p15 anomalies. A and B, Patient FD at age 11 years. Note the downslanting palpebral fissures and pointed chin. C and D, Patient RD at age 15 mo. Note the dolichocephaly, ocular hypertelorism, frontal bossing, sparseness of hair in frontoparietal region, and antimongoloid slant of the palpebral fissures.
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References

Electronic-Database Information

    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for Sotos syndrome, BWS, NSD1, KCNQ1OT, and H19)
    1. University of California–Santa Cruz (UCSC) Genome Bioinformatics, http://genome.cse.ucsc.edu/ (for chromosome 11 physical map [updated July 2003])

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