Childhood overgrowth in patients with common NF1 microdeletions

Spiegel, Miriam; Oexle, Konrad; Horn, Denise; Windt, Elke; Buske, Annegret; Albrecht, Beate; Prott, Eva-Christina; Seemanová, E; Seidel, Joerg; Rosenbaum, Thorsten; Jenne, Dieter E.; Kehrer‐Sawatzki, Hildegard; Tinschert, Sigrid

doi:10.1038/sj.ejhg.5201419

Cited by 46 publications

(37 citation statements)

References 45 publications

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“…This observation confirms results published by Spiegel et al who proposed that overgrowth was indeed a component of the phenotypic spectrum of the NF1 microdeletion syndrome (Spiegel et al, 2005). RNF135 haploinsufficiency was proposed to be responsible for the overgrowth often observed in individuals with NF1 microdeletions (Douglas et al, 2007).…”

Section: Discussionsupporting

confidence: 81%

“…A more severe clinical phenotype has been reported in NF1 patients carrying genomic microdeletions that involve the entire NF1 gene, compare to patients with intragenic NF1 mutations. This contiguous gene syndrome does appear to include dysmorphic features (Upadhyaya et al, 1998;López Correa et al, 1999, 2000Streubel et al, 1999;Riva et al, 2000;Castle et al, 2003;Venturin et al, 2004b), learning disabilities (Tonsgard et al, 1997;Upadhyaya et al, 1998;Korf et al, 1999;López Correa et al, 1999, 2000Streubel et al, 1999;Riva et al, 2000;Castle et al, 2003;Descheemaeker et al, 2004;Venturin et al, 2004b), cardiovascular malformations (Riva et al, 2000;Venturin et al, 2004bVenturin et al, , 2005Mensink et al, 2006), childhood overgrowth (Spiegel et al, 2005), a higher tumour burden and earlier onset of benign neurofibromas (Leppig et al, 1997;López Correa et al, 2000;Castle et al, 2003), and probably, a higher incidence of MPNSTs (De Raedt et al, 2003) and other malignancies (López Correa et al, 2000). While many reports of NF1 microdeleted patients (currently > 150 cases) (Mensink et al, 2006) have been published since the initial study in 1992 (Kayes et al, 1992), to date, little is known about this genotype-phenotype correlation.…”

Section: Introductionmentioning

confidence: 99%

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NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

et al. 2010

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ABSTRACT:In 5-10% of patients, neurofibromatosis type 1 (NF1) results from microdeletions that encompass the entire NF1 gene and a variable number of flanking genes. Two recurrent microdeletion types are found in most cases, with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion). A more severe phenotype is usually associated with NF1 microdeletion patients than in those with intragenic mutations. We characterized NF1 microdeletions in 70 unrelated NF1 microdeleted patients using a high-resolution NF1 custom array comparative genomic hybridization (CGH). Genotypephenotype correlations were studied in 58 of these microdeletion patients and compared to 389 patients with intragenic truncating NF1 mutations and phenotyped in the same standardized way. Our results confirmed in an unbiased manner the existence of a contiguous gene syndrome with a OFFICIAL JOURNAL www.hgvs.orgGenotype-phenotype Correlation in NF1 Microdeletion Patients E1507 significantly higher incidence of learning disabilities and facial dysmorphism in microdeleted patients compared to patients with intragenic NF1 mutations. Microdeleted NF1 patients also showed a trend toward significance for childhood overgrowth. High-resolution array-CGH identified a new recurrent ~1.0 Mb microdeletion type, designated as type-3, with breakpoints in the paralogous regions middle NF1-REP-b and distal NF1-REP-c.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

et al. 2010

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“…The first is a whole NF1 gene deletion associated with large numbers and early appearance of cutaneous neurofibromas, more frequent and more severe than average cognitive abnormalities, and sometimes somatic overgrowth, large hands and feet, and dysmorphic facial features. [107][108][109][110][111] The second is a 3-bp in-frame deletion of Exon 17 (c.2970 -2972 delAAT) associated with typical pigmentary features of NF1, but no cutaneous or surface plexiform neurofibromas. 112 The consistent familial transmission of NF1 variants such as Watson syndrome (multiple café-au-lait spots, pulmonic stenosis, and dull intelligence) 113,114 and familial spinal neurofibromatosis 115-117 also indicates that allelic heterogeneity plays a role in the clinical variability of NF1.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Clinical and genetic aspects of neurofibromatosis 1

Jett

Friedman

2010

Genetics in Medicine

422

382

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“…Attending school was postponed and she was enrolled at a special school for children with developmental delay. Her height data were included in the NF1 growth study of Spiegel et al (2005).…”

Section: Clinical Reportmentioning

confidence: 99%

“…Approximately 50% of the mutations are de novo (Huson and Hughes, 1994). 50-60% of with prominent nose and large ears, impaired learning or mild to moderate mental retardation, and increased risk for peripheral nerve sheath tumors (Wu et al, 1995;KehrerSawatzki et al, 2004;Spiegel et al, 2005).…”

mentioning

confidence: 99%

Two independent chromosomal rearrangements, a very small (550 kb) duplication of the 7q subtelomeric region and an atypical 17q11.2 <i>(NF1)</i> microdeletion, in a girl with neurofibromatosis

Bartsch

Vlckova²,

Erdogan

et al. 2007

Cytogenet Genome Res

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Most patients with neurofibromatosis (NF1) are endowed with heterozygous mutations in the NF1 gene. Approximately 5% show an interstitial deletion of chromosome 17q11.2 (including NF1) and in most cases also a more severe phenotype. Here we report on a 7-year-old girl with classical NF1 signs, and in addition mild overgrowth (97th percentile), relatively low OFC (10th–25th percentile), facial dysmorphy, hoarse voice, and developmental delay. FISH analysis revealed a 17q11.2 microdeletion as well as an unbalanced 7p;13q translocation leading to trisomy of the 7q36.3 subtelomeric region. The patient’s mother and grandmother who were phenotypically normal carried the same unbalanced translocation. The 17q11.2 microdeletion had arisen de novo. Array comparative genomic hybridization (CGH) demonstrated gain of a 550-kb segment from 7qter and loss of 2.5 Mb from 17q11.2 (an atypical NF1 microdeletion). We conclude that the patient’s phenotype is caused by the atypical NF1 deletion, whereas 7q36.3 trisomy represents a subtelomeric copy number variation without phenotypic consequences. To our knowledge this is the first report that a duplication of the subtelomeric region of chromosome 7q containing functional genes (FAM62B, WDR60, and VIPR2) can be tolerated without phenotypic consequences. The 17q11.2 microdeletion (containing nine more genes than the common NF1 microdeletions) and the 7qter duplication were not accompanied by unexpected clinical features. Most likely the 7qter trisomy and the 17q11.2 microdeletion coincide by chance in our patient.

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Childhood overgrowth in patients with common NF1 microdeletions

Cited by 46 publications

References 45 publications

NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

Clinical and genetic aspects of neurofibromatosis 1

Two independent chromosomal rearrangements, a very small (550 kb) duplication of the 7q subtelomeric region and an atypical 17q11.2 <i>(NF1)</i> microdeletion, in a girl with neurofibromatosis

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