Congenital Neuroblastoma in a Patient With Partial Trisomy of 2p

Abstract

We report the fourth example of a patient with germline partial trisomy of 2p21-pter and congenital neuroblastoma. The male infant had a dysmorphic facial expression and presented with congenital heart disease, supernumerary nipples, hypospadias, shawl scrotum, hemilateral persistent hyperplastic primary vitreous, and neuroblastoma. His germline karyotype of 46,XY,der(8)t(2;8)(p21;p23.2) was inherited from a maternal-balanced translocation, which indicates that the proto-oncogene MYCN region of 2p24.3 is tripicated in germline cells. A cytogenetic study of the biopsied tumor cells did not show MYCN amplification, but the DNA index was 2.4 and histologic fluorescent in situ hybridization analysis indicated somatic mutation with near-pentaploidy of the tumor cells. This could be an alternative mechanism of MYCN activation in the process of the tumorigenesis of neuroblastoma.

Neuroblastoma in a pediatric patient with a microduplication of 2p involving the MYCN locus

“…His developmental delay, dysmorphic features, and CGH results were consistent with those seen in patients with partial trisomy 2p [Lurie et al, 1995]. A subset of partial trisomy 2p patients has been described with neuroblastoma [Nagano et al, 1980;Say et al, 1980;Patel et al, 1997;Yuksel et al, 2002;Dowa et al, 2006], and that prompted further investigation.…”

“…[Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga] cation event that encompasses MYCN but not ALK (Table I) [Nagano et al, 1980;Say et al, 1980;Patel et al, 1997;Yuksel et al, 2002;Dowa et al, 2006]. Interestingly, approximately 5% of the <100 cases of partial trisomy 2p reported in the literature developed neuroblastoma as part of their phenotypic spectrum.…”

“…Additionally, Mosse et al showed that 22.8% of neuroblastomas had somatic gain of 2p including the ALK locus; a further 3.3% of cases had focal amplification of ALK (the amplification event co-occurred with MYCN in the majority of cases). Notably, the duplication events reported in the five published cases of neuroblastoma in partial trisomy 2p patients span both the ALK and MYCN loci [Nagano et al, 1980;Say et al, 1980;Patel et al, 1997;Yuksel et al, 2002;Dowa et al, 2006]. In aggregate, these data suggest that duplications of either or both genes might be important.…”

“…Previously described examples include mutations in PHOX2B [Mosse et al, 2004;Trochet et al, 2004] and ALK [Mosse et al, 2008]. Additionally, there have been five patients described to-date who developed neuroblastoma in the setting of partial trisomy 2p [Nagano et al, 1980;Say et al, 1980;Patel et al, 1997;Yuksel et al, 2002;Dowa et al, 2006]. Other features described in association with partial trisomy 2p include psychomotor delay, prominent high forehead with frontal upsweep of hair, hypertelorism, and a variety of other defects [Lurie et al, 1995].…”

The WNT-controlled transcriptional regulator LBH is required for mammary stem cell expansion and maintenance of the basal lineage

“…Lbh is expressed in additional embryonic and adult tissues, including the gut, brain, peripheral nervous system, spleen, lung, kidney and bones (Briegel and Joyner, 2001;Conen et al, 2009;Gawantka et al, 1998;Paris and Philippe, 1990), as well as during specific stages of postnatal mammary gland development . Aberrant gain-of function of LBH is associated with partial trisomy 2p syndrome (Briegel et al, 2005), a human autosomal disorder characterized by congenital heart disease, skeletal growth defects, supernumerary nipples and childhood cancers (Dowa et al, 2006). Overexpression of a Lbh transgene during murine heart development was sufficient to phenocopy the cardiovascular defects observed in these patients (Briegel et al, 2005), whereas retroviral Lbh overexpression in chick embryos delayed bone differentiation (Conen et al, 2009), suggesting LBH is causally implicated in this syndrome.…”