CLINICAL REPORT
Multiple Congenital Anomalies-Intellectual Disability (MCA-ID) and Neuroblastoma in a Patient Harboring a De Novo 14q23.1q23.3 Deletion Daphne´ Lehalle,1,2 Damien Sanlaville,3 Anne Guimier,1,2 Emmanuel Plouvier,4 Thierry Leblanc,5 Louise Galmiche,6 Isabelle Radford,1 Serge Romana,1 Laurence Colleaux,2 Loı¨c de Pontual,2 Stanislas Lyonnet,1,2 and Jeanne Amiel1,2* 1
De´partement de Ge´ne´tique Histologie-Embryologie-Cytoge´ne´tique, Hoˆpital Necker-Enfants Malades, Paris, France INSERM U781, Universite´ Sorbonne Paris Cite´, Institut IMAGINE, Paris, France 3 Hospices Civils de Lyon, Service de Ge´ne´tique and CRNL, CNRS UMR 5292, INSERM U1028, Universite´ Claude Bernard Lyon I, Lyon, France 4 Service d’Onco-He´matologie Pe´diatrique, Centre Hospitalo-Universitaire de Besanc¸on, Paris, France 5 De´partement d’He´matologie Pe´diatrique, Hoˆpitaux Robert Debre´ et Universite´ Paris Diderot, Paris, France 2
6
De´partement d’Anatomo-Pathologie, Hoˆpital Necker-Enfants Malades, Paris, France
Manuscript Received: 28 March 2013; Manuscript Accepted: 15 December 2013
Neuroblastoma is the most frequent extra cranial solid tumor in infants and children. Genetic predisposition to neuroblastoma has been suspected previously due to familial cases of sporadic NB and predisposition to NB in several syndromes. Here, we report on a de novo 14q23.1–q23.3 microdeletion in a male presenting with a neuroblastoma diagnosed at 9 months, and spherocytosis, congenital heart defect, cryptorchidism, hypoplasia of corpus callosum, epilepsy, and developmental delay. Mycassociated-factor X (MAX) haploinsufficiency could be regarded as the predisposing factor to NB. Indeed 14q deletion is a recurrent somatic rearrangement in NB and MAX somatic and germline loss of function mutation have recently been described in pheochromocytoma and paraganglioma. However, MAX was expressed in the tumor of the patient we report on and, accordingly, loss of heterozygosity, mutation, or promoter methylation were excluded. In addition, we discuss the potential involvement in the clinical spectrum presented by the patient of five of the deleted genes, namely DAAM1, PLEKHG3, SPTB, AKAP5, and ARID4A. Ó 2014 Wiley Periodicals, Inc.
Key words: neuroblastoma; 14q23 microdeletion; development; MAX; ARID4A
INTRODUCTION Neuroblastoma (NB OMIM 256700) is an embryonal tumor of the peripheral sympathetic nervous system (sympathetic ganglia and adrenals), which derives from neural crest cells. It is the most frequent solid tumor in children after brain tumors, accounting for about 8–10% of pediatric cancers. The prognosis is highly variable ranging from spontaneous resolution to invasive tumors with a
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Lehalle D, Sanlaville D, Guimier A, Plouvier E, Leblanc T, Galmiche L, Radford I, Romana S, Colleaux L, de Pontual L, Lyonnet S, Amiel J. 2014. Multiple congenital anomalies-intellectual disability (MCA-ID) and neuroblastoma in a patient harboring a de novo 14q23.1q23.3 deletion. Am J Med Genet Part A 164A:1310–1317.
poor outcome despite intensive treatment. Some recurrent somatic chromosomal rearrangements have been associated with a poor prognosis including MYCN amplification and loss of the 1pter chromosomal region. Conversely, hyperdiploid or near-triploid karyotypes are predictive of a good prognosis. NB generally occurs sporadically. However, reports of familial cases with vertical transmission, and occurrence in several chromosomal and genetic syndromes have long supported the involvement of genetic factors in NB [Munzer et al., 2008]. Several NBpredisposing genes were recently identified, such as NSD1, HRAS, PHOX2B, and ALK. Here, we report on a de novo 14q23.1q23.3
Correspondence to: Jeanne Amiel, Hoˆpital Necker—De´partement de Ge´ne´tique, 149 rue de Se`vres, Paris 75015, France. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 24 March 2014 DOI 10.1002/ajmg.a.36452
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LEHALLE ET AL. deletion detected by array CGH in a boy presenting with spherocytosis, neurological findings (developmental delay, epilepsy, hypoplasia of corpus callosum), congenital heart defects (ventriculoseptal defect and bicuspic aortic valve), and cryptorchidism. He developed an abdominal NB at 9 months of age. Interestingly, 14q deletion is a recurrent somatic rearrangement in NB, suggesting the presence of at least one tumor suppressor gene in the region. The best candidate is Myc-associated-factor X (MAX), which plays a pivotal role in the Myc–Mad–Max network. Max–Myc heterodimerization is required for Myc activation, while heterodimerization with Mad represses Myc [Nair and Burley, 2003; Atchley and Fernandes, 2005]. In addition, germline mutations in MAX have been identified in pheochromocytoma, another neural crest cell-derived tumor [Comino-Mendez et al., 2011].
PATIENT AND METHODS Clinical Report The index case, a male, is the only child of non-related parents, aged 24 and 34 years at the time of his birth. The mother subsequently had a miscarriage, and a second child with another partner. The father had a healthy daughter from a previous union. The family history was unremarkable except for Wolf–Parkinson–White syndrome in the mother, who had surgery at age 17 years. The patient was born after an uneventful pregnancy at 37 weeks of gestation by vaginal delivery and had low birth weight (BW: 2.070 kg [3rd centile], BL: 51 cm [50th centile], OFC: 33.5 cm [10th centile]). Apgar scores were 7, 6, and 10 at 1, 3, and 5 min, respectively. Axial hypotonia was noticed soon after birth. On day 2 of life, he developed a free bilirubin icterus, with a bilirubin level of 350 mmol/L, for which he received continuous phototherapy and a blood transfusion. ABO incompatibility was suspected but could not be proved. A congenital cardiac defect, with perimembranous ventriculoseptal defect and bicuspid aortic valve, as well as cryptorchidism were noted in the neonatal period. At the age of 9 months, an abdominal NB was incidentally diagnosed while investigating anemia. The CT and CT scan showed a calcified retroperitoneal mass of 51 mm 42 mm 30 mm with pelvic extension. Urinary catecholamine and its metabolites were high (HVA: 21.4–28.1 mmol/24 hr [N < 6.5], VMA: 36.8– 50.8 mmol/24 hr [N < 3.4], dopamine: 787 nmol/24 hr, adrenaline plus noradrenaline: 502–654 [N < 170], normetanephrines: 4.7– 6.1 mmol/24 hr [N < 0.63]). Metaiodobenzylguanidine (MIBG) scintigraphy revealed a local fixation and myelogram showed no invasion of the bone marrow. He had two chemotherapy courses with cyclophosphamide and vincristine, followed by surgical ablation of the tumor 1 month later. Excision was complete except for a left para-aortic metastatic adenopathy. The pathologic examination confirmed the diagnosis of NB stage 2B, with chromosome 2 trisomy and no MYCN amplification. Because of these data and his young age, chemotherapy was stopped. Developmental milestones were delayed; he sat at 16 months, walked at 3 years, and had significant speech delay. He developed seizures. Hematologic evolution was marked by chronic regenerative anemia. The diagnosis of hereditary spherocytosis was proposed from ektacytometry
1311 findings. Persistent anemia with splenomegaly and the need for blood transfusions led to splenectomy at the age of 3.5 years, with a good outcome. Orchidopexy was performed at age 4 years. The patient was referred to a geneticist at 5 years of age. His weight and length were above the 90th centile and his OFC was at the 50th centile. Facial features included a small mouth and brachycephaly (Fig. 1). He had flexible joints. A brain MRI was performed twice, at one month and 34 months of age, showing hypoplasia of the anterior part of the corpus callosum with mild enlargement of the frontal horns and anterior subarachnoid spaces. Skeletal survey was normal at 8 months. A standard chromosomal analysis revealed a normal karyotype 46, XY, with FISH analysis excluding 22q11.2, 1p36, and 8p23 microdeletions. Fragile X syndrome was ruled out. Blood count and smear test of the parents were normal. The mother had normal chromosomes, while the father’s chromosomes were not analyzed. Constitutional array-CGH: A 1-Mb resolution CytochipV2 array (Agilent) was performed on DNA extracted from leukocytes. Tumoral array-CGH: A 50-kb resolution Oligo 244K (Agilent) was performed on tumoral DNA. A frozen tumoral sample fixed in Tissue-Tek1 Optimal Cutting Temperature (OCT) Compound from the index case was also obtained.
Patients Blood samples were collected from the patient and his parents, after informed consent. DNA was extracted following standard methods. RNA was extracted from the tumor using the RNeasy midi kit (Qiagen1, Courtaboeuf, France). Constitutional DNA from three previously reported isolated and familial NB cases with no PHOX2B and ALK mutation [Trochet et al., 2004; Janoueix-Lerosey et al., 2008] was added for candidate gene analysis.
Sanger Sequencing We screened the MAX coding sequence by direct sequencing of DNA extracted form the patient’s tumor (primers available upon request) using the fluorometric method (Big Dye Terminator Cycle Sequencing kit [Applied Biosystems Life Technologies]) on an ABI 3100 automated sequencer.
MAX Expression Studies We performed a RT-PCR on MAX RNAs extracted from a tumoral sample, using the GeneAmp RNA PCR Core kit (Applied Biosystems). The PCR conditions were standard. Primers are available upon request.
RESULTS The constitutional array-CGH revealed a 14q23.1 deletion (from position 56,543,034 to 65,545,579, hg 18), confirmed by FISH (probe RP11-550M19) (Fig. 2). To assess a potential loss of heterozygosity in the tumoral cells, we performed an array CGH by hybridizing the patient’s
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FIG. 1. Facial phenotype of the patient, with small mouth, anteverted ears, long palpebral fissures.
tumoral and non-tumoral DNA, which revealed several mosaic rearrangements: loss of chromosomes 3, 4, 9, 10, 13, 14 16, 19, X, and Y, in about 20% of the cells, in addition to the 9 Mb interstitial loss at 14q23.1–q23.3. We then performed a FISH for the 14q23 locus (BAC 550M19) on a thin section of the tumor, after histological examination, which confirmed that the mosaic loss of the 14q23.1q23.3 region occurred in NB cells. Sanger sequencing in our patient’s tumoral DNA did not reveal any mutation or
FIG. 2. Constitutional array CGH, showing 14q23 deletion.
deletion in trans in the MAX gene coding sequence. No mutation was found either in the constitutional DNA of the three patients presenting with a familial NB. We then studied the methylation status of the MAX promoter in the patient’s DNA extracted from leukocytes and from a tumoral sample, and showed a nonmethylated pattern at this locus in both tumor and leukocytes. RT-PCR performed on RNA extracted from the tumor indicated expression of MAX.
LEHALLE ET AL.
þ þ ASD, autistic spectrum disorder; CHD, congenital heart defect; NB, neuroblastoma; NR, nonreported, y, year, m, month. a Single atrium, pulmonary stenosis, double outlet right ventricle, dextrocardia, and complete endocardial cushion defect. b Perimembranous ventriculoseptal defect and aortic bicuspidy.
þ 12 M
þ (9 m)
þb
þ þ þ 6 M
þ þ þ 4 F
NR NR NR NR NR Fœtus ?
Complexa
ASD þ Intellectual disability þ Macrocephaly Failure to thrive Velopharyngeal insufficiency CHD Spherocytosis NB Age (y) 14 Sex M
Constitutional 14q deletion 14q23.2–23.3 (64.7–66.2 Mb) 14q23.1 (59.5–59.8 Mb) 14q23.1 (60.7–60.8 Mb); þ16q23.1 (1.3 Mb) 14q23.2–q23.3 (64.1–66.4 Mb) 14q23.1–q23.3 (57.4–66.4 Mb) Refs. Griswold et al. [2011] Bao et al. [2012] Jiang et al. [2008] Lybaek et al. [2008] This report
TABLE I. Clinical Features of the Four Patients Reported in the Literature With a 14q23 Deletion, in Comparison With This Report (Hg 19)
The deletion we report contains at least 60 genes. Spectrin beta (SPTB) encodes a component of the cytoskeletal network, that builds the erythrocyte plasma membrane, and is the major diseasecausing gene in dominantly inherited spherocytosis type 2 and elliptocytosis type 3 [Delaunay, 2002]. Deletion of SPTB is the most likely cause of the spherocytosis presented by the patient. As the father is not affected by spherocytosis, it is highly unlikely that he carries the deletion. Four patients presenting with a 14q23 deletion have been reported in the literature (reviewed in Tables I and II). Griswold et al. [2011] reported on a de novo 1.5 Mb deletion of chromosome 14q23.2–23.3 in a male presenting with developmental delay, autistic spectrum disorder, spherocytosis, and mild dysmorphic features. This deletion, overlapping with our patient’s deletion, encompasses 15 genes, including spectrin beta (SPTB), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), pleckstrin homology domain-containing family G member 3 (PLEKHG3), and churchill domain containing protein 1 (CHURC1). MTHFD1 is a folate metabolizing enzyme previously associated with bipolar disorder and schizophrenia. PLEKHG3 codes for a protein expressed in the brain which contains a guanide nucleotide exchange factor (GEF) domain regulating Rho-dependent signal transduction. Mutations and deletions of other GEF domain containing proteins have been implicated in neuropsychiatric disorders including X-linked intellectual disability. Bao et al. [2012] reported a 286 kb deletion of chromosome 14q23.1 in a fetus presenting with a complex congenital heart defect, including single atrium, pulmonary stenosis, a double outlet right ventricle, dextrocardia and complete endocardial cushion defect. The deletion encompassed two genes, KIAA0666 and DAAM1 (dishevelled associated activator of morphogenesis 1), which encodes a protein mediating Wntinduced dishevelled-Rho complex formation, a key regulator of cytoskeleton architecture. These data strongly suggest that DAAM1 could be directly involved in cardiovascular development. Jiang et al. [2008] reported a de novo 0.9 Mb deletion at 14q23.1, associated with a 0.8 Mb deletion at 14q21.1 and a 1.3 Mb deletion at 16q23.1, in a female presenting with developmental delay, poor feeding, velopharyngeal insufficiency, severe gastroesophageal reflux, recurrent aspiration pneumonitis, and dysmorphic features. The authors suggested that developmental delay could be explained by deletion of the DAAM1 gene; mutations in several Rho GTPase family members, such as ARHGEF6, have indeed been previously shown to cause X-linked nonsyndromic intellectual disability [Kutsche et al., 2000; Sato et al., 2006]. Lybaek et al. [2008] reported a de novo 2.1 Mb 14q23.2–q23.3 deletion, adjacent to a 14q21q23 paracentric inversion, in a 6-year-old boy presenting with spherocytosis, developmental delay and post-natal macrocephaly. The deletion was characterized by array CGH and mapped to 56,543,034–65,545,579 Mb (hg 18). This deletion falls within the patient’s deletion we report on. They suggested that the learning difficulties could be explained by the haploinsufficiency of PLEKHG3. Another deleted gene deserves attention considering the phenotypic spectrum of our patient. Kinase anchor protein 5 (AKAP5), predominantly expressed in the cerebral cortex, codes for
Epilepsy
DISCUSSION
NR
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TABLE II. Size of the 14q23 Deletion and Genes Encompassed in the Four Patients Previously Reported in the Literature, in Comparison With This Report
a component of fractions enriched for postsynaptic densities. AKAP150 (AKAP5 homolog)-null mice present deficits in spatial memory, and motor coordination and strength [Tunquist et al., 2008]. Predisposition to NB in several syndromes has been noted for decades. Most overgrowth syndromes are known to increase the risk of tumors, especially hematologic cancers and NB. Such is the case in Sotos syndrome, caused by loss of function mutations or deletions in the NSD1 gene encoding a histone methyltransferase involved in chromatin regulation [Berdasco et al., 2009], Beckwith Wiedmann syndrome [Gaitanou et al., 2001; Merks et al., 2005], Simpson–Golabi–Behmel syndrome, an X-linked disorder caused by mutations in GPC3 gene encoding Glypican 3 [Weidle and Orstavik, 1998], and Weaver syndrome, which is caused by either NSD1 or EZH2 mutations [Douglas et al., 2003; Coulter et al., 2008; Tatton-Brown et al., 2011]. There is also an increased risk of NB in RAS-MAPK pathway disorders, such as neurofibromatosis type 1 [Kushner et al., 1986; Brems et al., 2009], Costello, Noonan and LEOPARD syndromes [Kratz et al., 2011]. NB has been reported in syndromes caused by a dysregulation of chromatin remodeling genes, such as Kabuki [Merks et al., 2005], Coffin Siris [Pollono et al., 2009], and Rubinstein–Taybi syndromes [Ihara et al., 1999]. Abbaszadeh et al. [2010] reported nine families segregating NB and Wilms tumor. Congenital central hypoventilation syndrome (CCHS, OMIM 209880) and Hirschsprung disease (OMIM 142623) have been demonstrated to be associated with an increased risk—about 500 times higher for CCHS—for development of
tumors of the sympathetic nervous system. Paired-like homeobox 2B, PHOX2B, the major disease causing gene in CCHS [Amiel et al., 2003], was also the first gene identified in familial isolated NB [Trochet et al., 2004; McConville et al., 2006]. However, PHOX2B mutations or silencing explain a small fraction of hereditary NB [de Pontual et al., 2007]. Germline or somatic gain-of-function mutations in the anaplastic lymphoma kinase (ALK) gene account for sporadic or familial isolated NB [Mosse et al., 2008]. Chromosomal imbalances are a key feature of NB. Recurrent unbalanced regions are being precisely mapped due to array CGH and SNP array studies. The most frequent imbalances are gain of 17q, loss of 1pter, amplification of the MYCN oncogene and loss of 14q. Interestingly, some of these rearrangements also predispose to NB when found to be constitutive, such as the kinesin KIF1Bbeta gene being the most likely tumor suppressor gene at the 1p36 locus [Schlisio et al., 2008]. Diskin et al. [2009] showed that inherited copy number variation (CNV) at 1q21.1 is associated with NB, and identified a previously unknown transcript within these CNVs that showed high sequence similarity to several NB breakpoint family (NBPF) genes and represents a new member of this gene family (NBPF23). Loss of heterozygosity (LOH) for 14q is a common somatic finding, found in 20–50% of NB. The region involved falls within 14q23–q32 between D14S588 and the 14q telomere, suggesting the presence of at least two tumor-suppressor genes in this region, one at 14q32 and one at 14q12–q23 [Theobald et al., 1999; Thompson et al., 2001].
LEHALLE ET AL. MAX, located at 14q23.3, is the most conserved dimerization component of the MYC–MAX–MXD1-4 network of basic helixloop-helix leucine zipper (bHLHZip) transcription factors that regulate cell proliferation, differentiation, and apoptosis. MAX has a central role as an obligate dimerization-DNA-binding partner for Myc oncogene protein and for Mad transcriptional repressors (Mad1, Mxi1, Mad3, Mad4). MYC is a well described oncogene whose enhanced or deregulated expression is known to be responsible for a wide variety of human cancers, including NB, Burkitt lymphoma, or small cell lung cancer. On the other hand, Max–Mad heterodimers repress Myc transcription and initiate differentiation and quiescence [Kretzner et al., 1992; Atchley and Fitch, 1995; Atchley and Fernandes, 2005; Hurlin and Huang, 2006; CominoMendez et al., 2011]. Max is ubiquitously and early expressed during development and Max-null embryo are embryonic lethal around E6.5 (being earlier than Myc and Mycn knock-outs), whereas heterozygous Max þ/ mice have no recognizable phenotype [Shen-Li et al., 2000]. Interestingly, the murine pheochromocytoma-derived PC12 cell line expresses a non-functional form of Max, lacking the carboxyl terminus of the protein. Reintroduction of Max in these cells results in transcriptional repression and reduction in growth rate [Ribon et al., 1994]. Recently, two teams demonstrated that MAX is an important susceptibility gene for pheochromocytoma (PCC) and paraganglioma (PGL), both being neural crest-derived tumors. CominoMendez et al. [2011] reported that MAX germline mutations are associated with familial predisposition to PCC and demonstrated that MAX behaves as a classic tumor suppressor gene in familial PCC. Burnichon et al. [2012] sequenced MAX, in 1694 patients with sporadic or familial PCC or PGL, and in 245 tumors samples; they found germline mutations in 16 patients (1.12%), somatic mutations in four tumors (1.65%) and arguments for a parent-of-origin effect. Of note, we do not know about the parental origin of the mutated allele in our patient. More recently, other teams confirmed MAX as a predisposing gene for PCC and PGL [Pe˛czkowska et al., 2013; Rattenberry et al., 2013]. Molenaar et al. [2012] performed a whole-genome sequence analysis of 87 NB of all stages, and found no mutation of MAX, demonstrating that it is not a frequent event in NB. However, the patient we report raises the hypothesis that germline MAX loss of function predisposes to the development of NB. ARID4A, also known as RBP1 or RBBP1 (Retinoblastoma binding-protein 1), is a DNA-binding protein. ARID4A binds to the pocket region of pRb, the product of the retinoblastoma tumor suppressor gene, and to the SAP30 subunit of the mSin3-HDAC transcriptional repressor complex and, thus, acts as a bridging protein in this multisubunit complex that represses E2F-mediated transcription [Suryadinata et al., 2011]. ARID4A expression has been studied in tumors, and found to be decreased in 49% of 47 samples of carcinomas [Rodrigues-Lisoni et al., 2010]. Moreover, Wu et al. [2008] showed that Arid4a-null mice presented hematologic malignancies, and suggested that ARID4A acts as a tumor suppressor gene. Interestingly, the Mad–Max heterodimer has been hypothesized to recruit the mSin3–HDAC corepressor complex [Laherty et al., 1997]; suggesting a potential link between MAX and ARID4A functions. Finally, two other chromatin-remodeling genes from the same family, ARID1A and ARID1B were recently identified
1315 in 11% of 71 NB samples, highlighting the importance of dysregulation of chromatin remodeling in NB tumorigenesis [Sausen et al., 2013].
CONCLUSION We report on a likely de novo 14q23.1–23.3 microdeletion in a boy presenting with a syndromic NB. This observation strengthens the hypothesis of a tumor suppressor gene at this locus. MAX appeared as an appealing candidate owing to its biological function in the Myc–Mad network and its recent implication as a tumor suppressor gene in PCC and PGL. However, we could not demonstrate a second event at the MAX locus in the tumor presented by the patient. ARID4A is another candidate gene and haploinsufficiency of both genes may have been the cause of NB in the case we report on. Further investigations, such as sequencing of the deleted region, should be done if other patients with a NB and a 14q23 deletion were to be reported. To the best of our knowledge, our patient is the only one presenting with a deletion of both MAX and ARID4A.
ACKNOWLEDGMENT We thank the patient and his family for their participation in this study.
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg PS. 2011. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet Part C 157C:83–89. Kretzner L, Blackwood EM, Eisenman RN. 1992. Transcriptional activities of the Myc and Max proteins in mammalian cells. Curr Top Microbiol Immunol 182:435–443. Kushner BH, Gilbert F, Helson L. 1986. Familial neuroblastoma. Case reports, literature review, and etiologic considerations. Cancer 57:1887– 1893. Kutsche K, Yntema H, Brandt A, Jantke I, Nothwang HG, Orth U, Boavida MG, David D, Chelly J, Fryns JP, Moraine C, Ropers HH, Hamel BC, van Bokhoven H, Gal A. 2000. Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nat Genet 26:247–250. Laherty C, Yang W-M, Sun J-M, Davie JR, Seto E, Eisenman RN. 1997. Histone deacetylases associated with the mSin3 corepressor mediate Mad transcriptional repression. Cell 89:349–356. Lybaek H, Oyen N, Fauske L, Houge G. 2008. A 2.1 Mb deletion adjacent but distal to a 14q21q23 paracentric inversion in a family with spherocytosis and severe learning difficulties. Clin Genet 74:553– 559. McConville C, Reid S, Baskcomb L, Douglas J, Rahman N. 2006. PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations and genotype–phenotype associations. Am J Med Genet Part A 140A:1297–1301. Merks JH, Caron HN, Hennekam RC. 2005. High incidence of malformation syndromes in a series of 1,073 children with cancer. Am J Med Genet Part A 134A:132–143. Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, Hamdi M, van Nes J, Westerman BA, van Arkel J, Ebus ME, Haneveld F, Lakeman A, Schild L, Molenaar P, Stroeken P, van Noesel MM, Ora I, Santo EE, Caron HN, Westerhout EM, Versteeg R. 2012. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483:589–593. Mosse YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM. 2008. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455:930– 935. Munzer C, Menegaux F, Lacour B, Valteau-Couanet D, Michon J, Coze C, Bergeron C, Auvrignon A, Bernard F, Thomas C, Vannier JP, Kanold J, Rubie H, Hemon D, Clavel J. 2008. Birth-related characteristics, congenital malformation, maternal reproductive history and neuroblastoma: The ESCALE study (SFCE). Int J Cancer 122:2315–2321. Nair SK, Burley SK. 2003. X-ray structures of Myc–Max and Mad–Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell 112:193–205. Pe˛czkowska M, Kowalska A, Sygut J, Waligo´rski D, Malinoc A, JanaszekSitkowska H, Prejbisz A, Januszewicz A, Neumann HP. 2013. Testing new susceptibility genes in the cohort of apparently sporadic phaeochromocytoma/paraganglioma patients with clinical characteristics of hereditary syndromes. Clin Endocrinol (Oxf) 0:1–7. Pollono D, Drut R, Cecotti N, Pollono A. 2009. Neuroblastoma in a patient with Coffin–Siris syndrome. Fetal Pediatr Pathol 28:185–191. Rattenberry E, Vialard L, Yeung A, Bair H, McKay K, Jafri M, Canham N, Cole T, Denes J, Hodgson S, Irving R, Izatt L, Korbonits M, Kumar A, Lalloo F, Morrison P, Woodward E, Macdonald F, Wallis Y, Maher E. 2013. A comprehensive next generation sequencing–based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 98:E1248–E1256.
LEHALLE ET AL. Ribon V, Leff T, Saltiel AR. 1994. c-Myc does not require max for transcriptional activity in PC-12 cells. Mol Cell Neurosci 5:277–282. Rodrigues-Lisoni F, Peitl P, Vidotto A, Polachini G, Maniglia J, CarmonaRaphe J, Cunha B, Henrique T, Souza C, Teixeira R, Fukuyama E, Michaluart P, de Carvalho M, Oliani S, Head Neck Genome Project GENCAPO9, Tajara E, 2010. Genomics and proteomics approaches to the study of cancer-stroma interactions. BMC Med Genomics 3:14. Sato A, Khadka DK, Liu W, Bharti R, Runnels LW, Dawid IB, Habas R. 2006. Profilin is an effector for Daam1 in non-canonical Wnt signaling and is required for vertebrate gastrulation. Development 133:4219–4231. Sausen M, Leary RJ, Jones S, Wu J, Reynolds CP, Liu X, Blackford A, Parmigiani G, Diaz JL Jr, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE, Hogarty MD. 2013. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat Genet 45:12–17. Schlisio S, Kenchappa RS, Vredeveld LC, George RE, Stewart R, Greulich H, Shahriari K, Nguyen NV, Pigny P, Dahia PL, Pomeroy SL, Maris JM, Look AT, Meyerson M, Peeper DS, Carter BD, Kaelin WG Jr. 2008. The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev 22:884–893. Shen-Li H, O’Hagan RC, Hou H Jr, Horner JW II, Lee HW, DePinho RA. 2000. Essential role for Max in early embryonic growth and development. Genes Dev 14:17–22. Suryadinata R, Sadowski M, Steel R, Sarcevic B. 2011. Cyclin-dependent kinase-mediated phosphorylation of RBP1 and pRb promotes their dissociation to mediate release of the SAP30_mSin3_HDAC transcriptional repressor complex. J Biol Chem 286:5108–5118. Tatton-Brown K, Hanks S, Ruark E, Zachariou A, Duarte Sdel V, Ramsay E, Snape K, Murray A, Perdeaux ER, Seal S, Loveday C, Banka S, Clericuzio
1317 C, Flinter F, Magee A, McConnell V, Patton M, Raith W, Rankin J, Splitt M, Strenger V, Taylor C, Wheeler P, Temple KI, Cole T, Childhood Overgrowth Collaboration, Douglas J, Rahman N. 2011. Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height. Oncotarget 2:1127–1133. Theobald M, Christiansen H, Schmidt A, Melekian B, Wolkewitz N, Christiansen NM, Brinkschmidt C, Berthold F, Lampert F. 1999. Sublocalization of putative tumor suppressor gene loci on chromosome arm 14q in neuroblastoma. Genes Chromosomes Cancer 26: 40–46. Thompson PM, Seifried BA, Kyemba SK, Jensen SJ, Guo C, Maris JM, Brodeur GM, Stram DO, Seeger RC, Gerbing R, Matthay KK, Matise TC, White PS. 2001. Loss of heterozygosity for chromosome 14q in neuroblastoma. Med Pediatr Oncol 36:28–31. Trochet D, Bourdeaut F, Janoueix-Lerosey I, Deville A, de Pontual L, Schleiermacher G, Coze C, Philip N, Frebourg T, Munnich A, Lyonnet S, Delattre O, Amiel J. 2004. Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Am J Hum Genet 74:761– 764. Tunquist BJ, Hoshi N, Guire ES, Zhang F, Mullendorff K, Langeberg LK, Raber J, Scott JD. 2008. Loss of AKAP150 perturbs distinct neuronal processes in mice. Proc Natl Acad Sci USA 105:12557– 12562. Weidle B, Orstavik KH. 1998. Simpson–Golabi–Behmel syndrome. A new overgrowth syndrome with increased risk of tumor development. Tidsskr Nor Laegeforen 118:1556–1558. Wu M-Y, Eldin KW, Beaudet AL. 2008. Identification of chromatin remodeling genes Arid4a and Arid4b as leukemia suppressor genes. J Natl Cancer Inst 100:1247–1259.
Multiple Congenital Anomalies-Intellectual Disability (MCA-ID) and Neuroblastoma in a Patient Harboring a De Novo 14q23.1q23.3 Deletion Daphne´ Lehalle,1,2 Damien Sanlaville,3 Anne Guimier,1,2 Emmanuel Plouvier,4 Thierry Leblanc,5 Louise Galmiche,6 Isabelle Radford,1 Serge Romana,1 Laurence Colleaux,2 Loı¨c de Pontual,2 Stanislas Lyonnet,1,2 and Jeanne Amiel1,2* 1
De´partement de Ge´ne´tique Histologie-Embryologie-Cytoge´ne´tique, Hoˆpital Necker-Enfants Malades, Paris, France INSERM U781, Universite´ Sorbonne Paris Cite´, Institut IMAGINE, Paris, France 3 Hospices Civils de Lyon, Service de Ge´ne´tique and CRNL, CNRS UMR 5292, INSERM U1028, Universite´ Claude Bernard Lyon I, Lyon, France 4 Service d’Onco-He´matologie Pe´diatrique, Centre Hospitalo-Universitaire de Besanc¸on, Paris, France 5 De´partement d’He´matologie Pe´diatrique, Hoˆpitaux Robert Debre´ et Universite´ Paris Diderot, Paris, France 2
6
De´partement d’Anatomo-Pathologie, Hoˆpital Necker-Enfants Malades, Paris, France
Manuscript Received: 28 March 2013; Manuscript Accepted: 15 December 2013
Neuroblastoma is the most frequent extra cranial solid tumor in infants and children. Genetic predisposition to neuroblastoma has been suspected previously due to familial cases of sporadic NB and predisposition to NB in several syndromes. Here, we report on a de novo 14q23.1–q23.3 microdeletion in a male presenting with a neuroblastoma diagnosed at 9 months, and spherocytosis, congenital heart defect, cryptorchidism, hypoplasia of corpus callosum, epilepsy, and developmental delay. Mycassociated-factor X (MAX) haploinsufficiency could be regarded as the predisposing factor to NB. Indeed 14q deletion is a recurrent somatic rearrangement in NB and MAX somatic and germline loss of function mutation have recently been described in pheochromocytoma and paraganglioma. However, MAX was expressed in the tumor of the patient we report on and, accordingly, loss of heterozygosity, mutation, or promoter methylation were excluded. In addition, we discuss the potential involvement in the clinical spectrum presented by the patient of five of the deleted genes, namely DAAM1, PLEKHG3, SPTB, AKAP5, and ARID4A. Ó 2014 Wiley Periodicals, Inc.
Key words: neuroblastoma; 14q23 microdeletion; development; MAX; ARID4A
INTRODUCTION Neuroblastoma (NB OMIM 256700) is an embryonal tumor of the peripheral sympathetic nervous system (sympathetic ganglia and adrenals), which derives from neural crest cells. It is the most frequent solid tumor in children after brain tumors, accounting for about 8–10% of pediatric cancers. The prognosis is highly variable ranging from spontaneous resolution to invasive tumors with a
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Lehalle D, Sanlaville D, Guimier A, Plouvier E, Leblanc T, Galmiche L, Radford I, Romana S, Colleaux L, de Pontual L, Lyonnet S, Amiel J. 2014. Multiple congenital anomalies-intellectual disability (MCA-ID) and neuroblastoma in a patient harboring a de novo 14q23.1q23.3 deletion. Am J Med Genet Part A 164A:1310–1317.
poor outcome despite intensive treatment. Some recurrent somatic chromosomal rearrangements have been associated with a poor prognosis including MYCN amplification and loss of the 1pter chromosomal region. Conversely, hyperdiploid or near-triploid karyotypes are predictive of a good prognosis. NB generally occurs sporadically. However, reports of familial cases with vertical transmission, and occurrence in several chromosomal and genetic syndromes have long supported the involvement of genetic factors in NB [Munzer et al., 2008]. Several NBpredisposing genes were recently identified, such as NSD1, HRAS, PHOX2B, and ALK. Here, we report on a de novo 14q23.1q23.3
Correspondence to: Jeanne Amiel, Hoˆpital Necker—De´partement de Ge´ne´tique, 149 rue de Se`vres, Paris 75015, France. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 24 March 2014 DOI 10.1002/ajmg.a.36452
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LEHALLE ET AL. deletion detected by array CGH in a boy presenting with spherocytosis, neurological findings (developmental delay, epilepsy, hypoplasia of corpus callosum), congenital heart defects (ventriculoseptal defect and bicuspic aortic valve), and cryptorchidism. He developed an abdominal NB at 9 months of age. Interestingly, 14q deletion is a recurrent somatic rearrangement in NB, suggesting the presence of at least one tumor suppressor gene in the region. The best candidate is Myc-associated-factor X (MAX), which plays a pivotal role in the Myc–Mad–Max network. Max–Myc heterodimerization is required for Myc activation, while heterodimerization with Mad represses Myc [Nair and Burley, 2003; Atchley and Fernandes, 2005]. In addition, germline mutations in MAX have been identified in pheochromocytoma, another neural crest cell-derived tumor [Comino-Mendez et al., 2011].
PATIENT AND METHODS Clinical Report The index case, a male, is the only child of non-related parents, aged 24 and 34 years at the time of his birth. The mother subsequently had a miscarriage, and a second child with another partner. The father had a healthy daughter from a previous union. The family history was unremarkable except for Wolf–Parkinson–White syndrome in the mother, who had surgery at age 17 years. The patient was born after an uneventful pregnancy at 37 weeks of gestation by vaginal delivery and had low birth weight (BW: 2.070 kg [3rd centile], BL: 51 cm [50th centile], OFC: 33.5 cm [10th centile]). Apgar scores were 7, 6, and 10 at 1, 3, and 5 min, respectively. Axial hypotonia was noticed soon after birth. On day 2 of life, he developed a free bilirubin icterus, with a bilirubin level of 350 mmol/L, for which he received continuous phototherapy and a blood transfusion. ABO incompatibility was suspected but could not be proved. A congenital cardiac defect, with perimembranous ventriculoseptal defect and bicuspid aortic valve, as well as cryptorchidism were noted in the neonatal period. At the age of 9 months, an abdominal NB was incidentally diagnosed while investigating anemia. The CT and CT scan showed a calcified retroperitoneal mass of 51 mm 42 mm 30 mm with pelvic extension. Urinary catecholamine and its metabolites were high (HVA: 21.4–28.1 mmol/24 hr [N < 6.5], VMA: 36.8– 50.8 mmol/24 hr [N < 3.4], dopamine: 787 nmol/24 hr, adrenaline plus noradrenaline: 502–654 [N < 170], normetanephrines: 4.7– 6.1 mmol/24 hr [N < 0.63]). Metaiodobenzylguanidine (MIBG) scintigraphy revealed a local fixation and myelogram showed no invasion of the bone marrow. He had two chemotherapy courses with cyclophosphamide and vincristine, followed by surgical ablation of the tumor 1 month later. Excision was complete except for a left para-aortic metastatic adenopathy. The pathologic examination confirmed the diagnosis of NB stage 2B, with chromosome 2 trisomy and no MYCN amplification. Because of these data and his young age, chemotherapy was stopped. Developmental milestones were delayed; he sat at 16 months, walked at 3 years, and had significant speech delay. He developed seizures. Hematologic evolution was marked by chronic regenerative anemia. The diagnosis of hereditary spherocytosis was proposed from ektacytometry
1311 findings. Persistent anemia with splenomegaly and the need for blood transfusions led to splenectomy at the age of 3.5 years, with a good outcome. Orchidopexy was performed at age 4 years. The patient was referred to a geneticist at 5 years of age. His weight and length were above the 90th centile and his OFC was at the 50th centile. Facial features included a small mouth and brachycephaly (Fig. 1). He had flexible joints. A brain MRI was performed twice, at one month and 34 months of age, showing hypoplasia of the anterior part of the corpus callosum with mild enlargement of the frontal horns and anterior subarachnoid spaces. Skeletal survey was normal at 8 months. A standard chromosomal analysis revealed a normal karyotype 46, XY, with FISH analysis excluding 22q11.2, 1p36, and 8p23 microdeletions. Fragile X syndrome was ruled out. Blood count and smear test of the parents were normal. The mother had normal chromosomes, while the father’s chromosomes were not analyzed. Constitutional array-CGH: A 1-Mb resolution CytochipV2 array (Agilent) was performed on DNA extracted from leukocytes. Tumoral array-CGH: A 50-kb resolution Oligo 244K (Agilent) was performed on tumoral DNA. A frozen tumoral sample fixed in Tissue-Tek1 Optimal Cutting Temperature (OCT) Compound from the index case was also obtained.
Patients Blood samples were collected from the patient and his parents, after informed consent. DNA was extracted following standard methods. RNA was extracted from the tumor using the RNeasy midi kit (Qiagen1, Courtaboeuf, France). Constitutional DNA from three previously reported isolated and familial NB cases with no PHOX2B and ALK mutation [Trochet et al., 2004; Janoueix-Lerosey et al., 2008] was added for candidate gene analysis.
Sanger Sequencing We screened the MAX coding sequence by direct sequencing of DNA extracted form the patient’s tumor (primers available upon request) using the fluorometric method (Big Dye Terminator Cycle Sequencing kit [Applied Biosystems Life Technologies]) on an ABI 3100 automated sequencer.
MAX Expression Studies We performed a RT-PCR on MAX RNAs extracted from a tumoral sample, using the GeneAmp RNA PCR Core kit (Applied Biosystems). The PCR conditions were standard. Primers are available upon request.
RESULTS The constitutional array-CGH revealed a 14q23.1 deletion (from position 56,543,034 to 65,545,579, hg 18), confirmed by FISH (probe RP11-550M19) (Fig. 2). To assess a potential loss of heterozygosity in the tumoral cells, we performed an array CGH by hybridizing the patient’s
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FIG. 1. Facial phenotype of the patient, with small mouth, anteverted ears, long palpebral fissures.
tumoral and non-tumoral DNA, which revealed several mosaic rearrangements: loss of chromosomes 3, 4, 9, 10, 13, 14 16, 19, X, and Y, in about 20% of the cells, in addition to the 9 Mb interstitial loss at 14q23.1–q23.3. We then performed a FISH for the 14q23 locus (BAC 550M19) on a thin section of the tumor, after histological examination, which confirmed that the mosaic loss of the 14q23.1q23.3 region occurred in NB cells. Sanger sequencing in our patient’s tumoral DNA did not reveal any mutation or
FIG. 2. Constitutional array CGH, showing 14q23 deletion.
deletion in trans in the MAX gene coding sequence. No mutation was found either in the constitutional DNA of the three patients presenting with a familial NB. We then studied the methylation status of the MAX promoter in the patient’s DNA extracted from leukocytes and from a tumoral sample, and showed a nonmethylated pattern at this locus in both tumor and leukocytes. RT-PCR performed on RNA extracted from the tumor indicated expression of MAX.
LEHALLE ET AL.
þ þ ASD, autistic spectrum disorder; CHD, congenital heart defect; NB, neuroblastoma; NR, nonreported, y, year, m, month. a Single atrium, pulmonary stenosis, double outlet right ventricle, dextrocardia, and complete endocardial cushion defect. b Perimembranous ventriculoseptal defect and aortic bicuspidy.
þ 12 M
þ (9 m)
þb
þ þ þ 6 M
þ þ þ 4 F
NR NR NR NR NR Fœtus ?
Complexa
ASD þ Intellectual disability þ Macrocephaly Failure to thrive Velopharyngeal insufficiency CHD Spherocytosis NB Age (y) 14 Sex M
Constitutional 14q deletion 14q23.2–23.3 (64.7–66.2 Mb) 14q23.1 (59.5–59.8 Mb) 14q23.1 (60.7–60.8 Mb); þ16q23.1 (1.3 Mb) 14q23.2–q23.3 (64.1–66.4 Mb) 14q23.1–q23.3 (57.4–66.4 Mb) Refs. Griswold et al. [2011] Bao et al. [2012] Jiang et al. [2008] Lybaek et al. [2008] This report
TABLE I. Clinical Features of the Four Patients Reported in the Literature With a 14q23 Deletion, in Comparison With This Report (Hg 19)
The deletion we report contains at least 60 genes. Spectrin beta (SPTB) encodes a component of the cytoskeletal network, that builds the erythrocyte plasma membrane, and is the major diseasecausing gene in dominantly inherited spherocytosis type 2 and elliptocytosis type 3 [Delaunay, 2002]. Deletion of SPTB is the most likely cause of the spherocytosis presented by the patient. As the father is not affected by spherocytosis, it is highly unlikely that he carries the deletion. Four patients presenting with a 14q23 deletion have been reported in the literature (reviewed in Tables I and II). Griswold et al. [2011] reported on a de novo 1.5 Mb deletion of chromosome 14q23.2–23.3 in a male presenting with developmental delay, autistic spectrum disorder, spherocytosis, and mild dysmorphic features. This deletion, overlapping with our patient’s deletion, encompasses 15 genes, including spectrin beta (SPTB), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), pleckstrin homology domain-containing family G member 3 (PLEKHG3), and churchill domain containing protein 1 (CHURC1). MTHFD1 is a folate metabolizing enzyme previously associated with bipolar disorder and schizophrenia. PLEKHG3 codes for a protein expressed in the brain which contains a guanide nucleotide exchange factor (GEF) domain regulating Rho-dependent signal transduction. Mutations and deletions of other GEF domain containing proteins have been implicated in neuropsychiatric disorders including X-linked intellectual disability. Bao et al. [2012] reported a 286 kb deletion of chromosome 14q23.1 in a fetus presenting with a complex congenital heart defect, including single atrium, pulmonary stenosis, a double outlet right ventricle, dextrocardia and complete endocardial cushion defect. The deletion encompassed two genes, KIAA0666 and DAAM1 (dishevelled associated activator of morphogenesis 1), which encodes a protein mediating Wntinduced dishevelled-Rho complex formation, a key regulator of cytoskeleton architecture. These data strongly suggest that DAAM1 could be directly involved in cardiovascular development. Jiang et al. [2008] reported a de novo 0.9 Mb deletion at 14q23.1, associated with a 0.8 Mb deletion at 14q21.1 and a 1.3 Mb deletion at 16q23.1, in a female presenting with developmental delay, poor feeding, velopharyngeal insufficiency, severe gastroesophageal reflux, recurrent aspiration pneumonitis, and dysmorphic features. The authors suggested that developmental delay could be explained by deletion of the DAAM1 gene; mutations in several Rho GTPase family members, such as ARHGEF6, have indeed been previously shown to cause X-linked nonsyndromic intellectual disability [Kutsche et al., 2000; Sato et al., 2006]. Lybaek et al. [2008] reported a de novo 2.1 Mb 14q23.2–q23.3 deletion, adjacent to a 14q21q23 paracentric inversion, in a 6-year-old boy presenting with spherocytosis, developmental delay and post-natal macrocephaly. The deletion was characterized by array CGH and mapped to 56,543,034–65,545,579 Mb (hg 18). This deletion falls within the patient’s deletion we report on. They suggested that the learning difficulties could be explained by the haploinsufficiency of PLEKHG3. Another deleted gene deserves attention considering the phenotypic spectrum of our patient. Kinase anchor protein 5 (AKAP5), predominantly expressed in the cerebral cortex, codes for
Epilepsy
DISCUSSION
NR
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE II. Size of the 14q23 Deletion and Genes Encompassed in the Four Patients Previously Reported in the Literature, in Comparison With This Report
a component of fractions enriched for postsynaptic densities. AKAP150 (AKAP5 homolog)-null mice present deficits in spatial memory, and motor coordination and strength [Tunquist et al., 2008]. Predisposition to NB in several syndromes has been noted for decades. Most overgrowth syndromes are known to increase the risk of tumors, especially hematologic cancers and NB. Such is the case in Sotos syndrome, caused by loss of function mutations or deletions in the NSD1 gene encoding a histone methyltransferase involved in chromatin regulation [Berdasco et al., 2009], Beckwith Wiedmann syndrome [Gaitanou et al., 2001; Merks et al., 2005], Simpson–Golabi–Behmel syndrome, an X-linked disorder caused by mutations in GPC3 gene encoding Glypican 3 [Weidle and Orstavik, 1998], and Weaver syndrome, which is caused by either NSD1 or EZH2 mutations [Douglas et al., 2003; Coulter et al., 2008; Tatton-Brown et al., 2011]. There is also an increased risk of NB in RAS-MAPK pathway disorders, such as neurofibromatosis type 1 [Kushner et al., 1986; Brems et al., 2009], Costello, Noonan and LEOPARD syndromes [Kratz et al., 2011]. NB has been reported in syndromes caused by a dysregulation of chromatin remodeling genes, such as Kabuki [Merks et al., 2005], Coffin Siris [Pollono et al., 2009], and Rubinstein–Taybi syndromes [Ihara et al., 1999]. Abbaszadeh et al. [2010] reported nine families segregating NB and Wilms tumor. Congenital central hypoventilation syndrome (CCHS, OMIM 209880) and Hirschsprung disease (OMIM 142623) have been demonstrated to be associated with an increased risk—about 500 times higher for CCHS—for development of
tumors of the sympathetic nervous system. Paired-like homeobox 2B, PHOX2B, the major disease causing gene in CCHS [Amiel et al., 2003], was also the first gene identified in familial isolated NB [Trochet et al., 2004; McConville et al., 2006]. However, PHOX2B mutations or silencing explain a small fraction of hereditary NB [de Pontual et al., 2007]. Germline or somatic gain-of-function mutations in the anaplastic lymphoma kinase (ALK) gene account for sporadic or familial isolated NB [Mosse et al., 2008]. Chromosomal imbalances are a key feature of NB. Recurrent unbalanced regions are being precisely mapped due to array CGH and SNP array studies. The most frequent imbalances are gain of 17q, loss of 1pter, amplification of the MYCN oncogene and loss of 14q. Interestingly, some of these rearrangements also predispose to NB when found to be constitutive, such as the kinesin KIF1Bbeta gene being the most likely tumor suppressor gene at the 1p36 locus [Schlisio et al., 2008]. Diskin et al. [2009] showed that inherited copy number variation (CNV) at 1q21.1 is associated with NB, and identified a previously unknown transcript within these CNVs that showed high sequence similarity to several NB breakpoint family (NBPF) genes and represents a new member of this gene family (NBPF23). Loss of heterozygosity (LOH) for 14q is a common somatic finding, found in 20–50% of NB. The region involved falls within 14q23–q32 between D14S588 and the 14q telomere, suggesting the presence of at least two tumor-suppressor genes in this region, one at 14q32 and one at 14q12–q23 [Theobald et al., 1999; Thompson et al., 2001].
LEHALLE ET AL. MAX, located at 14q23.3, is the most conserved dimerization component of the MYC–MAX–MXD1-4 network of basic helixloop-helix leucine zipper (bHLHZip) transcription factors that regulate cell proliferation, differentiation, and apoptosis. MAX has a central role as an obligate dimerization-DNA-binding partner for Myc oncogene protein and for Mad transcriptional repressors (Mad1, Mxi1, Mad3, Mad4). MYC is a well described oncogene whose enhanced or deregulated expression is known to be responsible for a wide variety of human cancers, including NB, Burkitt lymphoma, or small cell lung cancer. On the other hand, Max–Mad heterodimers repress Myc transcription and initiate differentiation and quiescence [Kretzner et al., 1992; Atchley and Fitch, 1995; Atchley and Fernandes, 2005; Hurlin and Huang, 2006; CominoMendez et al., 2011]. Max is ubiquitously and early expressed during development and Max-null embryo are embryonic lethal around E6.5 (being earlier than Myc and Mycn knock-outs), whereas heterozygous Max þ/ mice have no recognizable phenotype [Shen-Li et al., 2000]. Interestingly, the murine pheochromocytoma-derived PC12 cell line expresses a non-functional form of Max, lacking the carboxyl terminus of the protein. Reintroduction of Max in these cells results in transcriptional repression and reduction in growth rate [Ribon et al., 1994]. Recently, two teams demonstrated that MAX is an important susceptibility gene for pheochromocytoma (PCC) and paraganglioma (PGL), both being neural crest-derived tumors. CominoMendez et al. [2011] reported that MAX germline mutations are associated with familial predisposition to PCC and demonstrated that MAX behaves as a classic tumor suppressor gene in familial PCC. Burnichon et al. [2012] sequenced MAX, in 1694 patients with sporadic or familial PCC or PGL, and in 245 tumors samples; they found germline mutations in 16 patients (1.12%), somatic mutations in four tumors (1.65%) and arguments for a parent-of-origin effect. Of note, we do not know about the parental origin of the mutated allele in our patient. More recently, other teams confirmed MAX as a predisposing gene for PCC and PGL [Pe˛czkowska et al., 2013; Rattenberry et al., 2013]. Molenaar et al. [2012] performed a whole-genome sequence analysis of 87 NB of all stages, and found no mutation of MAX, demonstrating that it is not a frequent event in NB. However, the patient we report raises the hypothesis that germline MAX loss of function predisposes to the development of NB. ARID4A, also known as RBP1 or RBBP1 (Retinoblastoma binding-protein 1), is a DNA-binding protein. ARID4A binds to the pocket region of pRb, the product of the retinoblastoma tumor suppressor gene, and to the SAP30 subunit of the mSin3-HDAC transcriptional repressor complex and, thus, acts as a bridging protein in this multisubunit complex that represses E2F-mediated transcription [Suryadinata et al., 2011]. ARID4A expression has been studied in tumors, and found to be decreased in 49% of 47 samples of carcinomas [Rodrigues-Lisoni et al., 2010]. Moreover, Wu et al. [2008] showed that Arid4a-null mice presented hematologic malignancies, and suggested that ARID4A acts as a tumor suppressor gene. Interestingly, the Mad–Max heterodimer has been hypothesized to recruit the mSin3–HDAC corepressor complex [Laherty et al., 1997]; suggesting a potential link between MAX and ARID4A functions. Finally, two other chromatin-remodeling genes from the same family, ARID1A and ARID1B were recently identified
1315 in 11% of 71 NB samples, highlighting the importance of dysregulation of chromatin remodeling in NB tumorigenesis [Sausen et al., 2013].
CONCLUSION We report on a likely de novo 14q23.1–23.3 microdeletion in a boy presenting with a syndromic NB. This observation strengthens the hypothesis of a tumor suppressor gene at this locus. MAX appeared as an appealing candidate owing to its biological function in the Myc–Mad network and its recent implication as a tumor suppressor gene in PCC and PGL. However, we could not demonstrate a second event at the MAX locus in the tumor presented by the patient. ARID4A is another candidate gene and haploinsufficiency of both genes may have been the cause of NB in the case we report on. Further investigations, such as sequencing of the deleted region, should be done if other patients with a NB and a 14q23 deletion were to be reported. To the best of our knowledge, our patient is the only one presenting with a deletion of both MAX and ARID4A.
ACKNOWLEDGMENT We thank the patient and his family for their participation in this study.
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