Microdeletion del(22)(q12.2) encompassing the facial development-associated gene, MN1 (meningioma 1) in a child with Pierre-Robin sequence (including cleft palate) and neurofibromatosis 2 (NF2): a case report and review of the literature

abstract: ...Background Pierre-Robin sequence (PRS) is defined by micro- and/or retrognathia, glossoptosis and cleft soft palate, either caused by deformational defect or part of a malformation syndrome. Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome caused by mutations in the NF2 gene on chromosome 22q12.2. NF2 is characterized by bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas and ependymomas, and juvenile cataracts. To date, NF2 and PRS have not been described together in the same patient. Case presentation We report a female with PRS (micrognathia, cleft palate), microcephaly, ocular hypertelorism, mental retardation and bilateral hearing loss, who at age 15 was also diagnosed with severe NF2 (bilateral cerebellopontine schwannomas and multiple extramedullary/intradural spine tumors). This is the first published report of an individual with both diagnosed PRS and NF2. High resolution karyotype revealed 46, XX, del(22)(q12.1q12.3), FISH confirmed a deletion encompassing NF2 , and chromosomal microarray identified a 3,693 kb deletion encompassing multiple genes including NF2 and MN1 (meningioma 1). Five additional patients with craniofacial dysmorphism and deletion in chromosome 22-adjacent-to or containing NF2 were identified in PubMed and the DECIPHER clinical chromosomal database. Their shared chromosomal deletion encompassed MN1 , PITPNB and TTC28 . MN1 , initially cloned from a patient with meningioma, is an oncogene in murine hematopoiesis and participates as a fusion gene ( TEL / MN1 ) in human myeloid leukemias. Interestingly, Mn1 -haploinsufficient mice have abnormal skull development and secondary cleft palate. Additionally, Mn1 regulates maturation and function of calvarial osteoblasts and is an upstream regulator of Tbx22 , a gene associated with murine and human cleft palate. This suggests that deletion of MN1 in the six patients we describe may be causally linked to their cleft palates and/or craniofacial abnormalities. Conclusions Thus, our report describes a NF2 -adjacent chromosome 22q12.2 deletion syndrome and is the first to report association of MN1 deletion with abnormal craniofacial development and/or cleft palate in humans.

...BMC Med Genet BMC Med. Genet BMC Medical Genetics 1471-2350 BioMed Central 22436304 3359208 1471-2350-13-19 10.1186/1471-2350-13-19 Case Report Microdeletion del(22)(q12.2) encompassing the facial development-associated gene, MN1 (meningioma 1) in a child with Pierre-Robin sequence (including cleft palate) and neurofibromatosis 2 (NF2): a case report and review of the literature Davidson Tom B 1 6 tdavidson@mednet.ucla.edu Sanchez-Lara Pedro A 1 4 5 pedro.sanchez@chla.usc.edu Randolph Linda M 1

...), FISH confirmed a deletion encompassing NF2 , and chromosomal microarray identified a 3,693 kb deletion encompassing multiple genes including NF2 and MN1 (meningioma 1). Five additional patients with craniofacial dysmorphism and deletion in chromosome 22-adjacent-to or containing NF2 were identified in PubMed and the DECIPHER clinical chromosomal database. Their shared chromosomal deletion encompassed MN1 , PITPNB and TTC28 . MN1 , initially cloned from a patient with meningioma, is an oncogene in murine hematopoiesis and participates as a fusion gene ( TEL / MN1 ) in human myeloid leukemias. Interestingly, Mn1 -haploinsufficient mice have abnormal skull development and secondary cleft palate. Additionally, Mn1 regulates maturation and function of calvarial osteoblasts and is an upstream regulator of Tbx22 , a gene associated with murine and human cleft palate. This suggests that deletion of MN1 in the six patients we describe may be causally linked to their cleft palates and/or craniofacial abnormalities. Conclusions Thus, our report describes a NF2 -adjacent chromosome 22q12.2 deletion syndrome and is the first to report association of MN1 deletion with abnormal craniofacial development and/or cleft palate in humans. Chromosome 22q12.2 Cleft palate MN1 NF2 Pierre-Robin sequence Background Pierre-Robin sequence (PRS) refers to a combination of micrognathia or retrognathia, glossoptosis and respiratory distress, with or without cleft palate, named after the French stomatologist, Pierre Robin

... found a 22q12.2 deletion. Interestingly in addition to NF2 , this deletion also encompasses Meningioma1 ( MN1 ), a gene that is important in murine craniofacial development, and whose haploinsufficiency in mice causes skull abnormalities and secondary cleft palate, but which to date, has not been associated with malformations in humans. Case presentation Our patient (PRS-NF2) was born to healthy non-consanguineous parents (mother 39 years old) at week 36 by emergency cesarean section due to

... and/or intellectual delay. NF2 neurofibromatosis 2, MR mental retardation. Figure 3 Chromosome 22q12.2 deletions reveal loss of MN1 in six patients with facial dysmorphism and/or cleft palate and/or abnormal cranium . Schema of the deletions on chromosome 22q12.2 in the eight patients described in the text and Table 1. Black bars depict the six patients with abnormal cranium and/or facial dysmorphism, and/or cleft palate. pX and TC were too young to determine whether they manifest clinical NF2. Gray bars depict the two patients without these abnormalities but with NF2. Dashed black line indicates the approximated proximal deletion in patient p41. Genes: NF2 -purple, TTC28 -green, PITPNB -orange, MN1 -blue. Translucent vertical bars align the location of the deleted genes in relation to the chromosomal deletion found in each patient. The young age at which PRS-NF2 was diagnosed with bilateral vestibular schwannomas (15 years), the high tumor burden that included multiple spinal tumors, and

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Gene: MN1 - meningioma (disrupted in balanced translocation) 1 - (NCBI)

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