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Abstract
BackgroundPierre-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 presentationWe 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.ConclusionsThus, 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.
Highlights
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
Isolated PRS can be associated with chromosomal deletions such as 2q24.1-33.3, 4q32-qter, 11q21-23.1, and 17q21-24.3 [6]
Bruder et al hypothesized that the high severity of Neurofibromatosis type 2 (NF2) in JP may be due to loss of a putative second tumor suppressor gene within the 7.4 Mb deletion, that usually remained intact in patients with smaller chromosomal deletions that encompass all of NF2 [19]
Summary
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 [1,2,3,4,5]. We provide the first description of clinical association between PRS (including cleft palate) and NF2 in a patient in whom we found a 22q12.2 deletion. Motor development was delayed (rolled at 8 months, sat at 10 months, walked at 18 months), and she was later diagnosed with mental retardation From preschool age she had bilateral severe conductive hearing loss requiring hearing aids that was attributed to bony changes associated with her congenital dysmorphic features. At age 14 she had severe to profound mixed hearing loss to which the bony conductance only contributed mild to moderate impairment The left cerebellopontine tumor was partially-resected and identified as a schwannoma, consistent with diagnosis of NF2 (Figure 1G-H) Chromosomal microarray analysis (CMA; Affymetrix SNP 6.0 array) to better delineate the mutation detected a chromosome 22q12.2 deletion of approximately 3.7 Mb (3,693 kb) spanning the NF2 gene, with break points at base pairs 25937541 and 29635842 (UCSC Genome Browser version hg, release name NCBI build 36.1) (Figure 2C)
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