Linda Marie Randolph

Chimerism occurs when an organism contains cells derived from more than one distinct zygote. We focus on monochorionic dizygotic twin blood chimerism, and particularly twin–twin transfusion syndrome in such pregnancies. For years, researchers have understood chimerism to be a common phenomenon in cattle. Although, this review will not delve deeply into animal chimerism, an understanding of chimerism in the animal world can provide clues regarding health implications for human chimeras. This report serves two purposes: an update and assessment of the twins we reported previously in 2010 [Assaf et al., 2010] and a review on dizygotic monochorionic chimeric twins. First, our updated assessment of the twins shows no identifiable regression of Müllerian sex derivatives in the female, and normal neurodevelopment was documented in both. Our research has suggested several key points; one that blood chimerism persists from fetal life to at least age two years. Second, chimerism in humans is not as rare as previously thought, although it has been studied only recently. Third, assisted reproductive technologies appear to increase the risk of monochorionic dizygotic twin pregnancies.

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.