The Genetics Journey: A Case Report of a Genetic Diagnosis Made 30 Years Later

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant condition that was first described in 2006. The causative gene, EFTUD2, identified in 2012. We report on a family that initially presented to a pediatric genetics clinic in the 1980s for evaluation of multiple congenital anomalies. Re‐evaluation of one member thirty years later resulted in a phenotypic and molecularly confirmed diagnosis of MFDM. This family’s clinical histories and the novel EFTUD2 variant identified, c.1297_1298delAT (p.Met433Valfs*17), add to the literature about MFDM. This case presented several genetic counseling challenges and highlights that “the patient” can be multiple family members. We discuss testing considerations for an unknown disorder complicated by the time constraint of the patient’s daughter’s pregnancy and how the diagnosis changed previously provided recurrence risks. Of note, 1) the 1980s clinic visit letters provided critical information about affected family members and 2) the patient’s husband’s internet search of his wife’s clinical features also yielded the MFDM diagnosis, illustrating the power of the internet in the hands of patients. Ultimately, this case emphasizes the importance of re‐evaluation given advances in genetics and the value of a genetic diagnosis for both patient care and risk determination for family members.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147210/1/jgc40894.pd

Acro-cardio-facial syndrome

Acro-cardio-facial syndrome (ACFS) is a rare genetic disorder characterized by split-hand/split-foot malformation (SHFM), facial anomalies, cleft lip/palate, congenital heart defect (CHD), genital anomalies, and mental retardation. Up to now, 9 patients have been described, and most of the reported cases were not surviving the first days or months of age. The spectrum of defects occurring in ACFS is wide, and both interindividual variability and clinical differences among sibs have been reported. The diagnosis is based on clinical criteria, since the genetic mechanism underlying ACFS is still unknown. The differential diagnosis includes other disorders with ectrodactyly, and clefting conditions associated with genital anomalies and heart defects. An autosomal recessive pattern of inheritance has been suggested, based on parental consanguinity and disease's recurrence in sibs in some families. The more appropriate recurrence risk of transmitting the disease for the parents of an affected child seems to be up to one in four. Management of affected patients includes treatment of cardiac, respiratory, and feeding problems by neonatal pediatricians and other specialists. Prognosis of ACFS is poor

Brain size regulations by cbp haploinsufficiency evaluated by in-vivo MRI based volumetry

The Rubinstein-Taybi Syndrome (RSTS) is a congenital disease that affects brain development causing severe cognitive deficits. In most cases the disease is associated with dominant mutations in the gene encoding the CREB binding protein (CBP). In this work, we present the first quantitative analysis of brain abnormalities in a mouse model of RSTS using magnetic resonance imaging (MRI) and two novel self-developed automated algorithms for image volumetric analysis. Our results quantitatively confirm key syndromic features observed in RSTS patients, such as reductions in brain size (-16.31%, p < 0.05), white matter volume (-16.00%, p < 0.05), and corpus callosum (-12.40%, p < 0.05). Furthermore, they provide new insight into the developmental origin of the disease. By comparing brain tissues in a region by region basis between cbp(+/-) and cbp(+/+) littermates, we found that cbp haploinsufficiency is specifically associated with significant reductions in prosencephalic tissue, such us in the olfactory bulb and neocortex, whereas regions evolved from the embryonic rhombencephalon were spared. Despite the large volume reductions, the proportion between gray-, white-matter and cerebrospinal fluid were conserved, suggesting a role of CBP in brain size regulation. The commonalities with holoprosencephaly and arhinencephaly conditions suggest the inclusion of RSTS in the family of neuronal migration disorders.We are grateful to Begona Fernandez for her excellent technical assistance. We would like to thank S. Sawiak (Wolfson Imaging Centre, University of Cambridge, Cambridge, United Kingdom) for the mouse brain tissue probability maps and the SPMmouse plug-in, and to N. Kovacevic (Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada) for the atlas of the mouse brain. Supported by grants from the Spanish MINECO to S.C. (BFU 2012-39958) and MINECO and FEDER to D.M. (TEC 2012-33778) and from MINECO (SAF2011-22855) and Generalitat Valenciana (Prometeo/2012/005) to A.B. The Instituto de Neurociencias is "Centre of Excellence Severo Ochoa".Ateca Cabarga, JC.; Cosa, A.; Pallares, V.; Lopez-Atalaya, JP.; Barco, A.; Canals, S.; Moratal Pérez, D. (2015). Brain size regulations by cbp haploinsufficiency evaluated by in-vivo MRI based volumetry. Scientific Reports. 5. https://doi.org/10.1038/srep16256S5Rubinstein, J. H. & Taybi, H. Broad thumbs and toes and facial abnormalities. A possible mental retardation syndrome. Am J Dis Child 105, 588–608 (1963).Van Belzen, M., Bartsch, O., Lacombe, D., Peters, D. J. & Hennekam, R. C. Rubinstein-Taybi syndrome (CREBBP, EP300). Eur J Hum Genet. 19, preceeding 118–120 (2011).Hennekam, R. C. Rubinstein-Taybi syndrome. Eur J Hum Genet. 14, 981–985 (2006).Wiley, S., Swayne, S., Rubinstein, J. H., Lanphear, N. E. & Stevens, C. A. Rubinstein-Taybi syndrome medical guidelines. Am J Med Genet A. 119A, 101–110 (2003).Michail, J., Matsoukas, J. & Theodorou, S. Pouce bot arqué en forte abduction-extension et autres symptomes concomitants. Rev Chir Orthop 43, 142–146 (1957).Barco A. The Rubinstein-Taybi syndrome: modeling mental impairment in the mouse. Genes Brain Behav 6, 32–39 (2007).Lopez-Atalaya, J. P., Valor, L. M. & Barco, A. Epigenetic factors in intellectual disability: the Rubinstein-Taybi syndrome as a paradigm of neurodevelopmental disorder with epigenetic origin. Prog Mol Biol Transl Sci. 128, 139–176 (2014).Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C. M., Masuno, M., Tommerup, N., Van Ommen, G. J. B., Goodman, R. H., Peters, D. J. M. & Breuning, M. H. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376, 348–351 (1995).Zimmermann, N., Acosta, A. M., Kohlhase, J. & Bartsch, O. Confirmation of EP300 gene mutations as a rare cause of Rubinstein-Taybi syndrome. Eur J Hum Genet. 15, 837–842 (2007).Bartholdi, D. et al. Genetic heterogeneity in Rubinstein-Taybi syndrome: delineation of the phenotype of the first patients carrying mutations in EP300. J Med Genet. 44, 327–333 (2007).Roelfsema, J. H. et al. Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. Am J Hum Genet. 76, 572–580 (2005).Tanaka, Y., Naruse, I., Maekawa, T., Masuya, H., Shiroishi, T. & Ishii, S. Abnormal skeletal patterning in embryos lacking a single Cbp allele: a partial similarity with Rubinstein-Taybi syndrome. Proc Natl Acad Sci USA 94, 10215–10220 (1997).López-Atalaya, J. P. et al. CBP is required for environmental enrichment-induced neurogenesis and cognitive enhancement. EMBO J 30, 4287–4298 (2011).Wang, J. et al. CBP histone acetyltransferase activity regulates embryonic neural differentiation in the normal and Rubinstein-Taybi syndrome brain. Dev Cell. 18, 114–125 (2010).Marzuillo, P. et al. Brain magnetic resonance in the routine management of Rubinstein-Taybi syndrome (RTS) can prevent life-threatening events and neurological deficits. Am J Med Genet A. 164A, 2129–2132 (2014).de Kort, E., Conneman, N. & Diderich, K. A case of Rubinstein-Taybi syndrome and congenital neuroblastoma. Am J Med Genet A. 164A, 1332–1333 (2014).Lee, J. S. et al. Clinical and mutational spectrum in Korean patients with Rubinstein-Taybi syndrome: the spectrum of brain MRI abnormalities. Brain Dev. 37, 402–408 (2015).Marzuillo, P. et al. Novel cAMP binding protein-BP (CREBBP) mutation in a girl with Rubinstein-Taybi syndrome, GH deficiency, Arnold Chiari malformation and pituitary hypoplasia. BMC Med Genet. 14, 28 (2013). 10.1186/1471-2350-14-28.Li, Z. et al. Phenotypic expansion of the interstitial 16p13.3 duplication: a case report and review of the literature. Gene. 531, 502–505 (2013).Demeer, B. et al. Duplication 16p13.3 and the CREBBP gene: confirmation of the phenotype. Eur J Med Genet. 56, 26–31 (2013).Kumar, S., Suthar, R., Panigrahi, I. & Marwaha, R. K. Rubinstein-Taybi syndrome: Clinical profile of 11 patients and review of literature. Indian J Hum Genet. 18, 161–166 (2012).Giussani, C. et al. The association of neural axis and craniovertebral junction anomalies with scoliosis in Rubinstein-Taybi syndrome. Childs Nerv Syst. 28, 2163–2168 (2012).Parsley, L., Bellus, G., Handler, M. & Tsai, A. C. Identical twin sisters with Rubinstein-Taybi syndrome associated with Chiari malformations and syrinx. Am J Med Genet A. 155A, 2766–2770 (2011).Thienpont, B. et al. Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome. J Med Genet. 47, 155–161 (2010).Kim, S. H., Lim, B. C., Chae, J. H., Kim, K. J. & Hwang, Y. S. A case of Rubinstein-Taybi Syndrome with a CREB-binding protein gene mutation. Korean J Pediatr. 53, 718–721 (2010).Wójcik, C. et al. Rubinstein-Taybi syndrome associated with Chiari type I malformation caused by a large 16p13.3 microdeletion: a contiguous gene syndrome? Am J Med Genet A. 152A, 479–483 (2010).Wachter-Giner, T., Bieber, I., Warmuth-Metz, M., Bröcker, E. B. & Hamm, H. Multiple pilomatricomas and gliomatosis cerebri--a new association? Pediatr Dermatol. 26, 75–78 (2009).Verstegen, M. J., van den Munckhof, P., Troost, D. & Bouma, G. J. Multiple meningiomas in a patient with Rubinstein-Taybi syndrome. Case report. J Neurosurg. 102, 167–168 (2005).Agarwal, R., Aggarwal, R., Kabra, M. & Deorari, A. K. Dandy-Walker malformation in Rubinstein-Taybi syndrome: a rare association. Clin Dysmorphol. 11, 223–224 (2002).Ihara, K., Kuromaru, R., Takemoto, M. & Hara, T. Rubinstein-Taybi syndrome: a girl with a history of neuroblastoma and premature thelarche. Am J Med Genet. 83, 365–366 (1999).Sener, R. N. Rubinstein-Taybi syndrome: cranial MR imaging findings. Comput Med Imaging Graph 19, 417–418 (1995).Robinson, T. W., Stewart, D. L. & Hersh, J. H. Monozygotic twins concordant for Rubinstein-Taybi syndrome and implications for genetic counseling. Am J Med Genet. 45, 671–673 (1993).Guion-Almeida, M. L. & Richieri-Costa, A. Callosal agenesis, iris coloboma and megacolon in a Brazilian boy with Rubinstein-Taybi syndrome. Am J Med Genet. 43, 929–931 (1992).Albanese, A. et al. [Role of diagnostic imaging in Rubinstein-Taybi syndrome. personal experience with 8 cases]. Radiol Med. 81, 253–261 (1991).Rubinstein, J. H. Broad thumb-hallux (Rubinstein-Taybi) syndrome 1957-1988. Am J Med Genet Suppl. 6, 3–16 (1990).Hennekam, R. C., Stevens, C. A. & Van de Kamp, J. J. Etiology and recurrence risk in Rubinstein-Taybi syndrome. Am J Med Genet Suppl. 6, 56–64 (1990).Bonioli, E., Bellini, C. & Di Stefano, A. Unusual association: Dandy-Walker-like malformation in the Rubinstein-Taybi syndrome. Am J Med Genet. 33, 420–421 (1989).Beluffi, G., Pazzaglia, U. E., Fiori, P., Pricca, P. & Poznanski, A. K. [Oto-palato-digital syndrome. Clinico-radiological study]. Radiol Med. 74, 176–184 (1987).Cantani, A. & Gagliesi, D. Rubinstein-Taybi syndrome. Review of 732 cases and analysis of the typical traits. Eur Rev Med Pharmacol Sci. 2, 81–87 (1998).Viosca, J., Lopez-Atalaya, J. P., Olivares, R., Eckner, R. & Barco, A. Syndromic features and mild cognitive impairment in mice with genetic reduction on p300 activity: Differential contribution of p300 and CBP to Rubinstein-Taybi syndrome etiology. Neurobiol Dis. 37, 186–194 (2010).Martínez-Martínez, M. A., Pacheco-Torres, J., Borrell, V. & Canals, S. Phenotyping the central nervous system of the embryonic mouse by magnetic resonance microscopy. Neuroimage. 97, 95–106 (2014).Heikkinen, T. et al. Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington’s disease. PLoS One. 7, e50717 (2012), 10.1371/journal.pone.0050717.Alarcón, J. M. et al. Chromatin acetylation, memory and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron. 42, 947–959 (2004).Smith, S. M. et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23 Supp 1, S208–19 (2004).Smith, S. M. Fast robust automated brain extraction. Hum Brain Mapp 17, 143–155 (2002).Ashburner, J. & Friston, K. J. Unified segmentation. Neuroimage 26, 839–851 (2005).Sawiak, S. J., Wood, N. I., Williams, G. B., Morton, A. J. & Carpenter, T. A. Voxel-based morphometry in the R6/2 transgenic mouse reveals differences between genotypes not seen with manual 2D morphometry. Neurobiol Dis 33, 20–27 (2009).Kovačević, N. et al. A three-dimensional MRI atlas of the mouse brain with estimates of the average and variability. Cereb Cortex 15, 639–645 (2005).Zacharoff, L. et al. Cortical metabolites as biomarkers in the R6/2 model of Huntington’s disease. J Cereb Blood Flow Metab. 32, 502–514 (2012).Petryk, A., Graf, D. & Marcucio, R. Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes and the phenotypic variability in animal models and humans. Wiley Interdiscip Rev Dev Biol. 4, 17–32 (2015).Solomon, B. D., Gropman, A. & Muenke, M. Holoprosencephaly Overview. In: GeneReviews (eds Pagon, R. A. et al.), Seattle (WA): University of Washington, Seattle; 1993-2014, 2000 Dec 27 [Updated 2013 Aug 29]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1530/ [Date of access: September 4, 2015].Mazzone, D., Milana, A., Praticò, G. & Reitano, G. Rubinstein-Taybi syndrome associated with Dandy-Walker cyst. 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Frontonasal dysplasia, Poland anomaly and unilateral hypoplasia of lower limb: report on a male patient

We report a 13-year-old boy with an apparently previously undescribed combination of findings including facial features of frontonasal dysplasia, Poland anomaly, and contralateral hypoplasia of the lower limb. Clinical correlations among these features are discussed.12423323

Blepharocheilodontic (BCD) syndrome: Expanding the phenotype?

We describe affected individuals in three generations of a family and another sporadic case, all Brazilian patients, with a combination of signs that diagnose the BCD syndrome. In addition to the cardinal signs, the sporadic case has hypothyroidism and imperforate anus, which was observed previously in one patient. The broadened phenotype and the possibility of involvement of p63 and IRF6 genes in this condition are discussed. (C) 2003 Wiley-Liss, Inc.121A326627