Thomas M. Bosley, MD
Department of Ophthalmology
King Saud University, Riyadh, Saudi Arabia
tmbosley AT bosleynet.net
NANOS would like to assist in collecting patients and families with unusual congenital ocular motility abnormalities or strabismus. These individuals occur so uncommonly that it is difficult to collect enough individuals or families from one center for a comprehensive evaluation. We hope that the NANOS membership as a whole may be able to help collect both recognized and unrecognized congenital ocular motility problems for phenotypic description and genetic analysis. Your stewards in this process are Thomas M. Bosley, MD, who developed an interest in this area while working in Saudi Arabia, and Elizabeth C. Engle, MD, whose laboratory at Children's Hospital Boston has discovered the genes known to be mutated in multiple of these syndromes.
We are interested in collecting and evaluating patients and families with the less common types of congenital ocular motility disturbances that we refer to as the congenital cranial dysinnervation disorders (see below), and patients with currently unclassified eye movement disorders. We are also interested in more common types of strabismus such as comitant esotropia or exotropia of childhood, but only in familial cases (three or more first degree family members). We will use Dr. Engle's data collection form and, if appropriate, her informed consent form (see below), both of which are approved by the Children's Hospital Boston IRB.
To enroll a patient, what you have to do is:
- Complete the data collection form. This can be downloaded at the following link: [Data Collection Form]
- Contact Caroline Andrews, the Director of Clinical Research in Dr. Engle's lab at 617 919-2168 (candrews AT enders.tch.harvard.edu) to discuss whether your local IRB will require expedited review and approval of the Children's Hospital Boston protocol and consent form. She will provide both to you on request.
- Obtain signed informed consent. You will need to talk to the patient and available family members about the informed consent. You can use either Dr. Engle's [Participant Questionnaire] or your own. Use this time to address all of their questions. Once these issues are satisfied, ask each individual or guardian to sign the informed consent.
- Obtain blood or saliva from affected and unaffected family members. This will be used for DNA extraction. In general, it is better to obtain samples from proband, available siblings, and both parents. We can provide collection tubes and will undertake the DNA extraction.
- Send the informed consents, data forms, and samples to Dr. Engle's laboratory.
- Confirmation of receipt. We will notify you when we receive your package.
- Future correspondence. We will be in touch with additional questions about phenotyping and with notification about any manuscripts including individuals whom you have phenotyped and enrolled that may approach publication. Our aim is to be inclusive in this process.
The Engle lab can provide research-based genetic screening for mutations in candidate genes for all recognized disorders. Keep in mind that IRB rules prohibit you from informing your patients about the outcome of genetic analysis done for research purposes. However, genetic analyses, once perfected, are commonly moved to CLIA (Clinical Laboratory Improvement Act) federally approved certified laboratories. For many of the syndromes for which the disease gene has been identified, we can also offer diagnostic genetic testing in a CLIA-approved laboratory, either free through EyeGene or via insurance (or self-pay) at Children's Hospital Boston. Caroline Andrews will be available to discuss options when questions arise.
- Age 10 or greater plus…
- One of the following clinical criteria: retinal artery occlusion, encephalopathy or stroke-like event, or low frequency hearing loss, with…
- MRI evidence of one of the following: callosal lesions, or deep grey lesions, or leptomeningeal enhancement.
- Recurrent branch retinal artery occlusion patients can be enrolled without abnormal neuroimaging.
The following is a description of the congenital cranial dysinnervation disorders(Gutowski et al., 2003). This list is not intended to be comprehensive; rather, we provide it to give you some idea of the sort of congenital ocular motility problems that have been recognized. With luck, you will recognize some syndrome not yet described, but keep in mind that we are also interested in studying patients with recognized disorders.
Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; MIM # 135700) usually presents with ptosis OU and with both eyes infraducted. Patients have upgaze paralysis OU and bilateral, asymmetric restriction of ocular motility OU in other directions (Engle et al., 1995). This is an autosomal dominant syndrome in which heterozygous missense mutations in KIF21A (Engle et al., 1994; Yamada et al., 2003) cause dysinnervation of extra-ocular muscles (Demer et al., 2005).
Congenital fibrosis of the extraocular muscles type 2 (CFEOM2; MIM # 602078) looks like bilateral absence of the oculomotor and trochlear nerves with no adduction, elevation, or depression OU and with incomplete abduction (Bosley et al., 2006; Wang et al., 1998). It is an autosomal recessive disorder in which mutations in PHOX2A cause absence of the nuclei of cranial nerves 3 and 4 bilaterally (Nakano et al., 2001).
Congenital fibrosis of the extraocular muscles type 3 (CFEOM3; MIM #600638, #135700, %609384) is another congenital cranial dysinnervation disorder (CCDD) in which patients have asymmetric restriction of ocular motility in all directions OU, generally without the severe restriction of upgaze that is typical of CFEOM1 (Doherty et al., 1999; Mackey et al., 2002). Some individuals with CFEOM3 also have facial weakness, peripheral neuropathy, and/or developmental delay. Currently, autosomal dominant variants are known to be caused by mutations in TUBB3 (Tischfield et al., 2010) or KIF21A (Yamada et al., 2004).
Horizontal gaze palsy and progressive scoliosis (HGPPS; MIM # 607313) is marked neurologically by severe congenital bilateral horizontal gaze restriction, but the major clinical impact is the severe scoliosis that develops in the first or second decade of life (Bosley et al., 2005; Jen et al., 2002; Jen et al., 2004). It is an autosomal recessive syndrome caused by homozygous mutations in ROBO3. ROBO3 permits decussation of a number of neuronal tracts in the developing brainstem, so these individuals also lack decussation of the long motor and sensory tracts and have asynchronous blinking (Jen et al., 2002; Jen et al., 2004)
The HOXA1 Spectrum (BSAS/ABDS; MIM # 601536) is made up of the Bosley-Salih-Alorainy syndrome (Bosley et al., 2007; Tischfield et al., 2005) and the Athabascan Brainstem Dysgenesis syndrome (Holve et al., 2003), both of which are caused by autosomal recessive mutations in the HOXA1 gene (Tischfield et al., 2005). Clinical hallmarks of the syndrome are bilateral type 3 Duane retraction syndrome (or horizontal gaze palsy OU), bilateral deafness, variable cerebrovascular and cardiovascular dysplasia, and autism in some (Bosley et al., 2008; Holve et al., 2003; Tischfield et al., 2005).
DURS2-Duane retraction syndrome (DURS2-DRS; MIM %126800) is isolated Duane syndrome that can be inherited as an autosomal dominant trait and results from gain-of-function mutations in CHN1, which encodes a cell signaling molecule, alpha2-chimerin, believed to be essential for correct axon targeting of the abducens motor neurons to the lateral rectus muscle (Demer et al., 2007; Miyake et al., 2008).
Duane-Radial Ray syndrome (Okihiro syndrome; DRRS; MIM #607323) is an autosomal dominant syndrome in which DRS is inherited together with hand and upper limb anomalies, and less frequently with deafness. It is caused by heterozygous mutations in SALL4 (Al-Baradie et al., 2002).
Wildervanck syndrome (Cervicooculoacoutstic syndrome; MIM 314600) is a sporadic syndrome in which DRS occurs in association with congenital deafness and Klippel-Feil anomaly.
Moebius syndrome (Moebius sequence; MIM %157900) is the combination of abduction defects and facial weakness; we have identified individuals with CFEOM-like Moebius syndrome as well as Duane-like Moebius syndrome. It is most commonly sporadic and can be associated with limb anomalies and developmental deficits.
Congenital ptosis. (PTOS1&2; MIM %178300; %300245) is an isolated phenomenon that can be inherited as an autosomal dominant or an X-linked trait. Several genetic loci have been mapped but disease genes have yet to be identified(Engle et al., 1997).
Common strabismus. (MIM %185100) consists of simple comitant esotropia or exotropia. Most cases are sporadic, but it is nevertheless possible that the occurrence is influenced by the inheritance of complex rather than Mendelian traits. Enrollment of families with three or more affected members will assist in the identification of strabismus susceptibility genes.
- Al-Baradie, R., Yamada, K., St Hilaire, C., Chan, W.M., Andrews, C., McIntosh, N., Nakano, M., Martonyi, E.J., Raymond, W.R., Okumura, S., Okihiro, M.M., and Engle, E.C. (2002). Duane Radial Ray Syndrome (Okihiro Syndrome) Maps to 20q13 and Results from Mutations in SALL4, a New Member of the SAL Family. Am J Hum Genet 71, 1195-1199.
- Bosley, T.M., Alorainy, I.A., Salih, M.A., Aldhalaan, H.M., Abu-Amero, K.K., Oystreck, D.T., Tischfield, M.A., Engle, E.C., and Erickson, R.P. (2008). The clinical spectrum of homozygous HOXA1 mutations. Am J Med Genet A 146, 1235-1240.
- Bosley, T.M., Oystreck, D.T., Robertson, R.L., Al Awad, A., Abu-Amero, K., and Engle, E.C. (2006). Neurological features of congenital fibrosis of the extraocular muscles type 2 with mutations in PHOX2A. Brain.
- Bosley, T.M., Salih, M.A., Alorainy, I.A., Oystreck, D.T., Nester, M., Abu-Amero, K.K., Tischfield, M.A., and Engle, E.C. (2007). Clinical characterization of the HOXA1 syndrome BSAS variant. Neurology 69, 1245-1253.
- Bosley, T.M., Salih, M.A., Jen, J.C., Lin, D.D., Oystreck, D., Abu-Amero, K.K., MacDonald, D.B., al Zayed, Z., al Dhalaan, H., Kansu, T., Stigsby, B., and Baloh, R.W. (2005). Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROBO3. Neurology 64, 1196-1203.
- Demer, J.L., Clark, R.A., and Engle, E.C. (2005). Magnetic resonance imaging evidence for widespread orbital dysinnervation in congenital fibrosis of extraocular muscles due to mutations in KIF21A. Invest Ophthalmol Vis Sci 46, 530-539.
- Demer, J.L., Clark, R.A., Lim, K.H., and Engle, E.C. (2007). Magnetic Resonance Imaging Evidence for Widespread Orbital Dysinnervation in Dominant Duane's Retraction Syndrome Linked to the DURS2 Locus. Invest Ophthalmol Vis Sci 48, 194-202.
- Doherty, E.J., Macy, M.E., Wang, S.M., Dykeman, C.P., Melanson, M.T., and Engle, E.C. (1999). CFEOM3: a new extraocular congenital fibrosis syndrome that maps to 16q24.2-q24.3. Invest Ophthalmol Vis Sci 40, 1687-1694.
- Engle, E.C., Castro, A.E., Macy, M.E., Knoll, J.H.M., and Beggs, A.H. (1997). A gene for isolated congenital ptosis maps to a 3 cM region within 1p32-p34.1. Am J Hum Genet 60, 1150-1157.
- Engle, E.C., Kunkel, L.M., Specht, L.A., and Beggs, A.H. (1994). Mapping a gene for congenital fibrosis of the extraocular muscles to the centromeric region of chromosome 12. Nat Genet 7, 69-73.
- Engle, E.C., Marondel, I., Houtman, W.A., de Vries, B., Lowenstein, A., Lazar, M., Ward, D.C., Kucherlapati, R., and Beggs, A.H. (1995). Congenital fibrosis of the extraocular muscles (autosomal dominant congenital external ophthalmoplegia): genetic homogeneity, linkage refinement, and physical mapping on chromosome 12. Am J Hum Genet 57, 1086-1094.
- Gutowski, N.J., Bosley, T.M., and Engle, E.C. (2003). 110th ENMC International Workshop: The congenital cranial dysinnervation disorders (CCDDs). Naarden, The Netherlands, 25-27 October, 2002. Neuromuscul Disord 13, 573-578.
- Holve, S., Friedman, B., Hoyme, H.E., Tarby, T.J., Johnstone, S.J., Erickson, R.P., Clericuzio, C.L., and Cunniff, C. (2003). Athabascan brainstem dysgenesis syndrome. Am J Med Genet 120A, 169-173.
- Jen, J., Coulin, C.J., Bosley, T.M., Salih, M.A., Sabatti, C., Nelson, S.F., and Baloh, R.W. (2002). Familial horizontal gaze palsy with progressive scoliosis maps to chromosome 11q23-25. Neurology 59, 432-435.
- Jen, J.C., Chan, W.M., Bosley, T.M., Wan, J., Carr, J.R., Rub, U., Shattuck, D., Salamon, G., Kudo, L.C., Ou, J., Lin, D.D., Salih, M.A., Kansu, T., Al Dhalaan, H., Al Zayed, Z., MacDonald, D.B., Stigsby, B., Plaitakis, A., Dretakis, E.K., Gottlob, I., Pieh, C., Traboulsi, E.I., Wang, Q., Wang, L., Andrews, C., Yamada, K., Demer, J.L., Karim, S., Alger, J.R., Geschwind, D.H., Deller, T., Sicotte, N.L., Nelson, S.F., Baloh, R.W., and Engle, E.C. (2004). Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 304, 1509-1513.
- Mackey, D.A., Chan, W.M., Chan, C., Gillies, W.E., Brooks, A.M., O'Day, J., and Engle, E.C. (2002). Congenital fibrosis of the vertically acting extraocular muscles maps to the FEOM3 locus. Hum Genet 110, 510-512.
- Miyake, N., Chilton, J., Psatha, M., Cheng, L., Andrews, C., Chan, W.M., Law, K., Crosier, M., Lindsay, S., Cheung, M., Allen, J., Gutowski, N.J., Ellard, S., Young, E., Iannaccone, A., Appukuttan, B., Stout, J.T., Christiansen, S., Ciccarelli, M.L., Baldi, A., Campioni, M., Zenteno, J.C., Davenport, D., Mariani, L.E., Sahin, M., Guthrie, S., and Engle, E.C. (2008). Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome. Science 321, 839-843.
- Tischfield, M.A., Baris, H.N., Wu, C., Rudolph, G., Van Maldergem, L., He, W., Chan, W.M., Andrews, C., Demer, J.L., Robertson, R.L., Mackey, D.A., Ruddle, J.B., Bird, T.D., Gottlob, I., Pieh, C., Traboulsi, E.I., Pomeroy, S.L., Hunter, D.G., Soul, J.S., Newlin, A., Sabol, L.J., Doherty, E.J., de Uzcategui, C.E., de Uzcategui, N., Collins, M.L., Sener, E.C., Wabbels, B., Hellebrand, H., Meitinger, T., de Berardinis, T., Magli, A., Schiavi, C., Pastore-Trossello, M., Koc, F., Wong, A.M., Levin, A.V., Geraghty, M.T., Descartes, M., Flaherty, M., Jamieson, R.V., Moller, H.U., Meuthen, I., Callen, D.F., Kerwin, J., Lindsay, S., Meindl, A., Gupta, M.L., Jr., Pellman, D., and Engle, E.C. (2010). Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 140, 74-87.
- Tischfield, M.A., Bosley, T.M., Salih, M.A., Alorainy, I.A., Sener, E.C., Nester, M.J., Oystreck, D.T., Chan, W.M., Andrews, C., Erickson, R.P., and Engle, E.C. (2005). Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet 37, 1035-1037. Wang, S.M., Zwaan, J., Mullaney, P.B., Jabak, M.H., Al-Awad, A., Beggs, A.H., and Engle, E.C. (1998). Congenital fibrosis of the extraocular muscles type 2, an inherited exotropic strabismus fixus, maps to distal 11q13. Am J Hum Genet 63, 517-525.
- Yamada, K., Andrews, C., Chan, W.M., McKeown, C.A., Magli, A., De Berardinis, T., Loewenstein, A., Lazar, M., O'Keefe, M., Letson, R., London, A., Ruttum, M., Matsumoto, N., Saito, N., Morris, L., Monte, M.D., Johnson, R.H., Uyama, E., Houtman, W.A., De Vries, B., Carlow, T.J., Hart, B.L., Krawiecki, N., Shoffner, J., Vogel, M.C., Katowitz, J., Goldstein, S.M., Levin, A.V., Sener, E.C., Ozturk, B.T., Akarsu, A.N., Brodsky, M.C., Hanisch, F., Cruse, R.P., Zubcov, A.A., Robb, R.M., Roggenkaemper, P., Gottlob, I., Kowal, L., Battu, R., Traboulsi, E.I., Franceschini, P., Newlin, A., Demer, J.L., and Engle, E.C. (2003). Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet 35, 318-321.
- Yamada, K., Chan, W.M., Andrews, C., Bosley, T.M., Sener, E.C., Zwaan, J.T., Mullaney, P.B., Ozturk, B.T., Akarsu, A.N., Sabol, L.J., Demer, J.L., Sullivan, T.J., Gottlob, I., Roggenkaemper, P., Mackey, D.A., De Uzcategui, C.E., Uzcategui, N., Ben-Zeev, B., Traboulsi, E.I., Magli, A., De Berardinis, T., Gagliardi, V., Awasthi-Patney, S., Vogel, M.C., Rizzo, J.F., 3rd, and Engle, E.C. (2004). Identification of KIF21A Mutations as a Rare Cause of Congenital Fibrosis of the Extraocular Muscles Type 3 (CFEOM3). Invest Ophthalmol Vis Sci 45, 2218-2223.