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Last updated: 7/22/2024
Years published: 1992, 2004, 2017, 2020, 2024
NORD gratefully acknowledges Zacory Kobylarz, NORD Editorial Intern from the University of Notre Dame, and Stephen Robertson, FRACP, DPhil, Curekids Professor of Pediatric Genetics, Dunedin School of Medicine, University of Otago, New Zealand, for assistance in the preparation of this report.
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Otopalatodigital syndromes type I and II are rare X-linked genetic disorders in which complete expression of the disease occurs only in males. Females may be affected with some of the symptoms. OPD type I is the milder form of the disease and is characterized by cleft palate, hearing loss and skeletal abnormalities in the skull and limbs. OPD type II includes these abnormalities, frequently in a more severe form, as well as growth deficiency and, in a minority of patients, abnormalities of the brain. It is frequently associated with death in infancy.
Individuals with OPD type I typically have mild short stature, an incomplete closure of the roof of the mouth (cleft palate), a downward slant of the opening between the upper and lower eyelids, hearing loss due to a defect of the middle ear (conductive hearing loss) and abnormally shaped fingers and toes. Symptoms that are sometimes seen in people with OPD type I are: short, broad thumbs and great toes; wide spaces between the toes; one or more fingers bent to the side; two or more digits united (syndactyly); short fingernails; dislocation of the head of the radius (one of the bones of the forearm); a broad bridge of the nose; underdeveloped bones of the face; and/or slow speech development. Females with the disorder may have an overhanging brow, a depressed nasal bridge, a wide space between the eyes and a flat midface. The symptoms and signs expressed in females vary and are fewer. Females do not have the full expression of this disorder.
Individuals with OPD type II are more severely affected. Major characteristics in males with this disorder may be a small head, broad forehead, flat bridge of the nose, wide space between the eyes, small mouth, cleft palate, downward slant of the opening between the upper and lower eyelids, small mouth, small jaw, fingers that are bent and overlap, short fingers and toes, curved long bones of the forearms and legs, small chest, heart defects and occasionally intellectual disability. Less common symptoms may include split tongue-tip, clouded eyes and Dandy-Walker malformation (a brain malformation). OPD type II typically results in stillbirth or early infant death in males. Females do not have the full expression of OPD type II and may have mild symptoms such as an arched palate in the mouth, broad face, low-set ears, split uvula (the fleshy lobe in the middle of the back border of the soft palate), hearing loss, fingers bent to the side, short stature and a downward slant of the opening between the upper and lower eyelids.
OPD type I and II are caused by changes (variants) in the FLNA gene on the X chromosome. This gene is responsible for the production of the filamin (FLNA) protein. Different variants in FLNA are responsible for the two syndromes. The filamin protein is normally responsible for helping with the formation and function of the cell’s cytoskeleton, and the gene variants appear to give filamin a new function (referred to as a “gain-of-function” variant) that leads to OPD type I and II.
OPD type I and II are inherited in an X-linked pattern with variable expression in carrier females.
Chromosomes, which are present in the nucleus of human cells, carry genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
X-linked genetic disorders are conditions caused by a disease-causing gene variant on the X chromosome and mostly affect males. Females who have a disease-causing gene variant on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the gene variant. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease-causing gene variant, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the gene variant to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
OPD type 1 and II are rare disorders affecting less than 1 in every 100,000 individuals. The specific incidence for these conditions is unknown.
The diagnosis of OPD type I or II is based on physical features and X-ray findings. Clinical molecular genetic testing for variants in the FLNA gene is available to confirm the diagnosis. Skeletal abnormalities associated with these conditions can sometimes be seen on a prenatal ultrasound exam.
Treatment
Treatment for OPD type I and II is symptomatic. Infants may have difficulty breathing and require long-term respiratory care. Orthopedic and surgical procedures may be used to correct skeletal deformities. Treatment of hearing loss may be limited due to the severity of deformities within the ear.
Genetic counseling is recommended for patients and their family members.
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TEXTBOOKS
Hennekam RCM, Allanson J, Krantz I Otopalatodigital syndrome. in Gorlin’s Syndromes of the Head and Neck Fifth Edition 2010. Oxford University Press.
JOURNAL ARTICLES
Wade EM, Halliday BJ, Jenkins ZA, O’Neill AC, Robertson SP. The X-linked filaminopathies: Synergistic insights from clinical and molecular analysis. Hum Mutat. 2020 May;41(5):865-883. doi: 10.1002/humu.24002. Epub 2020 Mar 11. PMID: 32108395.
Moutton S, Fergelot P, Naudion S, Cordier MP, Solé G, Guerineau E, Hubert C, Rooryck C, Vuillaume ML, Houcinat N, Deforges J, Bouron J, Devès S, Le Merrer M, David A, Geneviève D, Giuliano F, Journel H, Megarbane A, Faivre L, Chassaing N, Francannet C, Sarrazin E, Stattin EL, Vigneron J, Leclair D, Abadie C, Sarda P, Baumann C, Delrue MA, Arveiler B, Lacombe D, Goizet C, Coupry I. Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum. J Hum Genet. 2016;61:693–9.
Murphy-Ryan M, Babovic-Vuksanovic D, Lindor N. Bifid tongue, corneal clouding, and Dandy–Walker malformation in a male infant with otopalatodigital syndrome type 2. Am J Med Genet 2011;155:855–859.
Clark AR, Sawyer GM, Robertson SP, Sutherland-Smith AJ. Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders. Hum Mol Genet 2009;18:4791-4800.
Robertson SP, Twigg SR, Sutherland-Smith AJ, Biancalana V, Gorlin RJ, Horn D, Kenwrick SJ, Kim CA, Morava E, Newbury-Ecob R, Orstavik KH, Quarrell OW, Schwartz CE, Shears DJ, Suri M, Kendrick-Jones J, Wilkie AO; OPD-spectrum Disorders Clinical Collaborative Group. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet. 2003 Apr;33(4):487-91. doi: 10.1038/ng1119. Epub 2003 Mar 3. PMID: 12612583.
Robertson SP, Walsh S, and Oldridge M, et al. Linkage of otopalatodigital syndrome type 2 (OPD2) to distal Xq28: evidence for allelism with OPD1. Am J Hum Genet 2001;69:223-227.
Fitch N, Jequier S, and Papageorgiou A. A familial syndrome of cranial, facial, oral and limb abnormalities. Clin Genet 1977;10:226-231.
INTERNET
Robertson S. X-Linked Otopalatodigital Spectrum Disorders. 2005 Nov 30 [Updated 2019 Oct 3]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1393/ Accessed May 5, 2024.
Otopalatodigital syndrome-1. Online Mendelian Inheritance in Man (OMIM). Updated 08/11/2023. https://omim.org/entry/311300 Accessed May 5, 2024.
Otopalatodigital syndrome-2. Online Mendelian Inheritance in Man (OMIM). Updated 08/08/2023. https://omim.org/entry/304120?search=304120&highlight=304120
Accessed May 5, 2024.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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