Otopalatodigital Syndrome Type I and II

Disease Overview

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.

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Synonyms

• cranioorodigital syndrome
• faciopalatoosseous syndrome
• FPO
• OPD syndrome
• Taybi syndrome

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Subdivisions

• OPD syndrome, type I
• OPD syndrome, type II

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Signs & Symptoms

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.

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Causes

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.

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Affected populations

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.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of otopalatodigital syndrome type I and II. Comparisons may be useful for a differential diagnosis:

Craniometaphyseal dysplasia is a rare genetic disorder that is characterized by head and facial differences, hearing loss and bone deformities of the legs. The nose is small with narrow nasal passages and the eyes are widely spaced and bulging. The limbs may be affected by a hardening or broadening of the shaft of the long bones close to the growth center. Craniometaphyseal dysplasia is usually inherited as an autosomal dominant pattern but may also be inherited in a recessive pattern. (For more information on this disorder, choose “craniometaphyseal” as your search term in the Rare Disease Database.)

Frontometaphyseal dysplasia is a rare genetic disorder characterized by coarse facial features that include a wide nasal bridge, widely spaced eyes, overgrowth of the bone over the eyes, a small jawbone and incomplete development of the sinuses. Multiple deformities of the teeth and bones may also be present. Occasionally intellectual disability may occur. This condition is very similar to OPD type 1 and since some individuals also have variants in FLNA it can be difficult to differentiate the two. Two other forms of frontometaphyseal dysplasia have autosomal dominant inheritance.

Larsen syndrome is a multi-system genetic disorder that is present at birth. It is characterized by multiple joint dislocations and other skeletal abnormalities, a high arch of the foot, non-tapering cylindrically shaped fingers and facial differences. Some patients have short stature, heart problems, cleft palate or lips and deafness. This disorder is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Larsen” as your search term in the Rare Disease Database.)

Oral-facial-digital syndrome is a rare genetic disorder in which there have been ten types identified. Symptoms common to all types include episodes of neuromuscular disturbances, split tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue, a broad based nose, vertical folds of the skin covering the inner angle where the eyelids meet (epicanthic folds), more than the normal number of fingers and/or toes, shorter than normal fingers and/or toes and more than the normal number of divisions between skull sections. (For more information on this disorder, choose “Oral-facial-digital syndrome” as your search term in the Rare Disease Database).

Osteopetrosis is a rare genetic bone disorder inherited in an autosomal dominant or autosomal recessive pattern. Initial symptoms of the dominant form may include bone fragility leading to easy fractures and unusual dental problems. Bone pain may occur in the spine and cranial nerves may be affected. Some vision abnormalities or facial palsy may also be symptomatic of the dominant form. (For more information on this disorder choose “osteopetrosis” as your search term in the Rare Disease Database.)

Melnick-Needles syndrome is a rare genetic disorder of bone characterized by skeletal abnormalities and a specific facial appearance. It is found only in females. The skeletal abnormalities include bowing of long bones, S-curved leg bones, ribbon-like ribs and a hardening of the skull base. The typical facial features include prominent, protruding eyes, full cheeks, an extremely small lower jaw and a hairy forehead. The condition may affect many bones of the body causing deformity and, in some people, short stature. MNS is inherited in an X-linked dominant pattern and is also caused by variants in FLNA. (For more information on this disorder choose “Melnick-Needles” as your search term in the Rare Disease Database).

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Diagnosis

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.

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Standard Therapies

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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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

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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