Antley-Bixler Syndrome

Resumen

Antley-Bixler syndrome is a rare genetic disorder that can cause structural changes of the skull, bones of the face and other skeletal abnormalities. The disorder is typically associated with premature closure of joints (cranial sutures) between particular bones of the skull (craniosynostosis). Many affected infants and children also may have a prominent forehead, underdeveloped midfacial regions (midfacial hypoplasia), protruding eyes (proptosis), and low-set ears.

Additional skeletal abnormalities are usually present, such as fusion of certain bones of the arms (e.g., radiohumeral or radioulnar synostosis), long, thin fingers and toes (arachnodactyly), and bowing of the thigh bones. In addition, certain joints in the arms and legs may become permanently flexed or extended in fixed postures (joint contractures), resulting in restricted movements.

Antley-Bixler syndrome can be caused by changes (mutations) in the POR gene and the FGFR2 gene.

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Sinónimos

• ABS
• craniosynostosis, choanal atresia, radial humeral synostosis
• trapezoidocephaly-multiple synostosis syndrome

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Subdivisiones

• ABS1
• ABS2

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Signos y Síntomas

Antley-Bixler syndrome is typically characterized by structural changes of the skull, bones of the face and other skeletal abnormalities. In most affected infants, there is premature closure of the joints (sutures) between different portions of the skull (craniosynostosis) Additional craniofacial abnormalities may include a large, prominent forehead (frontal bossing), underdeveloped middle regions of the face (midfacial hypoplasia); a large nose with a low nasal bridge; protruding eyes (proptosis); and low-set, malformed (dysplastic) ears.

Antley-Bixler syndrome is also characterized by other distinctive skeletal changes. These may include fusion of bones of the arms that are next to each other (adjacent), particularly the forearm bone on the thumb side of the arm (radius) and the long bone of the upper arm (radiohumeral synostosis). In addition, there can be permanent flexion or extension of certain joints in a fixed position (joint contractures), leading to limited movements of the fingers, wrists, ankles, knees, and/or hips. Affected individuals may also have unusually long, thin fingers and toes (camptodactyly), structural changes on the bottom of the feet (“rocker-bottom” feet); or bowing and/or fractures of the thigh bones.

In some affected infants, a bony or thin layer of tissue may block the passageway between the nose and throat (choanal stenosis or atresia), leading to difficulty breathing. If this symptom is not treated promptly early in life, it may cause life-threatening respiratory problems.

Some individuals with Antley-Bixler syndrome may have additional symptoms. These may include certain structural defects of the urinary and genital organs (urogenital defects), inability to produce cholesterol from steroids (impaired steroidogenesis), developmental delay, and intellectual disability. ABS1 is the name given to the subtype that includes genital anomalies and disordered steroidogenesis. ABS1 is also a severe form of cytochrome P450 oxidoreductase deficiency. ABS2 is the name given to the subtype that does not include genital anomalies and disordered steroidogenesis.

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Causas y Herencia

Antley-Bixler syndrome can be caused by mutations in two different genes. ABS1 is associated with mutations in the POR gene and is inherited in an autosomal recessive pattern. This means that a person will have ABS1 when he or she inherits two non-working copies of the POR gene, one from each parent. If an individual receives one working copy of the gene and one not working copy of the gene, the person will be a carrier for the syndrome but will not show symptoms. When both parents are carriers for the syndrome, there is a 25 percent chance the child will have ABS1. Additionally, there is fifty percent chance their child will be carriers of the condition (just like their parents) and a twenty-five percent chance that their child will receive both working copies of the gene. The risk is the same for each pregnancy.

ABS2 is associated with mutations in the FGFR2 gene. In this subtype, the condition is thought to be caused by spontaneous (new) changes of the gene. The condition then may be transmitted in an autosomal dominant pattern in subsequent generations. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

It is important to note that there are a number of syndromes that have been identified which are associated with mutations of the FGFR2 gene including Apert, Crouzon, and Pfeiffer syndromes. (For further information on these disorders, please see the “Related Disorders” section of this report below.)

There have been a few reported cases which show that symptoms similar to Antley-Bixler syndrome may have resulted from maternal use of the antifungal medication (fluconazole) during early pregnancy. There is not a lot of research showing why this medication causes symptoms similar to Antley-Bixler syndrome.

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Frecuencia

This condition has been described in over 30 patients to date. The estimated prevalence for the condition is less than 1 in 1,000,000.

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Enfermedades con síntomas similares

Symptoms of the following disorders can be similar to those of Antley-Bixler syndrome. Comparisons may be useful for a differential diagnosis:

Primary craniosynostosis is a rare disorder of the skull. It occurs when there is an early closure of the bones (sutures) in the skull resulting in an abnormally shaped head. The severity of the symptoms and shape of the skull depend on which skull bones close early. In this condition, the head may be larger than normal due to accumulation of fluid (hydrocephaly) in the skull. (For more information on this disorder, choose “primary craniosynostosis” as your search term in the Rare Disease Database.)

Camptomelic syndrome is a rare congenital skeletal disorder inherited in an autosomal recessive pattern. It is characterized by short stature and structural defects in the long bones of the legs. The bones of the shoulder and the pelvis can also have structural defects. Eleven pairs of ribs instead of the usual twelve may also be present. Respiratory distress due to the underdevelopment of the rib cage is the most serious complication of this condition. (For more information on this disorder, choose “camptomelic” as your search term in the Rare Disease Database.)

Acrocephalosyndactyly syndromes are rare disorders that are characterized by a pointed head caused by the early closure of the bones in the skull. Other physical characteristics may include webbed fingers and other structural changes in the skeleton. Some characteristics of these syndromes are similar to those in Antley-Bixler syndrome.

Apert syndrome is a rare inherited disorder characterized by intellectual disability along with malformations of the head, fingers, and toes. Apert syndrome is also known as acrocephalosyndactyly type I. The head has a long narrow appearance with a pointed top (acrocephaly or oxycephaly) and some fingers may be webbed (syndactyly). Other features may include widely spaced eyes (hypertelorism), a bulging appearance to the eyeballs (exophthalmos), and/or a high pointed palate. (For more information on this disorder, choose “Apert” as your search term in the Rare Disease Database.)

Crouzon disease is a rare inherited disorder characterized by the premature closure of the bones of the skull (craniosynostosis) accompanied by unusual facial features, developmental delay, intellectual disability, and disturbances in vision and hearing. This disorder is also known as acrocephalosyndactyly type II. Other features of this disorder may include widely spaced eyes (hypertelorism), a bulging appearance to the eyeballs (exophthalmos), crossed eyes (strabismus), a beaked nose with a deviated septum, and/or underdevelopment of the jaw (hypoplastic maxilla). Spinal anomalies may also be present. (For more information on this disorder, choose “Crouzon” as your search term in the Rare Disease Database.)

Saethre-Chotzen syndrome is a rare congenital disorder thought to be inherited in an autosomal dominant pattern. This disorder is characterized by various craniofacial and skeletal abnormalities. It is also known as acrocephalosyndactyly type III. Features include a small head (microcephaly), premature closure of the bones of the skull (craniosynostosis), mildly fused webbed fingers and/or toes (syndactyly), droopy eyelids, widely spaced eyes, mild to moderate intellectual disability, and facial abnormalities. (For more information on this disorder, choose “Saethre-Chotzen” as your search term in the Rare Disease Database.)

Pfeiffer syndrome is a rare disorder inherited in an autosomal dominant pattern that primarily affects the bones. This disorder is also known as acrocephalosyndactyly type V. Infants with Pfeiffer syndrome usually have a short, pointed head (acrobrachycephaly) and other deformities of the face, jaws, and teeth. Webbed fingers or toes (syndactyly) and other abnormalities of the thumbs or big toes may also occur. Symptoms can vary from mild to severe. (For more information on this disorder, choose “Pfeiffer” as your search term in the Rare Disease Database.)

Carpenter syndrome is a rare inherited disorder characterized by abnormalities of the head, hands, and genitals. Intellectual disability is also present in children with this disorder. This disorder is also known as acrocephalopolysyndactyly type II. Carpenter syndrome is a form of craniosynostosis, marked by the premature closure of the bones of the skull resulting in an abnormally shaped head. Other features may include down- slanting eyes, a flattened nose, low-set eyes, and an usually small jaw. Obesity and heart anomalies may also occur. (For more information on this disorder, choose “Carpenter” as your search term in the Rare Disease Database.)

Sakati syndrome (also known as acrocephalopolysyndactyly type III) is a rare inherited disorder characterized by an abnormally shaped head and abnormalities of the fingers. Other features include unusually short legs, bowing of the bone that extends from the hips to the knees (femur), underdevelopment of the ears, lack of scalp hair (alopecia), unusually dry skin, failure of the testicles to descend into the scrotum (cryptorchidism), an abnormally small penis (microphallus), and/or congenital heart disease.

Goodman syndrome is a rare inherited disorder of infancy characterized by abnormalities of the head, hands, and genitals. This disorder is also known as acrocephalopolysydactyly type IV and is a mild form of Carpenter syndrome. The head is typically abnormally shaped and the eyes may be low-set. Intellectual disability does not occur and hand deformities are less pronounced than in Carpenter syndrome.

B3GAT3-related disorder is a rare inherited disorder of infancy characterized by many of the same symptoms and signs as Antley-Bixler syndrome. However, this condition is associated with multiple neonatal fractures and cardiovascular abnormalities which are less common in ABS.

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Diagnóstico

The diagnosis of Antley-Bixler syndrome is usually made after birth (postnatally) based upon a thorough clinical evaluation and characteristic physical findings. Other imaging procedures and genetic testing may also be conducted to diagnose the disorder.

In some children, a diagnosis of Antley-Bixler syndrome may be suggested before birth (prenatally) based upon test such as ultrasound. Ultrasound allows us to generate an image of the developing fetus, which may then reveal characteristic findings that are associated with the disorder. If there is a known family history of the condition, targeted genetic testing is available for patient families.

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Tratamiento

Treatment

The treatment of Antley-Bixler syndrome is directed toward the specific symptoms that are seen in each individual. Such treatment requires the coordinated efforts of a team of medical professionals who may need to systematically and comprehensively plan the treatment for a child with this condition. These professionals may include pediatricians, surgeons, physicians who specialize in disorders of specific body areas and organs. In individuals with Antley-Bixler syndrome, treatment typically includes surgery. The surgical procedures performed will depend upon the severity of the skeletal problems and its associated symptoms. It is possible that multiple surgeries will be needed in order to treat the malformations present.

There is no cure for the condition. All treatment is supportive and aimed at managing symptoms. However, early intervention may be important in ensuring that affected children reach their potential. For example, physical therapy is typically recommended to help improve the range of movement at certain joint contractures. Other therapies that may aide in managing symptoms include occupational therapy and speech therapy.

Because this is a genetic condition, individuals with Antley-Bixler syndrome and their families would benefit from meeting with a genetic counselor. Genetic counselors are professionals who have specialized education in genetics and counseling to provide personalized help patients may need as they make decisions about their genetic health.

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Investigaciones

Information on current clinical trials is posted on the Internet at https://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:

Tollfree: (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, contact: https://www.centerwatch.com/

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

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Referencias

TEXTBOOKS

Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 7th ed. New York, NY; Oxford University Press; 2013.

JOURNAL ARTICLES

Yauy K, Mau-Them FT, Willems M, et al. B3GAT3-related disorder with craniosynostosis and bone fragility due to a unique mutation. Genetics in Medicine. 2017;20(2):269-274. doi:10.1038/gim.2017.109

Oldani E, Gare C, Bucourt M and Carbillon L. Prenatal diagnosis of Antley-Bixler syndrome and POR deficiency. American Journal of Case Reports. 2015; 16: 882–885.

McGlaughlin KL, Witherow H, Dunaway DJ, David DJ, Anderson PJ. Spectrum of Antley-Bixler syndrome. Journal of Craniofacial Surgery. 2010;21(5):1560-1564. doi:10.1097/scs.0b013e3181ec6afe.

INTERNET

Idkowiak J, Cragun D, Hopkin RJ, et al. Cytochrome P450 Oxidoreductase Deficiency. 2005 Sep 8 [Updated 2017 Aug 3]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1419/ Accessed May 9, 2019.

Robin NH, Falk MJ, Haldeman-Englert CR. FGFR-Related Craniosynostosis Syndromes. 1998 Oct 20 [Updated 2011 Jun 7]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1455/ Accessed May 9, 2019.

Antley Bixler syndrome. Orphanet. Last update: January 2007. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=83. Accessed May 9, 2019.

Cytochrome P450 oxidoreductase deficiency – Genetics Home Reference – NIH. U.S. National Library of Medicine.Reviewed March 2014. https://ghr.nlm.nih.gov/condition/cytochrome-p450-oxidoreductase-deficiency. Accessed May 9, 2019.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 207410; Updated 04/24/2012Available at: https://www.omim.org/entry/207410 Accessed May 9, 2019.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 201750; 09/07/2016. Available at: https://www.omim.org/entry/201750?search=201750&highlight=201750 Accessed May 9, 2019.

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