Last updated:
8/7/2024
Years published: 2019, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Samantha A. Vergano, MD, FAAP, Attending Physician, Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, Norfolk, VA, for the preparation of this report.
Summary
Bohring-Opitz syndrome (BOS) is a rare genetic disorder that is usually noticeable at birth. It affects an individual’s growth, development and multiple organ systems. People with BOS often have severe growth restrictions, making them quite small. They may have feeding difficulties, distinctive facial features and a red or pink birthmark (nevus flammeus) on their forehead or eyelids, as well as seizures and heart anomalies. A characteristic sign of this condition is known as ‘BOS posture’ where the elbows are bent and wrists angle outwards. Other possible issues include a smaller than average head size (microcephaly), a visible ridge over the forehead (metopic ridge), cleft lip and/or palate, eye abnormalities, recurrent infections and sleep apnea, as well as sleep difficulties. Children with BOS often have severe learning differences, and most do not develop typical speech or walking abilities.
Bohring-Opitz syndrome is caused by changes (variants) in the ASXL1 gene. BOS can theoretically be inherited in an autosomal dominant manner (where there is a 50% chance for each child to inherit the gene variant), but most people with BOS do not reproduce due to developmental and neurological impairments. No cases of an ASXL1 gene variant being passed from parent to child have been reported; all known cases are caused by new (de novo) variants in the affected person.
There are no specific medications or therapies for BOS, but supportive treatments such as physical, occupational and speech therapy, along with managing individual symptoms, are the standard of care. Based on a review of reported case series and case reports, some people with BOS have been able to walk with walkers or braces, but most are unable to walk independently.
Introduction
BOS was first described in 1999 by Bohring and colleagues. Variants in the ASXL1 gene were identified in individuals with BOS features and reported in 2011.
BOS and other conditions caused by variants in ASXL genes can be classified under chromatin modifying disorders (CMD), also called Mendelian disorders of the epigenetic machinery. Variants in these genes affect proteins responsible for chromatin regulation. Chromatin is a mix of DNA and proteins that package DNA into the cell structures called chromosomes.
There are three ASXL genes (ASXL1, ASXL2, ASXL3) and all of them play a critical role in embryonic development. The exact mechanism of action of disease in the ASXL– related disorders remains under investigation.
Signs and symptoms in people affected with BOS are usually present at birth, although not all signs may be immediately apparent. Symptoms can include:
BOS is caused by changes (variants) in the ASXL1 gene.
This gene provides instructions for making a protein that is involved in a process called “chromatin remodeling”. Chromatin is a mix of DNA and proteins that package DNA into the cell structures called chromosomes. The way chromatin is packed into the chromosomes can be adjusted (remodeled) to control how tightly the DNA is wound up. When DNA is tightly packed, the genes are less active (i.e., the gene expression is lower), and when the DNA is loosely packed, the genes are more active (i.e., the gene expression is higher).
The ASXL1 protein has an important function in this chromatin remodeling, regulating many genes, including a group called HOX genes, that are important for development before birth. Depending on when they are needed, the ASXL1 protein can turn these genes on (activate) or off (repress).
In addition, the ASXL1 protein helps to regulate genes by signaling other molecules to add a small chemical group called a methyl group to a specific area near a gene known as the promoter region. The promoter region controls the activity of the gene. When the promoter is methylated, the gene is turned off, and when it is not methylated, the gene is active.
Variants in the ASXL1 gene decrease the amount of functional ASXL1 protein available, which likely results in an abnormal regulation of the activity of HOX genes and other genes during development. As a result, the altered activity of these genes probably leads to the neurological and physical features of this condition.
All people known to have ASXL1 gene variants that cause the disease appear to be spontaneous (de novo) and there are no reported cases that were inherited from a parent. If BOS were inherited, it would likely follow an autosomal dominant pattern, meaning an individual with BOS would have a 50% chance of passing the gene variant that causes the disease to each child.
In some dominant disorders, individuals may have varying signs and symptoms. Therefore, not all individuals with BOS have the same medical issues, although many share similar characteristics. Very rarely, individuals with BOS inherit the ASXL1 gene variant from their unaffected mother, who has the variant only in some cells, including egg cells, but not in other cells. This is known as germline mosaicism.
As of 2023 around 90 cases of BOS were reported in the literature. BOS does not affect one population more than another and males and females are equally affected. There are no specific geographic areas where BOS is more common due to founder variants or inbreeding (consanguinity).
Doctors may suspect BOS based in the characteristic BOS hand and elbow posturing, delayed growth and developmental milestones and characteristic facial features, including the distinctive birthmarks. While these characteristics are classic, BOS should not be excluded based solely on clinical presentation unless there are obvious signs of another condition.
A definitive diagnosis of BOS is made through genetic testing for variants in the ASXL1 gene.
There are currently no definitive treatments, medications or therapies to reverse BOS symptoms as there are no proven treatments to change the ASXL1 gene variants.
Treatment is focused on managing symptoms specific to each individual. Most children benefit from a combination of physical, occupational and speech therapies. They may also benefit from augmented communication devices and other mobility aids, including standers, gait trainers and adaptive strollers.
Children with feeding difficulties may need G-tubes or GJ tubes. Those at risk for recurrent aspiration or who develop lung disease may require a tracheostomy and/or ventilator support.
Children with BOS should receive regular abdominal ultrasounds every three months from birth (or at the time of diagnosis) until eight years to screen for Wilms tumor. It is also recommended to screen for hepatoblastoma. Regular evaluations should focus on growth, feeding, nutrition and management of other complications.
Common respiratory infections in individuals with BOS should be treated aggressively with secretion clearance and appropriate management to reduce complications. All individuals with BOS, unless there is evidence of cellular immunodeficiency, should follow the standard schedule of childhood immunizations, including prophylaxis for RSV if appropriate, and influenza vaccines.
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.
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JOURNAL ARTICLES
Ayoub MC, Anderson JT, Russell BE, Wilson RB. Examining the neurodevelopmental and motor phenotypes of Bohring-Opitz syndrome (ASXL1) and Bainbridge-Ropers syndrome (ASXL3). Front Neurosci. 2023;17:1244176. Published 2023 Nov 6. doi:10.3389/fnins.2023.1244176
Lin I, Wei A, Awamleh Z, et al. Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation. JCI Insight. 2023;8(10):e167744. Published 2023 May 22. doi:10.1172/jci.insight.167744
Russell BE, Kianmahd RR, Munster C, Yu A, Ahad L, Tan WH. Clinical findings in 39 individuals with Bohring-Opitz syndrome from a global patient-driven registry with implications for tumor surveillance and recurrence risk. Am J Med Genet A. 2023;191(4):1050-1058. doi:10.1002/ajmg.a.63125
Balasubramanian M, Willoughby J, Fry AE, Weber A, Firth HV, Deshpande C, Berg JN, Chandler K, Metcalfe KA, Lam W, Pilz D, Tomkins S. Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature. J Med Genet. 2017;54:537–43.
Bruel AL, Bigoni S, Kennedy J, Whiteford M, Buxton C, Parmeggiani G, Wherlock M, Woodward G, Greenslade M, Williams M, St-Onge J, Ferlini A, Garani G, Ballardini E, van Bon B, Acuna-Hidalgo R, Bohring A, Deleuze J, Boland A, Meyer V, Olaso R, Ginglinger E, Study D, Rivière J, Brunner HG, Hoischen A, Newbury-Ecob R, Faivre L, Thauvin-Robinet C, Thevenon J. Expanding the clinical spectrum of recessive truncating mutations of KLHL7 to a Bohring-Opitz-like phenotype. J Med Genet. 2017;54:830–5.
Shashi V, Pena LD, Kim K, Burton B, Hempel M, Schoch K, Walkiewicz M, McLaughlin HM, Cho M, Stong N, Hickey SE, Shuss CM, Freemark MS, Bellet JS, Keels MA, Bonner MJ, El-Dairi M, Butler M, Kranz PG, Stumpel CT, Klinkenberg S, Oberndorff K, Alawi M, Santer R, Petrovski S, Kuismin O, Korpi-Heikkilä S, Pietilainen O, Aarno P, Kurki MI, Hoischen A, Need AC, Goldstein DB, Kortüm F, et al. De novo truncating variants in ASXL2 are associated with a unique and recognizable clinical phenotype. Am J Hum Genet. 2016;99:991–9.
Dangiolo SB, Wilson A, Jobanputra V, Anyane-Yeboa K. Bohring-Opitz Syndrome (BOS) with a New ASXL1 Pathogenic Variant: Review of the Most Prevalent Molecular and Phenotypic Features of the Syndrome. Am J Med Genet Part A. 2015; 167A: 3161-3166.
Russell B, Johnston JJ, Biesecker LG, Kramer N, Pickart A, Rhead W, Tan W-H, Brownstein CA, Kate Clarkson L, Dobson A, Rosenberg AZ, Vergano SAS, Helm BM, Harrison RE, Graham Jr JM. Clinical management of patients with ASXL1 mutations and Bohring–Opitz syndrome, emphasizing the need for Wilms tumor surveillance. Am J Med Genet Part A. 2015;167A:2122–31.
Bohring A, Oudesluijs GG, Grange DK, Zampino G, Thierry P. New Cases of Bohring-Opitz Syndrome, Update, and Critical Review of the Literature. 2006. Am J Med Genet Part A. 140A: 1257-1263.
Bohring A, Silengo M, Lerone M, Superneau DW, Spaich C, Braddock SR, Poss A, Opitz JM. Severe end of Opitz trigonocephaly (C) syndrome or new syndrome? Am J Med Genet. 1999;85:438–46.
INTERNET
Russell B, Tan WH, Graham JM Jr. Bohring-Opitz Syndrome. 2018 Feb 15. 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/NBK481833/ Accessed August 6, 2024.
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