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Last updated: 9/16/2024
Years published: 2015, 2018, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Richard J. Gibbons, MD, MRC, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, for assistance in the preparation of this report.
Summary
ATR-16 syndrome is a rare genetic disorder that occurs when a person loses genetic material from the tip of the short arm (p) of chromosome 16. This loss affects multiple adjacent genes and leads to a variety of symptoms, with the most common being a blood disorder and intellectual disability. The severity of symptoms depends on how much genetic material is missing.
The two primary features of ATR-16 syndrome are a blood disorder known as alpha thalassemia (AT stands for alpha thalassemia in the term ATR-16), a condition affects the production of hemoglobin, the substance in red blood cells that carries oxygen, and intellectual disability. Some affected children may experience developmental and speech delays, as well as seizures. Other common symptoms include a smaller-than-normal head size (microcephaly), clubfeet, growth delays and distinctive facial features.
ATR-16 syndrome is a contiguous gene syndrome, in which the loss of genetic material on chromosome 16 causes the loss of function of several adjacent genes. ATR-16 syndrome occurs as a spontaneous (de novo) event with no previous family history or in parents with a balanced chromosomal translocation that is inherited in an unbalanced manner.
ATR-16 syndrome results from large and variable deletions or rearrangements on chromosome 16, which makes it difficult to define a consistent set of clinical features or a specific โclinical phenotype.โ In simpler terms, because the amount of genetic material lost can differ greatly between individuals, the symptoms and severity of the condition vary widely. This variability means that no single set of symptoms is guaranteed to occur in every person with ATR-16 syndrome. Instead, each child may have a unique combination of characteristics depending on the size and location of the deletion on chromosome 16.
Because these deletions affect many adjacent genes, the disorderโs complexity increases, and itโs often difficult to predict exactly what symptoms will appear.
This lack of consistent features complicates both diagnosis and treatment, as physicians must assess each case individually. Moreover, additional chromosomal abnormalities often coexist with the ATR-16 deletion, further contributing to the wide variability in symptoms. Treatment aims to improve the symptoms.
Introduction
The uncommon combination of alpha thalassemia and intellectual disability was first reported in the medical literature in 1981 by Weatherall, et al. Since that original description, two distinct syndromes have been defined through additional case reports in medical literature. One is alpha thalassemia X-linked intellectual disability or ATR-X syndrome. NORD has a separate report on this disorder in the Rare Disease Database. The other is ATR-16 syndrome, the subject of this report.
ATR-16 syndrome is caused by the loss of genetic material from chromosome 16. This loss can affect multiple genes, leading to a variety of symptoms that can differ widely between individuals. The severity of the symptoms often depends on how much genetic material is lost, with larger deletions generally leading to more noticeable and severe effects.
The wide variety of symptoms, combined with the possibility of other genetic factors influencing the disorder, has prevented doctors from developing a full understanding of the condition. However, what is clear is that the larger the deletion, the more severe the symptoms.
The most common signs and symptoms are:
Other common symptoms may include
In people with larger deletions, these features are more pronounced.
Children with larger deletions may also have skeletal abnormalities, such as:
In boys, genital abnormalities may include:
In rare cases, children with larger deletions may experience more serious health problems. For example, one child with a large deletion developed tuberous sclerosis, a condition that causes benign tumors in various organs, and polycystic kidney disease, where cysts form in the kidneys. These additional conditions were linked to the loss of specific genes (TSC2 and PKD1) from chromosome 16.
Tumor Development
Although extremely rare, tumor development has been reported in two people with ATR-16 syndrome. One child developed osteosarcoma (a type of bone cancer), and a fetus was found to have a neurocytoma (a brain tumor). At present, it is unclear whether these tumors are directly related to ATR-16 syndrome.
ATR-16 syndrome is caused by the loss or deletion of genetic material from chromosome 16, specifically from band 13.3 on the short arm (p) to the end (terminus) of the chromosome. This region contains several adjacent genes, and when they are deleted, it disrupts the function of many of the bodyโs systems.
Human cells typically have 46 chromosomes, which contain our genetic material. Chromosomes are arranged in pairs, numbered 1 through 22, along with two sex chromosomes (X and Y). Males have one X and one Y chromosome, while females have two X chromosomes. Each chromosome has a short arm (designated โpโ) and a long arm (designated โqโ). Chromosomes are further divided into numbered bands. For example, chromosome 16p13.3-pter refers to the section on the short arm of chromosome 16, from band 13.3 to the end of the chromosome.
The loss of genetic material on chromosome 16 includes the loss of multiple genes that are responsible for producing proteins essential to various body functions. When a gene is missing or changed, the protein it codes for may be defective, inefficient, or absent. This can disrupt important biological processes, affecting organs and systems such as the brain, where it leads to intellectual disabilities in ATR-16 syndrome.
The most well-known genetic consequence of ATR-16 syndrome is the loss of the HBA1 and HBA2 genes, which are necessary to produce hemoglobin (the protein in red blood cells that carries oxygen). The deletion of these genes leads to alpha thalassemia, a type of anemia where red blood cells are smaller and carry less hemoglobin.
The intellectual disabilities seen in ATR-16 syndrome are likely caused by the loss of one or more yet-to-be-identified genes located in this same region of chromosome 16. While alpha thalassemia is well understood, the exact functions of other genes in this region are still being studied.
A pure deletion of genetic material from chromosome 16 (referred to as isolated monosomy) is extremely rare. Most individuals with ATR-16 syndrome have additional chromosomal abnormalities, which leads to a broad range of symptoms. This variability makes it challenging to define a consistent clinical picture of the syndrome.
In many patients, the chromosome deletion in ATR-16 occurs spontaneously. This is referred to as a spontaneous (de novo) variant, meaning the deletion happens randomly during early development in the womb. These deletions occur for unknown reasons and are not inherited from the parents. In these families, the parents of the affected child usually have normal chromosomes and a low risk of having another child with the same condition.
In other instances, ATR-16 syndrome can result from a balanced chromosomal rearrangement in one of the parents. A balanced rearrangement, such as a translocation, occurs when parts of chromosomes break off and swap places. No genetic material is lost or gained in this process, so the carrier parent is usually unaffected. However, this rearrangement can increase the risk of having children with unbalanced chromosomes, where extra (trisomic) or missing (monosomic) genetic material may lead to disorders like ATR-16.
The exact number of patients with ATR-16 syndrome is not known, but more than 20 have been documented in the medical literature. Because ATR-16 syndrome presents with a wide variety of symptoms and can be linked to different chromosomal abnormalities, the condition may still be underreported or misdiagnosed. However, the consensus is that it is an extremely rare disorder, with limited patients identified.
ATR-16 syndrome is diagnosed using genetic tests that identify missing parts of chromosome 16. These tests include:
In some patients, a more detailed SNP array or MLPA (Multiplex Ligation-Dependent Probe Amplification) may be used to confirm the diagnosis.
Treatment
There is no cure for ATR-16 syndrome, but treatment focuses on managing the individual symptoms. This often requires a team of specialists, including pediatricians, hematologists and neurologists. Some key aspects of treatment include:
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:
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:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Babbs C, Brown J, Horsley SW, Slater J, Maifoshie E, Kumar S, Ooijevaar P, Kriek M, Dixon-McIver A, Harteveld CL, Traeger-Synodinos J, Wilkie AOM, Higgs DR, Buckle VJ. ATR-16 syndrome: mechanisms linking monosomy to phenotype. J Med Genet. 2020 Jun;57(6):414-421. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279195/
Gibbons RJ. ฮฑ-thalassemia, mental retardation, and myelodysplastic syndrome. Cold Spring Harb Perspect Hed. 2012;2:a011759. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475406/
Gibson WT, Harvard C, Ojao Y, et al. Phenotype-genotype characterization of alpha-thalassemia mental retardation syndrome due to isolated monosomy of 16p13.3. Am J Med Genet A. 2008;146A:225-232. https://www.ncbi.nlm.nih.gov/pubmed/18076105
Harteveld CL, Kriek M, Bijlsma EK, et al. Refinement of the genetic cause of ATR-16. Hum Genet. 2007;122:283-292. https://www.ncbi.nlm.nih.gov/pubmed/17598130
Gallego MS, Zelaya G, Feliu AS, et al. ATR-16 due to a de novo complex rearrangement of chromosome 16. Hemoglobin. 2005;29:141-150. https://www.ncbi.nlm.nih.gov/pubmed/15921166
Holinski-Feder E, Reyniers E, Uhrig S, et al. Familial mental retardation syndrome ATR-16 due to an inherited cryptic subteloric translocation,, t(3;16) (q29;p13.3). Am J Hum Genet. 2000;66:16-25. https://www.ncbi.nlm.nih.gov/pubmed/10631133
Wilkie AO, Buckle VJ, Harris PC, et al. Clinical features and molecular analysis of the alpha thalassemia/mental retardation syndromes. I. Cases due to deletions involving chromosome band 16p13.3. Am J Hum Genet. 1990;46:1112-1126. https://www.ncbi.nlm.nih.gov/pubmed/2339704
INTERNET
Badens C. Alpha-thalassemia-intellectual disability syndrome linked to chromosome 16. Orphanet. January 2020. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=98791 Accessed Sept 16, 2024.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:141750; Last Update: 12/18/2022. Available at: https://omim.org/entry/141750 Accessed Sept 16, 2024.
16p13 deletions. Understanding Chromosome Disorders. UNIQUE. 2007. https://rarechromo.org/media/information/Chromosome%2016/16p13%20deletions%20FTNW.pdf Accessed Sept 16, 2024.
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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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