ATR-16 Syndrome

National Organization for Rare Disorders, Inc.

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Important

It is possible that the main title of the report ATR-16 Syndrome is not the name you expected.

Disorder Subdivisions

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General Discussion

Summary



ATR-16 syndrome is an extremely rare genetic disorder in which affected individuals have a large loss of genetic material (monosomy) on chromosome 16 in which several adjacent genes are lost. Symptoms include intellectual disability, clubfoot, head circumference that is smaller than would be expected based upon an infant's age and gender (microcephaly), and alpha thalassemia, a blood disorder characterized in this disorder by reduced levels of functional hemoglobin. Hemoglobin, a protein that is found in red blood cells, is responsible for carrying oxygen throughout the body via the blood. Some affected infants have distinctive facial features including eyes that are spaced apart farther than usual (hypertelorism), a broad, prominent bridge of the nose, small ears, and a short neck. 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.



Introduction



The uncommon combination of alpha thalassemia and intellectual disability was first reported in the medical literature in 1981 by Dr. Weatherall, et al. Since that original description, two distinct syndromes have been defined through additional case reports in the 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.

Symptoms

Researchers have experienced difficulty establishing a clear syndrome with characteristic or "core" symptoms and much about the disorder is not fully understood. In many cases, there are other chromosomal abnormalities (in addition to the deletion on chromosome 16) and it is difficult to determine what symptoms are associated with what chromosomal abnormality. In addition, the small overall number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Not surprisingly, the specific symptoms and severity of ATR-16 syndrome can vary greatly from one individual to another.



Infants with ATR-16 syndrome have alpha thalassemia a form of anemia associated with abnormally small (microcytic) red blood which do not contain enough functional hemoglobin. Although anemia from various causes can be associated with symptoms for example fatigue, weakness and shortness of breath, in ATR-16 syndrome the anemia is usually mild, asymptomatic and commonly, an incidental finding.



Alpha thalassemia is caused by mutations in two different genes, the HBA1 and the HBA2 genes, which are located on the chromosome 16. All individuals have two copies of each of these genes (for a total of four). Infants with ATR-16 syndrome will have a condition called alpha thalassemia minor or trait because the loss of genetic material on chromosome 16 includes one copy of each of these genes. If they receive a mutation in one of these genes on the other chromosome 16, they will develop a form of alpha thalassemia known as hemoglobin H (HbH) disease. Such individuals usually have mild HbH disease. (NORD has a separate report on alpha thalassemia. For more information, choose "alpha thalassemia" as your search term in the Rare Disease Database.)



Intellectual disability, which often ranges from mild to moderate, also occurs in children with ATR-16 syndrome. Developmental and speech delays become apparent as an affected child ages. Less commonly, seizures have been reported. Head circumference may be smaller than would be expected based upon an infant's age and gender (microcephaly). Growth delays can result in short stature, in which children are shorter than would be expected based upon age and gender.



Infants with ATR-16 syndrome may also have distinctive facial features including eyes that are spaced apart farther than usual (hypertelorism), downward-slanting palpebral fissures (which means the openings between the eyelids slant downward), a broad, prominent bridge of the nose, small ears, receding chin (retrognathia), and a short neck.



Skeletal malformations may occur in some cases including clubfoot (talipes equinovarus) and pinkies that are fixed or "locked" in a bent position. In males certain genital abnormalities may be present such as failure of the testes to descend (cryptorchidism) and the abnormal placement of the urinary opening on the underside of the penis (hypospadias).

Causes

ATR-16 syndrome is caused by the loss or deletion of genetic material affecting multiple genes that are next to (adjacent) to one another on chromosome 16, specifically from band 13.3 on the short arm (p) to the end (terminus) of the chromosome. Chromosomes, which are present in the nucleus of human cells, carry the 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. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 16p13.3-pter" refers to the region on the short arm of chromosome 16 encompassing band 13.3 to the end or terminus.



The loss of genetic material on chromosome 16 includes the loss of multiple genes. Genes provides instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the specific functions of the particular protein, this can affect many organ systems of the body, including the brain.



Alpha thalassemia is caused by the loss of the HBA1 and HBA2 genes. The other genes in this chromosome region and their specific functions have not yet been identified, although the loss of one of these as-yet-unidentified genes most likely causes the intellectual disability associated with the disorder. A pure loss of genetic material (isolated monosomy) on chromosome 16p unassociated with another chromosomal abnormality is extremely rare. Many individuals have an additional chromosomal abnormality or abnormalities, which results in the wide variety of reported symptoms and prevents ATR-16 syndrome from being clearly defined.



In many cases, the deleted section of chromosome 16 appears to result from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically). In such de novo cases, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality.



In other cases, ATR-16 syndrome may be due to a balanced chromosomal rearrangement in one of the parents. In most cases, the parental rearrangement is described as a "balanced translocation." Translocations occur when portions of a chromosome break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. However, no genetic material is gained or lost, only rearranged. If a chromosomal rearrangement is balanced, meaning that it consists of an altered but balanced set of chromosomes, it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier's offspring. Such children may inherit an unaltered set of chromosomes, the same balanced translocation as the parent, or an unbalanced translocation, in which a chromosome has extra (trisomic) or missing (monosomic) genetic material.

Affected Populations

ATR-16 syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder is unknown. Cases may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. More than 20 cases have been reported in the medical literature.

Diagnosis

A diagnosis of ATR-16 syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.

Standard Therapies

Clinical Testing and Workup

Routine cytogenetic studies can be performed to diagnose ATR-16 syndrome when it is associated with a gross chromosomal abnormality such as a translocation but in the case of deletions and subtelomeric translocations such high resolution cytogenetic analysis appears entirely normal. A specific chromosomal study known as G-band analysis, which demonstrates rearranged chromosomal material, can be used to help obtain a diagnosis. Chromosomes may be obtained from a blood sample. During this test the chromosomes are stained so that they can be more easily seen and then are examined under a microscope where the rearranged chromosomes can be detected (karyotyping). To determine the precise breakpoint or to look for a suspected deletion not detected by G-band analysis, a more sensitive test known as fluorescent in situ hybridization (FISH) may be necessary. During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific chromosome allowing researchers to better view that specific region of the chromosome.



As a first line investigation these technologies are being superseded by a newer technique known as chromosomal microarray analysis. During this exam, a person's DNA is compared to the DNA of a person without a chromosomal abnormality (‘control' person). A chromosome abnormality is noted when a difference is found between the DNA samples. Chromosomal microarray analysis allows for the detection of very small changes or alterations.



Treatment

The treatment of ATR-16 syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, hematologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.



Early intervention services during infancy and toddlerhood (before the age of three) are important in ensuring that affected children reach their potential. Special services that may be beneficial during childhood include special remedial education, speech therapy and/or other medical, and social services. An Individualized Family Support Plan (IFSP) may be developed to guide the early intervention process for infants and toddlers with disabilities. An individual education plan (IEP) may be developed to assist children in school if special services are required, or a 504 plan which can ensure that the child receives access to an equal education through accommodations in their learning environment. Such planning is individualized, especially because the degree of intellectual disability is highly variable.



Alpha thalassemia and HbH disease do not require treatment in most cases. It is conceivable with a more severe expression of the disorder, affected individuals may require occasional blood transfusions and/or medications that remove excess iron from the blood (chelators). Additional therapies for ATR-16 syndrome depend upon the specific abnormalities present and generally follow standard guidelines.

Investigational Therapies

Information on current clinical trials is posted on the Internet at <a href="http://www.clinicaltrials.gov">www.clinicaltrials.gov</a>. 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: <a title="prpl@cc.nih.gov" href="mailto:prpl@cc.nih.gov" target="_blank">prpl@cc.nih.gov</a>



For information about clinical trials sponsored by private sources, in the main, contact:



<a href="http://www.centerwatch.com">www.centerwatch.com</a>



For more information about clinical trials conducted in Europe, contact: <a href="https://www.clinicaltrialsregister.eu/">https://www.clinicaltrialsregister.eu/</a>

References

JOURNAL ARTICLES



Gibbons RJ. α-thalassemia, mental retardation, and myelodysplastic syndrome. Cold Spring Harb Perspect Hed. 2012;2:a011759. <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475406/">//www.ncbi.nlm.nih.gov/pmc/articles/PMC3475406/</a>



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. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18076105">//www.ncbi.nlm.nih.gov/pubmed/18076105</a>



Harteveld CL, Kriek M, Bijlsma EK, et al. Refinement of the genetic cause of ATR-16. Hum Genet. 2007;122:283-292. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17598130">//www.ncbi.nlm.nih.gov/pubmed/17598130</a>



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. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15921166">//www.ncbi.nlm.nih.gov/pubmed/15921166</a>



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. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10631133">//www.ncbi.nlm.nih.gov/pubmed/10631133</a>



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. <a href="http://www.ncbi.nlm.nih.gov/pubmed/2339704">//www.ncbi.nlm.nih.gov/pubmed/2339704</a>



INTERNET



Badens C. Alpha-thalassemia-intellectual disability syndrome linked to chromosome 16. Orphanet Encyclopedia, February 2013. Available at: <a href="http://www.orpha.net/">//www.orpha.net/</a> Accessed April 22, 2015.



McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:141750; Last Update:02/16/2012. Available at: <a href="http://omim.org/entry/141750">//omim.org/entry/141750</a> Accessed April 22, 2015.

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For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.