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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, a head circumference that is smaller than would be expected based on 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.
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. But it is clear that the larger the loss of genetic material from chromosome 16 the more severe the consequences.
Infants with ATR-16 syndrome have alpha thalassemia a form of anemia associated with abnormally small (microcytic) red blood cells 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 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 who have lost at least 1 Mb of genetic material including 55 genes. Developmental and speech delays become apparent as the affected child ages. Less commonly, seizures have been reported. Head circumference may be smaller than would be expected based on 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 who have larger deletions of genetic material 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).
In one individual with a deletion of at least 2Mb of genetic information associated with an unbalanced chromosomal translocation, the clinical picture is dominated by more severe intellectual disability, tuberous sclerosis (associated with the loss of the gene TSC2), and polycystic kidney disease (associated with loss of the gene PKD1).
Tumor development has been described in two cases with ATR-16; osteosarcoma (bone cancer) was identified in one child and a neurocytoma (brain tumor) was identified in a fetus. It is unclear at present whether the tumor development was directly related to the ATR-16.
ATR-16 syndrome affects the blood, development, and brain; symptoms vary based on the specific genes deleted on chromosome 16. Because it is so rare, it is difficult to determine the “core” symptoms of the disease. People with ATR-16 have alpha-thalassemia, a blood disorder where there is less normal hemoglobin in the blood than there should be, and the red blood cells are smaller than they should be (microcytic anemia). Affected children have various characteristic physical features, including clubfoot, “locked” little fingers, microcephaly (small head), hypertelorism (widely spaced eyes), broad, prominent nose bridge, downward-slanted palpebral fissures, small ears, retrognathia, and short neck. Children with ATR-16 syndrome also have mild to moderate intellectual disabilities, developmental delays/growth delays, and speech delays. Some children with ATR-16 have seizures, cryptorchidism (undescended testes), or hypospadias.[rx][rx][rx]
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 provide 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 a 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 the 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.
Diagnosis
A diagnosis of ATR-16 syndrome is based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests.
Clinical Testing and Workup
Routine cytogenetic studies can be performed to diagnose ATR-16 syndrome when it is associated with a 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 newer techniques. One is known as array comparative genome hybridization (array CGH). 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. Analysis by array CGH or a related approach, SNParray, allow for the detection of very small changes or alterations. An alternative approach is multiple ligation-dependent probe amplification (MLPA).
Though only definitively diagnosable by genetic sequence testing, including a G band analysis, ATR-16 syndrome may be diagnosed from its constellation of symptoms. It must be distinguished from ATR-X syndrome, a very similar disease caused by a mutation on the X chromosome, and cases of alpha-thalassemia that co-occur with intellectual disabilities with no underlying genetic relationship
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 affected child’s treatment. Psychosocial support for the entire family is essential as well.
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. Genetic counseling is recommended for affected individuals and their families.
References
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