The Gale Genetic Disorders of encyclopedia vol 1 - part 6 pps

especially in the knees and shoulders. The joints in an individual with DTD are also prone to partial or complete dislocations in the shoulders, hips, kneecaps, and elbows. Hands and feet The hands of a child with diastrophic dysplasia are distinct. The fingers are short (brachydactyly) and there may be fusion of the joints between the bones of the fingers (symphalangism). The metacarpal bone of the thumb is short and oval-shaped; these bony deformations cause the thumb to deviate away from the hand and assume the appearance of the so-called “hitchhiker thumb,” a classic feature of DTD. The bony changes in the feet are similar to those found in the hands. The great toes may deviate outward, much like the thumbs. Clubfoot deformity (talipes), due to abnormal formation 338 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Diastrophic dysplasia KEY TERMS Amniocentesis—A procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman’s abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus. Cartilage—Supportive connective tissue which cushions bone at the joints or which connects muscle to bone. Chondrocyte—A specialized type of cell that secretes the material which surrounds the cells in cartilage. Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10-12 weeks gesta- tion. Under ultrasound guidance a needle is inserted either through the mother’s vagina or abdominal wall and a sample of cells is collected from around the fetus. These cells are then tested for chromosome abnormalities or other genetic dis- eases. Chromosome—A microscopic thread-like structure found within each cell of the body and consists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities. Cleft palate—A congenital malformation in which there is an abnormal opening in the roof of the mouth that allows the nasal passages and the mouth to be improperly connected. Clubfoot—Abnormal permanent bending of the ankle and foot. Also called talipes equinovarus. Collagen—The main supportive protein of cartilage, connective tissue, tendon, skin, and bone. Deoxyribonucleic acid (DNA)—The genetic material in cells that holds the inherited instructions for growth, development, and cellular functioning. DNA mutation analysis—A direct approach to the detection of a specific genetic mutation or mutations using one or more laboratory techniques. Dysplasia—The abnormal growth or development of a tissue or organ. Epiphyses—The growth area at the end of a bone. Fibroblast—Cells that form connective tissue fibers like skin. Founder effect—increased frequency of a gene mutation in a population that was founded by a small ancestral group of people, at least one of whom was a carrier of the gene mutation. Gene—A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome. Linkage analysis—A method of finding mutations based on their proximity to previously identified genetic landmarks. Metacarpal—A hand bone extending from the wrist to a finger or thumb. Metaphyses—The growth zone of the long bones located between the epiphyses the ends (epiphyses) and the shaft (diaphysis) of the bone. Mutation—A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring. Nanism—Short stature. Sulfate—A chemical compound containing sulfur and oxygen. Vertebra—One of the 23 bones which comprise the spine. Vertebrae is the plural form. and limited mobility of the bones of the feet, is a common birth defect found in newborns with DTD. Diagnosis At birth the diagnosis of diastrophic dysplasia is based on the presence of the characteristic physical and radiologic (x ray) findings. DNA mutation analysis may be helpful in confirmation of a suspected diagnosis. In those rarer cases where DNA mutation analysis does not detect changes, a laboratory test that measures the uptake of sulfate by fibroblasts or chondrocytes may be useful in making a diagnosis. If there is a family history of diastrophic dysplasia and DNA is available from the affected individual, then prenatal diagnosis using DNA methods, either mutation analysis or linkage analysis, may be possible. DNA mutation analysis detects approximately 90% of DTDST mutations in suspected patients. In patients where the mutations are unknown or undetectable, another DNA method known as linkage analysis may be possible and, if so, it can usually distinguish an affected from an unaf- fected pregnancy with at least 95% certainty. In linkage analysis, DNA from multiple family members, including the person with DTD, is required. DNA-based testing can be performed through chorionic villus sampling or through amniocentesis. If DNA-based testing is not possible, prenatal diagnosis of diastrophic dysplasia in an at-risk pregnancy may be made during the second and third trimesters through ultrasound. The ultrasound findings in an affected fetus may include: a small chin (micrognathia), abnormally short limbs, inward (ulnar) deviation of the hands, the “hitchhiker” thumb, clubfeet, joint contractures, and spinal curvature. General population carrier screening is not available except in Finland where the frequency of a single ancestral mutation is high. Treatment and management There is currently no treatment that normalizes the skeletal growth and development in a child with diastrophic dysplasia. The medical management and treatment of individuals with DTD generally requires a multidisciplinary team of specialists that should include experts in orthopedics. At birth it is recommended that a neonatologist be present because of the potential for respiratory problems. Surgery may be indicated in infancy if congenital abnormalities such as open cleft palate and/or clubfoot deformity are present. Throughout childhood and adulthood, bracing, surgery, and physical therapy are measures often used to treat the spinal and joint deformities of DTD. Such measures, however, may not fully correct these deformities. Due to the significant short-limbed short stature associated with diastrophic dysplasia, certain modifica- tions to home, school, and work environments are necessary in order for a person with DTD to perform daily tasks. Occupational therapy may help affected individuals, especially children, learn how to use assistive devices and to adapt to various situations. Prognosis In infancy there is an increased mortality rate, as high as 25%, due to respiratory complications caused by weakness and collapse of the cartilage of the wind pipe (trachea) and/or the voice box (larynx), conditions which may require surgical intervention. Some forms of cleft palate and micrognathia may be life threatening in early life as they can result in respiratory obstruction. Severe spinal abnormalities such as cervical kyphosis may also cause respiratory problems. After the newborn period, the life span of an individual with DTD is usually normal with the exception of those cases where spinal cord compression occurs as a result of severe cervical kyphosis with vertebrae subluxation. Spinal cord compression is a significant medical problem that can lead to muscle weakness, paralysis, or death. In a susceptible individual, spinal cord compression may occur for the first time during surgery due to the hyperextended neck position used during intubation. Other anesthetic techniques may be indicated for such cases. People with diastrophic dysplasia are of normal intelligence and are able to have children. Since many of the abnormalities associated with DTD are relatively resistant to surgery, many individuals with DTD will have some degree of physical handicap as they get older. They may continue to require medical management of their spinal and joint complications throughout adult life. Resources BOOKS Bianchi, Diana W., et al. Fetology: Diagnosis and Management of the Fetal Patient. New York: McGraw-Hill, 2000. Jones, Kenneth Lyons. Smith’s Recognizable Patterns of Human Malformation. Philadelphia: W.B. Saunders Company, 1997. PERIODICALS Makitie, Outi, et al. “Growth in Diastrophic Dysplasia.” The Journal of Pediatrics 130 (1997): 641–6. Remes, Ville, et al. “Cervical Kyphosis in Diastrophic Dysplasia.” Spine 24, no. 19 (1999): 1990–95. Rossi, Antonio, et al. “Mutations in the Diastrophic Dysplasia Sulfate Transporter (DTDST) gene (SLC26A2): 22 Novel GALE ENCYCLOPEDIA OF GENETIC DISORDERS 339 Diastrophic dysplasia Mutations, Mutation Review, Associated Skeletal Phenotypes, and Diagnostic Relevance.” Human Mutation 17 (2001): 159–71. Satoh, Hideshi, et al. “Functional analysis of Diastrophic Dysplasia Sulfate Transporter.” The Journal of Biological Chemistry 273, no. 20 (1998): 12307–15. ORGANIZATIONS National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923 (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. Ͻhttp://www .rarediseases.orgϾ. WEBSITES Diastrophic Help Web Site. Ͻhttp://pixelscapes.com/ddhelp/Ͼ. The Kathryn and Alan C. Greenberg Center for Skeletal Dysplasias Web Page. Ͻhttp://www.med.jhu.edu/ Greenberg.Center/Greenberg.htmϾ. Dawn Cardeiro, MS, CGC Diffuse angiokeratomia see Fabry disease Disorder of cornification 10 see Sjögren Larsson syndrome I Distal arthrogryposis syndrome Definition Distal arthrogryposis syndrome is a rare genetic disorder in which affected individuals are born with a characteristic bending at the joints of the hands and feet. A contracture is the word used to describe what happens at the joints to cause this bending. In addition to contractures of the hand and feet, individuals with distal arthrogryposis are born with a tightly clenched fist and overlapping fingers. Description The word arthrogryposis means a flexed (bent) or curved joint. Distal means the furthest from any one point of reference or something that is remote. Therefore, distal arthrogryposis syndrome causes the joints at the most remote parts of our limbs, the hands and feet, to be flexed. Consistent fetal movement during pregnancy is necessary for the development of the joints. Without regular motion, the joints become tight resulting in contractures. The first cases of arthryogryposis were identified in 1923. Arthryogryposis multiple congenital (AMC) is also referred to as fetal akinesia/hypokinesia sequence that is not a disorder, but describes what happens when there is no fetal movement during fetal development. The reasons for lack of fetal motion include neurologic, muscular, connective tissue, or skeletal abnormalities or intrauter- ine crowding. There are various disorders that involve some form of arthrogryposis. Distal arthrogryposis was identified as a separate genetic disorder in 1982. Two types of distal arthrogryposis have been identified. Type 1 or typical distal arthrogryposis, is used to describe individuals with distal contractures of the hands and feet, characteristic positioning of the hands and feet, and normal intelligence. Type 2 distal arthrogryposis is known as the atypical form. It is characterized by additional birth defects and mild intellectual delays. There are other syndomes which include arthrogryposis, however distal arthrogryposis has been characterized as its own syndrome by its inheritance pattern. In addition to the inheritance pattern, there are other features that differentiate this type of arthrogryposis from other forms. Some of these features include a characteristic position of the hands at birth; the fists are clenched and the fingers are bent and overlapping. In addition, problems with the positioning of the feet, called clubfoot is often seen in these individuals. Another distinguishing characteristic is an extremely wide variability in the severity and number of joint contractures someone may exhibit. This variability is often noticed between two affected individuals from the same family. Genetic profile Distal arthrogryposis syndrome is inherited in an autosomal dominant manner. Autosomal dominant inheritance patterns only require one genetic mutation on one of the chromosome pairs to exhibit symptoms of the disease. Chromosomes are the structures that carry genes. Genes are the blueprints for who we are and what we look like. Humans have 23 pairs, or 46 total chromosomes in every cell of their body. The first 22 chromosomes are numbered 1–22 and are called autosomes. The remaining pair is assigned a letter either an X or a Y and are the sex determining chromosomes. A typical male is described as 46, XY. A typical female is 46, XX. Each parent contributes one of their paired chromosomes to their children. Before fertilization occurs, the father’s sperm cell divides in half and the total number of chromosomes reduces from 46 to 23. The mother’s egg cell undergoes the same type of reduction as well. At the 340 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Distal arthrogryposis syndrome time of conception, each parent contributes 23 chromosomes, one of each pair, to their children. All of the genetic information is contained on each chromosome. If either the father or the mother is affected with distal arthrogryposis, there is a 50% chance they will pass on the chromosome with the gene for this disease to each of their children. The specific gene for distal arthrogryposis is not known, however we do know that it is located on chromosome number 9. The symptoms of distal arthrogryposis can be different between two affected relatives. For example, a mother may have contractures in all of her joints, but her child may only be affected with contractures in the hands. Because of this variability in the symptoms of this disease, it is believed there is more than one gene mutation that causes distal arthrogryposis. As of 2001, the only gene thought to cause this disease is on chromosome number 9. The exact location and type of genetic mutation on chromosome 9 is not known and therefore, the only genetic testing available as of 2001 is research based. Demographics Distal arthrogryposis can affect individuals from all types of populations and ethnic groups. This disease can affect both males and females. There have been only a handful of individuals described with this type of arthrogryposis. The physician, Dr. Hall, who named the disorder in 1982, had initially identified 37 patients with type 1 and type 2 distal arthrogryposis syndrome. She identified 14 individuals with type 1 and 23 individuals with type 2. Since then, numerous other individuals have been diagnosed with distal arthrogryposis. The exact incidence has not been reported in the literature. Signs and symptoms At birth, many individuals have been diagnosed based on their characteristic hand positioning. Virtually all individuals with distal arthrogryposis are born with their hands clenched tightly in a fist. The thumb is turned inwards lying over the palm, called abduction. The fingers are also overlapping on eachother. This hand positioning is also characteristic of a more serious condition called trisomy 18. The majority of patients with distal arthrogryposis will also have problems with the positioning of their feet. Many patients will have some form of clubfoot, where the foot is twisted out of shape or position. Another word for clubfoot is talipes. In addition to the hand and foot involvement, a small percentage of patients will have a dislocation or separa- GALE ENCYCLOPEDIA OF GENETIC DISORDERS 341 Distal arthrogryposis syndrome KEY TERMS Amniotic fluid—The fluid which surrounds a developing baby during pregnancy. Cell—The smallest living units of the body which group together to form tissues and help the body perform specific functions. Flexion—The act of bending or condition of being bent. Inheritance pattern—The way in which a genetic disease is passed on in a family. Neurologic—Pertaining the nervous system. Trisomy 18—A chromosomal alteration where a child is born with three copies of chromosome number 18 and as a result is affected with multiple birth defects and mental retardation. Ultrasound evaluation—A procedure which examines the tissue and bone structures of an individual or a developing baby. tion of the hip joint as well as difficulty bending at the hips and tendency for there to be a slight degree of unnat- ural bending at the hip joints. The knees may also exhibit similar problems of being slightly bent and fixed at that point. Few individuals are born with stiff shoulders. Type 2 distal arthrogryposis syndrome includes other birth defects not seen in type 1 individuals. For example, type 2 distal arthrogryposis involves problems with the closure of the lip called cleft lip or an opening in the roof of the mouth called cleft palate. Other abnormalities seen in type 2 distal arthrogryposis include a small tongue, short stature, a curvature of the spine, more serious joint contractures, and mental delays. Diagnosis The diagnosis of distal arthrogryposis can sometimes be made during pregnancy from an ultrasound evaluation. An ultrasound may detect the characteristic hand finding as well as the flexion deformities of both the hands and the feet. An affected fetus may have difficulty swallowing and this is exhibited on an ultrasound evaluation as extra amniotic fluid surrounding the baby called polyhydramnios. Another very important and specific diagnositic sign for distal arthrogryposis during a pregnancy is no fetal movement. Ultrasound findings have been detected as early as 17 weeks of a pregnancy. After birth, a diagnosis is made by a physician per- forming a physical examination of a baby suspected of having this disorder. If a baby is affected with type 2 distal arthrogryposis, they may have a difficult time eating properly. As of 2001, the only type of genetic testing available is research based. Because there is likely more than one gene that causes the disease, the genetic testing being performed at this time is not yet offered to affected individuals in order to confirm a diagnosis. Treatment and management The treatment for individuals with distal arthrogryposis is adjusted to the needs of the affected child. With therapy after birth to help loosen the joints and retrain the muscles, most individuals do remarkably well. The hands do not remain clenched an entire lifetime, but will even- tually unclench. Sometimes the fingers will remain bent to some degree. Clubfoot can usually be corrected so that the feet can be positioned to be straight. Prognosis The prognosis depends on how severely affected an individual is and how many joints are involved. Some of the more severe cases may be associated with an early death due to sudden respiratory failure and difficulty breathing properly. The majority of individuals with distal arthrogryposis do very well after receiving the necessary therapies and sometimes surgery to correct severe joint contractions. Resources BOOKS Fleischer, A., et al. Sonography in Obstetrics and Gynecology, Principles & Practice. Stamford, Conn.: 1996. Jones, Kenneth. Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia: W.B. Saunders Company, 1997. PERIODICALS Sonoda, T. “Two brothers with distal arthrogryposis, peculiar facial appearance, cleft palate, short stature, hydronephro- sis, retentio testis, and normal intelligence: a new type of distal arthrogryposis?” American Journal of Medical Genetics. (April 2000): 280–85. Wong, V. “The spectrum of arthrogryposis in 33 Chinese children.” Brain Development. (April 1997): 187–96. WEBSITES “Arthrogryposis Multiplex Congenita, Distal, Type 1.” Online Mendelian Inheritance in Man. Ͻhttp://www.ncbi.nlm .gov/Omim/Ͼ. Limb Anomalies. Ͻhttp://www.kumc.edu/gec/support/limb.htmlϾ. Katherine S. Hunt, MS I DNA (deoxyribonucleic acid) Genetics is the science of heredity that involves the study of the structure and function of genes and the methods by which genetic infomation contained in genes is passed from one generation to the next. The modern science of genetics can be traced to the research of Gregor Mendel (1823–1884), who was able to develop a series of laws that described mathematically the way hereditary characteristics pass from parents to offspring. These laws assume that hereditary characteristics are contained in discrete units of genetic material now known as genes. The story of genetics during the twentieth century is, in one sense, an effort to discover the gene itself. An important breakthrough came in the early 1900s with the work of the American geneticist, Thomas Hunt Morgan (1866–1945). Working with fruit flies, Morgan was able to show that genes are somehow associated with the chromosomes that occur in the nuclei of cells. By 1912, Hunt’s colleague, American geneticist A. H. Sturtevant (1891–1970) was able to construct the first chromosome map showing the relative positions of different genes on a chromosome. The gene then had a concrete, physical referent; it was a portion of a chromosome. During the 1920s and 1930s, a small group of scientists looked for a more specific description of the gene by focusing their research on the gene’s molecular composition. Most researchers of the day assumed that genes were some kind of protein molecule. Protein molecules are large and complex. They can occur in an almost infi- nite variety of structures. This quality is expected for a class of molecules that must be able to carry the enor- mous variety of genetic traits. A smaller group of researchers looked to a second family of compounds as potential candidates for the molecules of heredity. These were the nucleic acids. The nucleic acids were first discovered in 1869 by the Swiss physician Johann Miescher (1844–1895). Miescher orig- inally called these compounds “nuclein” because they were first obtained from the nuclei of cells. One of Miescher’s students, Richard Altmann, later suggested a new name for the compounds, a name that better reflected their chemical nature: nucleic acids. Nucleic acids seemed unlikely candidates as molecules of heredity in the 1930s. What was then known about their structure suggested that they were too simple to carry the vast array of complex information needed in a molecule of heredity. Each nucleic acid molecule consists of a long chain of alternating sugar and phosphate fragments to which are attached some sequence of four of five different nitrogen bases: adenine, cytosine, guanine, uracil and thymine (the exact bases found in a molecule depend slightly on the type of nucleic acid). 342 GALE ENCYCLOPEDIA OF GENETIC DISORDERS DNA (deoxyribonucleic acid) It was not clear how this relatively simple structure could assume enough different conformations to “code” for hundreds of thousands of genetic traits. In compari- son, a single protein molecule contains various arrange- ments of twenty fundamental units (amino acids) making it a much better candidate as a carrier of genetic information. Yet, experimental evidence began to point to a possible role for nucleic acids in the transmission of hereditary characteristics. That evidence implicated a specific sub-family of the nucleic acids known as the deoxyribonucleic acids, or DNA. DNA is characterized by the presence of the sugar deoxyribose in the sugar-phosphate backbone of the molecule and by the presence of adenine, cytosine, guanine, and thymine, but not uracil. As far back as the 1890s, the German geneticist Albrecht Kossel (1853–1927) obtained results that pointed to the role of DNA in heredity. In fact, historian John Gribbin has suggested that the evidence was so clear that it “ought to have been enough alone to show that the hereditary information must be carried by the DNA.” Yet, somehow, Kossel himself did not see this point, nor did most of his colleagues for half a century. As more and more experiments showed the connec- tion between DNA and genetics, a small group of researchers in the 1940s and 1950s began to ask how a DNA molecule could code for genetic information. The two who finally resolved this question were a somewhat unusual pair, James Watson, a 24-year old American trained in genetics, and Francis Crick, a 36-year old Englishman, trained in physics and self-taught in chemistry. The two met at the Cavendish Laboratories of Cambridge University in 1951, and became instant friends. They were united by a common passionate belief that the structure of DNA held the key to understanding how genetic information is stored in a cell and how it is transmitted from one cell to its daughter cells. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 343 DNA (deoxyribonucleic acid) G H H Hydrogen bonds 3' 3' 5' 5' 3' 5' 5' 5' 3' 5' 3' 3' P O O O O P O – OO – O – O – O O P O O O P O H OH O O P O O – O O P O O – O OH H H H H H H H H O P O O – O O O P O O – O TA C C G GC CG TA AT A 5' 5' 3' 3' T The structure of a DNA molecule. (Gale Group) In one sense, the challenge facing Watson and Crick was a relatively simple one. A great deal was already known about the DNA molecule. Few new discoveries were needed, but those few discoveries were crucial to solving the DNA-heredity puzzle. Primarily the question was one of molecular architecture. How were the various parts of a DNA molecule oriented in space such that the molecule could hold genetic information? The key to answering that question lay in a technique known as x-ray crystallography. When x rays are directed at a crystal of some material, such as DNA, they are reflected and refracted by atoms that make up the crystal. The refraction pattern thus produced consists of a collec- tion of spots and arcs. A skilled observer can determine from the refraction pattern the arrangement of atoms in the crystal. The technique is actually more complex than described here. For one thing, obtaining satisfactory x-ray patterns from crystals is often difficult. Also, inter- preting x-ray patterns—especially for complex molecules like DNA—can be extremely difficult. Watson and Crick were fortunate in having access to some of the best x-ray diffraction patterns that then existed. These “photographs” were the result of work being done by Maurice Wilkins and Rosalind Elsie Franklin at King’ s College in London. Although Wilkins and Franklin were also working on the structure of DNA, they did not recognize the information their photographs contained. Indeed, it was only when Watson accidentally saw one of Franklin’s photographs that he suddenly saw the solution to the DNA puzzle. Racing back to Cambridge after seeing this photograph, Watson convinced Crick to make an all-out attack on the DNA problem. They worked continuously for almost a week. Their approach was to construct tinker- toy-like models of the DNA molecule, shifting atoms around into various positions. They were looking for an arrangement that would give the kind of x-ray photograph that Watson had seen in Franklin’s laboratory. Finally, on March 7, 1953, the two scientists found the answer. They built a model consisting of two helices (corkscrew-like spirals), wrapped around each other. Each helix consisted of a backbone of alternating sugar and phosphate groups. To each sugar was attached one of the four nitrogen bases, adenine, cytosine, guanine, or thymine. The sugar-phosphate backbone formed the out- side of the DNA molecule, with the nitrogen bases tucked inside. Each nitrogen base on one strand of the molecule faced another nitrogen base on the opposite strand of the molecule. The base pairs were not arranged at random, however, but in such a way that each adenine was paired with a thymine, and each cytosine with a guanine. The Watson-Crick model was a remarkable achieve- ment, for which the two scientists won the 1954 Nobel Prize in Chemistry. The molecule had exactly the shape and dimensions needed to produce an x-ray photograph like that of Franklin’s. Furthermore, Watson and Crick immediately saw how the molecule could “carry” genetic information. The sequence of nitrogen bases along the molecule, they said, could act as a genetic code. A sequence, such as A-T-T-C-G-C-T . . . etc., might tell a cell to make one kind of protein (such as that for red hair), while another sequence, such as G-C-T-C-T-C-G . . . etc., might code for a different kind of protein (such as that for blonde hair). Watson and Crick themselves contributed to the deciphering of this genetic code, although that process was long and difficult and involved the efforts of dozens of researchers over the next decade. Watson and Crick had also considered, even before their March 7th discovery, what the role of DNA might be in the manufacture of proteins in a cell. The sequence that they outlined was that DNA in the nucleus of a cell might act as a template for the formation of a second type of nucleic acid, RNA (ribonucleic acid). RNA would then leave the nucleus, emigrate to the cytoplasm and then itself act as a template for the production of protein. That theory, now known as the Central Dogma, has since been largely confirmed and has become a crit- ical guiding principal of much research in molecular biology. Scientists continue to advance their understanding of DNA. Even before the Watson-Crick discovery, they knew that DNA molecules could exist in two configurations, known as the “A” form and the “B” form. After the Watson-Crick discovery, two other forms, known as the “C” and “D” configurations, were also discovered. All four of these forms of DNA are right-handed double helices that differ from each other in relatively modest ways. In 1979, however, a fifth form of DNA known as the “Z” form was discovered by Alexander Rich and his colleagues at the Massachusetts Institute of Technology. The “Z” form was given its name partly because of its zig-zag shape and partly because it is different from the more common A and B forms. Although Z-DNA was first rec- ognized in synthetic DNA prepared in the laboratory, it has since been found in natural cells whose environment is unusual in some respect or another. The presence of certain types of proteins in the nucleus, for example, can cause DNA to shift from the B to the Z conformation. The significance and role of this most recently discovered form of DNA remains a subject of research among molecular biologists. Judyth Sassoon, ARCS, PhD 344 GALE ENCYCLOPEDIA OF GENETIC DISORDERS DNA (deoxyribonucleic acid) I Donohue syndrome Definition Donohue syndrome, also formerly called leprechaunism, is a genetic disorder caused by mutations in the insulin receptor gene. W. L. Donohue first described this rare syndrome in 1948. Description Donohue syndrome is a disorder that causes low birth weight, unusual facial features, and failure to thrive in infants. Donohue syndrome is associated with the over-development of the pancreas, a gland located near the stomach. It is also considered to be the most insulin resistant form of diabetes. Donohue syndrome results from a mutation of the insulin receptor gene which prevents insulin in the blood from being processed. Therefore, even before birth, the fetus exhibits “insulin resistance” and has high levels of unprocessed insulin in the blood. Insulin is one of two hormones secreted by the pancreas to control blood sugar (glucose) levels. Donohue syndrome is known as a pro- gressive endocrine disorder because it relates to the growth and functions of the endocrine system, the col- lection of glands and organs that deliver hormones via the bloodstream. Hormones are chemicals released by the body to control cellular function (metabolism) and maintain equi- librium (homeostasis). These hormones are released either by the endocrine system or by the exocrine system. The endocrine system consists of ductless glands that secrete hormones into the bloodstream. These hormones then travel through the blood to the parts of the body where they are required. The exocrine system consists of ducted glands that release their hormones via ducts directly to the site where they are needed. The pancreas is both an endocrine and an exocrine gland. As part of the endocrine system, the pancreas acts as the original pro- ducer of estrogen and other sex hormones in fetuses of both sexes. It also regulates blood sugar through its production of the hormones insulin and glucagon. The pancreas releases insulin in response to high levels of glucose in the blood. Glucagon is released when glucose levels in the blood are low. These two hormones act in direct opposition to each other (antagonistically) to maintain proper blood sugar levels. As an exocrine gland, the pancreas secretes digestive enzymes directly into the small intestine. In an attempt to compensate for the high blood insulin level, the pancreas overproduces glucagon as well as the female hormone estrogen and other related (estro- genic) hormones. As excess estrogen and related hormones are produced, they affect the development of the external and internal sex organs (genitalia) of the growing baby. Insulin mediates the baby’s growth in the womb through the addition of muscle and fat. A genetic link between fetal insulin resistance and low birthweight has been suggested. Without the proper processing of insulin, the fetus will not gain weight as fast as expected. Therefore, the effects of Donohue syndrome tend to become visible during the seventh month of development when the fetus either stops growing entirely or shows a noticeable slowdown in size and weight gain. This lack of growth is further evident at birth in affected infants, who demonstrate extreme thinness (emaciation), difficulty gaining weight, a failure to thrive, and delayed maturation of the skeletal structure. Genetic profile Donohue syndrome is a non-sex-linked (autosomal) recessive disorder. In 1988, Donohue syndrome was identified as the first insulin receptor gene mutation directly related to a human disease. The gene responsible for the appearance of Donohue syndrome is the insulin receptor gene located at 19p13.2. Over 40 distinct mutations of this gene have been identified. Besides Donohue syndrome, other types of non-insulin-dependent (Type II) diabetes mellitus (NIDDM) can result from mutations of this gene, including Rabson-Mendenhall syndrome and type A insulin resistance. Demographics Donohue syndrome occurs in approximately one out of every four million live births. As in all recessive genetic disorders, both parents must carry the gene mutation in order for their child to have the disorder. Therefore, Donohue syndrome has been observed in cases where the parents are related by blood (consanguineous). Parents with one child affected by Donohue syndrome have a 25% likelihood that their next child will also be affected with the disease. Signs and symptoms Infants born with Donohue syndrome have characteristic facial features that have been said to exhibit “elfin” or leprechaun-like qualities, such as: a smallish head with large, poorly developed and low-set ears; a flat nasal ridge with flared nostrils, thick lips, a greatly exag- gerated mouth width, and widely spaced eyes. They will be very thin and have low blood sugar (hypoglycemia) due to their inability to gain nutrition through insulin pro- GALE ENCYCLOPEDIA OF GENETIC DISORDERS 345 Donohue syndrome cessing. They will exhibit delayed bone growth and maturation, and difficulty in gaining weight and developing (failure to thrive). Donohue syndrome patients are prone to persistent and recurrent infections. Delayed bone growth not only leads to skeletal abnormalities, it also leads to a compro- mised immune system. Many of the chemicals used by the body to fight infection are produced in the marrow of the bones. When bone maturation is delayed, these chemicals are not produced in sufficient quantities to fight off or prevent infection. At birth, affected individuals can also have an enlarged chest, with possible breast development, excessive hairiness (hirsutism), as well as overdeveloped external sex organs, because of increased estrogen production caused by an overactive pancreas. As an additional side effect of the increased sex hormones released in Donohue syndrome, these individuals often have extremely large hands and feet relative to their non-affected peer group. As the result of a lack of insulin, the infant is likely to have a relatively small amount of muscle mass, very little fat, and a distended abdomen (due to malnutrition). Additional symptoms of Donohue syndrome include pachyderma, or elephant skin, in which there is excess skin production causing large, loose folds; and abnormal coloration (pigmentation) of the skin. These individuals are also quite susceptible to both umbilical and inguinal hernias. In addition to the defect in the insulin receptor gene, Donohue syndrome is associated with problems in the epidermal growth factor receptor, which controls growth of the skin. An abnormal functioning of the epidermal growth factor receptor has been identified in three unre- lated individuals affected with Donohue syndrome. This suggests that the probable cause of leprechaunism is more than just the insulin receptor. These observations may help explain the physical symptom of pachyderma in those affected with Donohue syndrome. It has also been suggested that the high concentrations of insulin close to the cell membranes lead to receptor activity at these loca- 346 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Donohue syndrome KEY TERMS Autosomal—Relating to any chromosome besides the X and Y sex chromosomes. Human cells contain 22 pairs of autosomes and one pair of sex chromosomes. Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10-12 weeks gesta- tion. Under ultrasound guidance a needle is inserted either through the mother’s vagina or abdominal wall and a sample of cells is collected from around the fetus. These cells are then tested for chromosome abnormalities or other genetic dis- eases. Consanguineous—Sharing a common bloodline or ancestor. Endocrine system—A system of ductless glands that regulate and secrete hormones directly into the bloodstream. Fibroblast—Cells that form connective tissue fibers like skin. Hirsutism—The presence of coarse hair on the face, chest, upper back, or abdomen in a female as a result of excessive androgen production. Histologic—Pertaining to histology, the study of cells and tissues at the microscopic level. Hypoglycemia—An abnormally low glucose (blood sugar) concentration in the blood. Insulin—A hormone produced by the pancreas that is secreted into the bloodstream and regulates blood sugar levels. Insulin receptor gene—The gene responsible for the production of insulin receptor sites on cell surfaces. Without properly functioning insulin receptor sites, cells cannot attach insulin from the blood for cellular use. Insulin resistance—An inability to respond normally to insulin in the bloodstream. Insulin-like growth factor I—A hormone released by the liver in response to high levels of growth hormone in the blood. This growth factor is very similar to insulin in chemical composition; and, like insulin, it is able to cause cell growth by causing cells to undergo mitosis (cell division). Pachyderma—An abnormal skin condition in which excess skin is produced that appears similar to that of an elephant (pachyderm). Pancreas—An organ located in the abdomen that secretes pancreatic juices for digestion and hormones for maintaining blood sugar levels. Serological—Pertaining to serology, the science of testing blood to detect the absence or presence of antibodies (an immune response) to a particular antigen (foreign substance). tions. This lowered growth hormone activity, in turn, causes slowed cellular growth which leads to systemic growth failure in affected patients. Diagnosis In families with a history of the disease, diagnosis in utero before birth of the fetus is possible through molecular DNA analysis of tissue samples from the chorionic villi, which are cells found in the placenta. After birth, the diagnosis of Donohue syndrome is usually made based on the blood tests that show severe insulin resistance coupled with hypoglycemia. The presence of sev- eral of the physical symptoms listed above in addition to positive results in a test for severe insulin resistance, such as an insulin receptor defect test or a fasting hypoglycemia test, is usually sufficient for a diagnosis of Donohue syndrome. The diagnosis of Donohue syndrome may be confirmed by observed cellular (histologic) changes in the ovaries, pancreas, and breast that are not normal for the age of the patient. Treatment and management Genetic counseling of parents with a Donohue syndrome affected child may help prevent the conception of additional children affected with this genetic disorder. After birth, affected infants may require treatment for malnutrition as well as insulin resistant diabetes. Patients with a demonstrated residual insulin receptor function may survive past infancy. In these cases, the treatment regimen must certainly include on-going insulin resistant diabetes care and dietetic counseling to assist with weight gain. It may also be necessary to administer growth hormone therapy to certain patients to spur growth, but this is only indicated in those individuals who show signs of functioning growth hormone recep- tors and no signs of higher than normal resistance to growth hormone. The revolutionary impact of recombinant DNA technology, whereby scientists can mass produce genetic material for use in medicine, has made possible another treatment method which involves the introduction of recombinant human insulin-like growth factor 1 (rhIGF- 1) into the body. A case study has been reported of a female affected with Donohue syndrome and low levels of insulin-like growth factor 1 (IGF-1), which is indica- tive of a higher than normal resistance to growth hormone. Examination of the patient’s fibroblasts showed normal binding of IGF-1 and normal functioning of these fibroblasts in response to IGF-1. Fibroblasts are connective tissue cells that accomplish growth in humans by dif- ferentiating into chondroblasts, collagenoblasts, and osteoblasts, all of which are the precursor cells necessary to produce bone growth in humans. This case report indi- cates that if enough IGF-1 could get to the fibroblasts in the patient’s body, there is every reason to believe that these fibroblasts would function normally and mature into the precursor cells needed for bone growth. This finding made the patient an ideal candidate for rhIGF-1 treatments. The long- and short-term effects on growth patterns and glucose metabolism in the patient were studied after the treatment with recombinant human insulin-like growth factor 1 (rhIGF-1). The rhIGF-1 that was not immediately utilized by the patient was rapidly destroyed in the cellular conditions produced by Donohue syndrome. Therefore, to maintain the desired levels of rhIGF-1 in the blood, the patient received rhIGF-1 both in injection form prior to every meal and via a continuous subcutaneous infusion method similar to that used to continuously pump insulin for some patients with diabetes. Recombinant human IGF-1 was administered to this patient over a period of six years with an observation of normal blood glucose levels and a return to normal growth patterns. Moreover, the treatment did not cause negative side effects. The results of this case study offer a promising new treatment for certain individuals affected with Donohue syndrome. As of 2001, other clinical studies of treatments with rhIGF-1 are in progress. Prognosis Individuals born with Donohue syndrome generally die in infancy from either malnutrition or recurrent and persistent infection. All individuals affected with Donohue syndrome that survive past infancy have severe mental retardation and profound motor skill impairment. Survival into childhood is thought to be due to some remaining insulin receptor function and the ability of extremely high insulin concentrations to transmit signals through alternate pathways. Resources PERIODICALS Desbois-Mouthon, C., et al. “Molecular analysis of the insulin receptor gene for prenatal diagnosis of leprechaunism in two families.” Prenatal Diagnosis (July 1997): 657–63. Hattersley, A. “The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease.” Lancet (May 1999): 1789–92. Nakae, J., et al. “Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism.” Journal of Clinical Endocrinology and Metabolism (February 1998): 542–9. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 347 Donohue syndrome [...]... Ectodermal Dysplasias PO Box 11 4, 410 E Main, Mascoutah, IL 62 25 8- 011 4 ( 61 8 ) 56 6- 2 020 Fax: ( 61 8 ) 56 6- 4 718 Ͻhttp://www.nfed.orgϾ National Organization for Rare Disorders (NORD) PO Box 8923, New Fairfield, CT 06 812 -8 923 (203) 74 6- 6 518 or (800) 99 9 -6 67 3 Fax: (203) 74 6- 6 4 81 Ͻhttp://www rarediseases.orgϾ Judy C Hawkins, MS Dysplasia giantism syndrome X-linked (DGSX) see Simpson-Golabi-Behmel syndrome I Dystonia... Chicago, IL 60 6 01 ( 312 ) 75 5- 019 8 Ͻhttp://www.dystonia-foundation.orgϾ National Institute of Neurological Disorders and Stroke 31 Center Drive, MSC 2540, Bldg 31, Room 88 06, Bethesda, MD 20 814 (3 01) 49 6- 5 7 51 or (800) 35 2-9 424 Ͻhttp://www.ninds.nih.govϾ National Organization for Rare Disorders (NORD) PO Box 8923, New Fairfield, CT 06 812 -8 923 (203) 74 6- 6 518 or (800) 99 9 -6 67 3 Fax: (203) 74 6- 6 4 81 Ͻhttp://www... Quarterly (September 19 99) Hattori, M., A Fujiyama, D Taylor, H Watanabe, et al The DNA sequence of human chromosome 21. ” Nature (18 May 2000): 311 19 National Down Syndrome Society 66 6 Broadway, New York, NY 10 012 -2 317 ( 212 ) 46 0-9 330 or (800) 2 2 1- 460 2 Fax: ( 212 ) 97 9-2 873 Ͻhttp://www.ndss.org info@ndss.orgϾ WEBSITES Down Syndrome Health Issues Ͻhttp://www.ds-health.com/Ͼ (15 February 20 01) Down Syndrome... of Linkage of Duane’s Syndrome and Refinement of the Disease Locus to an 8.8-cM Interval on Chromosome 2q 31. ” Human Genetics 10 6 (2000): 63 6–38 ORGANIZATIONS American Association for Pediatric Ophthalmology and Strabismus Ͻhttp://med-aapos.bu.edu/Ͼ Genetic Alliance 43 01 Connecticut Ave NW, #404, Washington, DC 2000 8-2 304 (800) 3 3 6- GENE (HelpGALE ENCYCLOPEDIA OF GENETIC DISORDERS line) or (202) 96 6- 5 557... 96 6- 5 557 Fax: (888) 39 4-3 937 info @geneticalliance Ͻhttp://www.geneticalliance.orgϾ March of Dimes Birth Defects Foundation 12 75 Mamaroneck Ave., White Plains, NY 10 60 5 (888) 66 3-4 63 7 or ( 914 ) 42 8- 710 0 resourcecenter@modimes.org Ͻhttp://www modimes.orgϾ National Eye Institute National Institutes of Health 31 Center Dr., Bldg 31, Rm 6A32, MSC 2 510 , Bethesda, MD 2089 2-2 510 (3 01) 49 6- 5 248 2020@nei.nih.gov... Cheshire, CW 1 -6 UR UK 12 7 025 02 21 Fax: 087 0-7 70 0-3 27 Ͻhttp://www.climb.org.ukϾ National Center for Biotechnology Information National Library of Medicine, Building 38A, Room 8N805, Bethesda, MD 20894 (3 01) 49 6- 2 475 Ͻhttp://www.ncbi nlm.nih.govϾ National Organization for Rare Disorders (NORD) PO Box 8923, New Fairfield, CT 06 812 -8 923 (203) 74 6- 6 518 or (800) 99 9 -6 67 3 Fax: (203) 74 6- 6 4 81 Ͻhttp://www rarediseases.orgϾ... opening of the uterus to retrieve a small sample of the placenta (the organ that attaches the growing baby to the mother via the umbilical cord, and provides oxygen and nutrition) In amniocentesis, a small 3 51 Down syndrome Down Syndrome Family Robertsonian Translocation Heart disease Down syndrome d.40y 3 d .62 y Heart attack 2 2 29y 4y 31y 36y 2y 1y 9y 46, XX, der (14 ; 21) (q10;q10), + 21 34y 3y 46, XX, der (14 ; 21) ... Craniofacial Association PO Box 280297, Dallas, TX 7524 3-4 522 (972) 99 4-9 902 or (800) 53 5-3 64 3 contactcca@ccakids.com Ͻhttp://www.ccakids.comϾ FACES: The National Craniofacial Assocation PO Box 11 082, Chattanooga, TN 374 01 (423) 266 -1 6 32 or (800) 3322373 faces@faces-cranio.org Ͻhttp://www.faces-cranio org/Ͼ Greenberg Center for Skeletal Dysplasias 60 0 North Wolfe St., Blalock 10 12C, Baltimore, MD 212 8 7-4 922... Ͻhttp://www.muscular-dystrophy.orgϾ Muscular Dystrophy Family Foundation 61 5 North Alabama St., Ste 330, Indianapolis, IN 462 04 -1 2 13 ( 317 ) 63 28255 or (800) 544 -1 2 13 mdff@prodigy.net Ͻhttp://www mdff.orgϾ Parent Project for Muscular Dystrophy Research 10 12 N University Blvd., Middletown, OH 45042 ( 413 ) 42 4-0 69 6 or (800) 714 -5 437 parentproject@aol.com Ͻhttp://www parentdmd.orgϾ WEBSITES Addresses of Muscular... Blalock 10 12C, Baltimore, MD 212 8 7-4 922 ( 410 ) 61 4 -0 977 Ͻhttp://www.med.jhu.edu/Greenberg.Center/ Greenbrg.htmϾ Johns Hopkins University-McKusick Nathans Institute of Genetic Medicine 60 0 North Wolfe St., Blalock 10 08, Baltimore, MD 212 8 7-4 922 ( 410 ) 95 5-3 0 71 Little People of America, Inc National Headquarters, PO Box 745, Lubbock, TX 79408 (8 06) 73 7- 818 6 or (888) LPA20 01 lpadatabase@juno.com Ͻhttp://www.lpaonline . as a genetic code. A sequence, such as A-T-T-C-G-C-T . . . etc., might tell a cell to make one kind of protein (such as that for red hair), while another sequence, such as G-C-T-C-T-C-G . (770) 60 4-9 500 or (800) 23 2 -6 372. Fax: (770) 60 4-9 898. ndsccenter@aol.com. Ͻhttp://www.ndsccenter .orgϾ. National Down Syndrome Society. 66 6 Broadway, New York, NY 10 012 -2 317 . ( 212 ) 46 0-9 330. small GALE ENCYCLOPEDIA OF GENETIC DISORDERS 3 51 Down syndrome Down Syndrome Chromosomal Sporadic trisomy 21 d .63 y 3 2 42y50y 17 y 11 y 4y P Melanoma Stomach cancer 47,XY,+ 21 (Gale Group) amount of the

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