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Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

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drome. NS1 has been called Male Turner syndrome because so many features overlap between NS1 and Turner syndrome. The striking difference between the two conditions is that Turner syndrome is caused by a chromosome abnormality, and affects females only. In contrast, men and women are affected with Noonan syndrome equally.

Individuals with NS1 may often have a heart defect, pulmonic stenosis, found at birth. A chest wall abnormality is common, typically with pectus carinatum at the upper portion (near the neck) and pectus excavatum below it, creating a “shield-like” appearance. Developmental delays are sometimes a part of the condition.

Facial features such as a tall forehead, wide-set eyes, low-set ears, and a short neck are common. Young children with NS1 often have very obvious facial features, and may have a “dull” facial expression, similar to conditions caused by muscle weakness. However, facial features may change over time, and adults with Noonan syndrome often have more subtle facial characteristics. This makes the face a less obvious clue of the condition in older individuals. Other associated features in NS1 are smaller genitalia in males, as well as cryptorchidism. Some individuals with the condition develop thrombocytopenia, or a low number of blood platelets, as well as other problems with normal blood coagulation (clotting).

Another type of the condition is Noonan syndrome, Type 2 (NS2). This involves the same characteristic features as Type 1, but the inheritance pattern is proposed as recessive, rather than the more commonly seen dominant pattern.

The final type of the syndrome is neurofibromatosisNoonan syndrome, also known as Noonan-neurofibro- matosis syndrome, and neurofibromatosis with Noonan Phenotype. In this, individuals often have some features of both neurofibromatosis and NS1. It has been proposed that this may simply be a chance occurrence of two conditions. This is because these conditions have two distinct gene locations, with no apparent overlap.

Genetic profile

In 1994, Ineke van der Burgt and others discovered the gene for Noonan syndrome located on chromosome 12, on the q (large) arm. They found this through careful studies of a large Dutch family, as well as 20 other smaller families, all with people affected by Noonan syndrome. As of 2001, research studies are taking place to further narrow down the gene location. It is proposed to be at 12q24 (band 24 on the q arm of chromosome 12).

Historically, NS1 has been inherited in an autosomal dominant manner, and this is still the most common

inheritance pattern for the condition. This means that an affected individual has one copy of the mutated gene, and has a 50% chance to pass it on to each of his or her children, regardless of that child’s gender. As of 2000, about half of people with Noonan syndrome have a family history of it. For the other half, the mutated gene presumably occurred as a new event in their conception, so they would likely be the first person in their family to be diagnosed with the condition.

New studies have identified evidence for other inheritance patterns. van der Burgt and Brunner studied four Dutch individuals with Noonan syndrome and their families and proposed an autosomal recessive form of the condition, NS2. In autosomal recessive conditions individuals may be carriers, meaning that they carry a copy of a mutated gene. However, carriers often do not have symptoms of the condition. Someone affected with an autosomal recessive condition has two copies of a mutated gene, having inherited one copy from their mother, and the other from their father. Thus, only two carrier parents can have an affected child. For each pregnancy that two carriers have together, there is a 25% chance for them to have an affected child, regardless of the child’s gender. Consanguineous parents (those that are blood-related to each other) are more likely (when compared to unrelated parents) to have similar genes. Therefore, two consanguineous parents may have the same abnormal genes, which together may result in a child with a recessive condition. The hallmark feature of the families in the Dutch study is that the parents of the affected children were consanguineous, making an autosomal recessive form of Noonan syndrome a possibility.

Demographics

As of 2001, Noonan syndrome is thought to occur between one in 1,000 to one in 2,500 live births. There appears to be no ethnic bias in Noonan syndrome, though many studies have arisen from Holland, Canada, and the United States.

Signs and symptoms

Occasionally, feeding problems may occur in infants with Noonan syndrome, because of a poor sucking reflex. Short stature by adulthood is common, though birth length is typically normal. Developmental delays may become apparent because individuals are slower to attain milestones, such as sitting and walking. Behavioral problems may be more common, but often are not significant enough for medical attention. Heart defects are common, with pulmonary stenosis being the most common defect. Muscle weakness is sometimes present, as is increased

syndrome Noonan

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K E Y T E R M S

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.

Café-au-lait spots—Birthmarks that may appear anywhere on the skin; named after the French coffee drink because of the light-brown color of the marks.

Cryptorchidism—A condition in which one or both testes fail to descend normally.

Cystic hygroma—An accumulation of fluid behind the fetal neck, often caused by improper drainage of the lymphatic system in utero.

Karyotype—A standard arrangement of photographic or computer-generated images of chromosome pairs from a cell in ascending numerical order, from largest to smallest.

Neurofibromatosis—Progressive genetic condition often including multiple café-au-lait spots, multiple raised nodules on the skin known as neurofibromas, developmental delays, slightly larger head sizes, and freckling of the armpits, groin area, and iris.

Nystagmus—Involuntary, rhythmic movement of the eye.

Pectus carinatum—An abnormality of the chest in which the sternum (breastbone) is pushed outward. It is sometimes called “pigeon breast.”

Pectus excavatum—An abnormality of the chest in which the sternum (breastbone) sinks inward; sometimes called “funnel chest.”

Phenotype—The physical expression of an individuals genes.

Pterygium colli—Webbing or broadening of the neck, usually found at birth, and usually on both sides of the neck.

Pulmonary stenosis—Narrowing of the pulmonary valve of the heart, between the right ventricle and the pulmonary artery, limiting the amount of blood going to the lungs.

Strabismus—An improper muscle balance of the ocular musles resulting in crossed or divergent eyes.

Suture—“Seam” that joins two surfaces together.

Turner syndrome—Chromosome abnormality characterized by short stature and ovarian failure, caused by an absent X chromosome. Occurs only in females.

flexibility of the joints. Less common neurologic complications may include schwannomas, or growths (common in neurofibromatosis) of the spinal cord and brain. These schwannomas may also occur in the muscle.

Many facial features are found in Noonan syndrome, often involving the eyes. Eyes may be wide-set, may appear half-closed because of droopy eyelids, and the corners may turn downward. Some other findings, such as nystagmus and strabismus may occur. Interestingly, most people with Noonan syndrome have beautiful pale blueor green-colored eyes. Often, the ears are low-set (lower than eye-level), and the top portion of cartilage on the ear is folded down more than usual. Hearing loss may occur, most often due to frequent ear infections. A very high and broad forehead is very common. An individual’s face may take on an inverted triangular shape. As mentioned earlier, facial features may change over time. An infant may appear more striking than an adult does, as the features may gradually become less obvious. Sometimes, studying childhood photographs of an individual’s presumably “unaffected” parents may reveal clues. Parents

may have more obvious features of the condition in their childhood photographs.

As of 2001, chest wall abnormalities such as a shield chest, pectus carinatum, and pectus excavatum occur in 90-95% of people with NS1. These are thought to occur because of early closure of the sutures underneath these areas. Additionally, widely-spaced nipples are not uncommon. Scoliosis (curving of the spine) may occur, along with other spine abnormalities.

Lymphatic abnormalities may be common, often due to abnormal drainage or blockage in the lymph glands. This may cause lymphedema, or swelling, in the limbs. Lymphedema may occur behind the neck (often prenatally) and this is thought to be the cause of the broad/webbed neck in the condition. Prenatal lymphedema is thought to obstruct the proper formation of the ears, eyes, and nipples as well, causing the mentioned abnormalities in all three.

Individuals with Noonan syndrome may have problems with coagulation, shown by abnormal bleeding or

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mild to severe bruising. von Willebrand disease and abnormalities in levels of factors V, VIII, XI, XII, and protein C (all proteins involved in clotting of blood) are common, alone or in combination. These problems may lessen as the person ages, even though the mentioned coagulation proteins may still be present in abnormal amounts. Rarely, some forms of leukemia and other cancers occur.

Kidney problems are often mild, but can occur. The most common finding is a widening of the pelvic (cupshaped) cavity of the kidney. In males, smaller penis size and cryptorchidism are sometimes seen. Cryptorchidism may lead to improper sperm formation in these men, although sexual function is typically normal. It is not as common to see an affected man have a child with Noonan syndrome, and this is probably due to cryptorchidism. Puberty may be delayed in some women with NS1, but fertility is not usually compromised.

Lastly, follicular keratosis is common on the face and joints. It is a set of dark birthmarks that often show up during the first few months of life, typically along the eyebrows, eyes, cheeks, and scalp. Generally, it progresses until puberty, then stops. Sometimes it may leave scars, which may prevent hair growth in those areas. café-au-lait spots can occur, not unlike those seen in neurofibromatosis.

Diagnosis

As of 2001, there are no molecular or biochemical tests for Noonan syndrome, which would aid in confirming a diagnosis. Therefore, it is a clinical diagnosis, based on findings and symptoms. The challenge is that there are several conditions that mimic Noonan syndrome. If a female has symptoms, a chromosomal study is crucial to determine whether she has Turner syndrome, as she would have a missing X chromosome. Other chromosomal conditions that are similar include trisomy 8p (three copies of the small arm of chromosome 8) and trisomy 22 mosaicism (mixed cell lines with some having three copies of chromosome 22). A karyotype would help to rule these out.

An extremely similar condition is Cardio-facio-cuta- neous syndrome (CFC), which has similar facial features, short stature, lymphedema, developmental delays, as well as similar heart defects and skin findings. It has been debated as to whether CFC and NS1 are the same condition. The most compelling argument that they are two, distinct condition lies with the fact that all cases of CFC are sporadic (meaning there is no family history), whereas NS1 may often be seen with a family history.

Other similar conditions include Watson and multiple lentigines/LEOPARD syndrome, as they are associated with pulmonary stenosis, wide-set eyes, chest

deformities and mental delays. Careful study would identify Noonan syndrome from these.

Most individuals are diagnosed with NS1 in childhood, however some signs may present in late stages of a pregnancy. Lymphedema, cystic hygroma, and heart defects can sometimes be seen on a prenatal ultrasound. With high-resolution technology, occasionally some facial features may be seen as well. After such findings, an amniocentesis would typically be offered (as Turner syndrome would also be suspected) and a normal karyotype would further suspicion of NS1.

Treatment and management

Treatment is very symptom-specific, as not everyone will have the same needs. For short stature, some individuals have responded to growth hormone therapy. The exact cause of the short stature is not well defined, and therapies are currently being studied. Muscle weakness and early delays often necessitate an early intervention program, which combines physical, speech, and occupational therapies. Heart defects need to be closely followed, and treatment can sometimes include beta-blockers or surgeries, such as opening of the pulmonary valve. For individuals with clotting problems, aspirin and medications containing it should be avoided, as they prevent clotting. Treatments using various blood factors may be necessary to help with proper clotting. Drainage may be necessary for problematic lymphedema, but it is rare. Cryptorchidism may be surgically corrected, and testosterone replacement should be considered in males with abnormal sexual development. Back braces may be needed for scoliosis and other skeletal problems. Unfortunately, medications such as creams for the follicular keratosis are usually not helpful. Developmental delays should be assessed early, and special education classes may help with these. In summary, these various treatment modalities require careful coordination, and many issues are lifelong. A team approach may be beneficial.

Prognosis

Prognosis for Noonan syndrome is largely dependent on the extent of the various medical problems, particularly the heart defects. Individuals with a severe form of the condition may have a shorter life span than those with a milder presentation. In addition, presence of mental deficiency in 25% of individuals affects the long term prognosis.

Resources

ORGANIZATIONS

The Noonan Syndrome Support Group, Inc. c/o Mrs. Wanda Robinson, PO Box 145, Upperco, MD 21155.(888)

syndrome Noonan

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686-2224 or (410) 374-5245. andar@bellatlantic.net.http://www.noonansyndrome.org .

WEBSITES

“Noonan Syndrome.” Ability.http://www.ability.org.uk/Noonan_Syndrome.html .

“Noonan Syndrome.” Family Village.http://www.familyvillage.wisc.edu/lib_noon.htm

“Noonan Syndrome.” Pediatric Database.http://www.icondata.com/health/pedbase/files/ NOONANSY.HTM

Deepti Babu, MS

Norman-Landing disease see GM1 gangliosidosis

I Norrie disease

Definition

Norrie disease (ND) is a severe form of blindness that is evident at birth or within the first few months of life and may involve deafness, mental retardation, and behavioral problems.

Description

ND was first described in the 1920s and 1930s as an inherited form of blindness affecting only males. Recognizable changes in certain parts of the eye were identified that lead to a wasting away or shrinking of the eye over time.

At birth, a grayish yellow, tumor-like mass is observed to cover or replace the retina of the eye, whereas the remainder of the eye is usually of normal shape, size, and form. Over time, changes in this mass and progressive deterioration of the lens, iris, and cornea cause the eye to appear milky in color and to become very small and shrunken. ND is always present in both eyes and although some abnormalities in the eye develop later, blindness is often present at birth. Some degree of mental retardation, behavior problems, and deafness may also occur.

ND is inherited in an X-linked recessive manner and so it affects only males. The gene for ND was found in the 1990s and genetic testing is available in the year 2001.

ND has also been referred to as:

Norrie-Warburg syndrome

Atrophia bulborum hereditaria

Congenital progressive oculo-acoustico-cerebral degeneration

Episkopi blindness

Pseudoglioma congenita

Genetic profile

It has been known for several years by the analysis of many large families, that ND is an inherited condition that affects primarily males. Mothers of affected males do not show any symptoms of the disease. From this observation it was suspected that a gene on the X chromosome was responsible for the occurrence of ND. Genetic studies of many families led to the identification of a gene, named NDP (Norrie Disease Protein), located at Xp11. This means the gene is found on the shorter or upper arm of the X chromosome. NDP, a very small gene, was determined to produce a protein named norrin. The function of the norrin protein is not well understood. Preliminary evidence suggests that norrin plays a role in directing how cells interact and grow to become more specialized (differentiation).

Many different kinds of mistakes have been described in the NDP gene that are thought to lead to ND. The majority of these genetic mistakes or mutations alter a single unit of the genetic code and are called point mutations. Most of the identified point mutations are unique to the family studied. Few associations between the type of point mutation and severity of disease have been described. Other occasional errors in the NDP gene are called deletions, which permanently remove a portion of the genetic code from the gene. Individuals with deletions in the NDP gene are thought to have a more severe form of ND that usually includes profound mental retardation, seizures, small head size, and growth delays.

The X chromosome is one of the human sex chromosomes. A human being has 23 pairs of chromosomes in nearly every cell of their body. One of each kind (23) is inherited from the mother and another of each kind (23) is inherited from the father, which makes a total of 46. The twenty-third pair is the sex chromosome pair. Females have two X chromosomes and males have an X and a Y chromosome. Females therefore have two copies of all genes on the X chromosome but males have only one copy. The genes on the Y chromosome are different than those on the X chromosome. Mothers pass on either one of their X chromosomes to all of their children and fathers pass on their X chromosome to their daughters and their Y to their sons.

Males affected with ND have a mutation in their only copy of the NDP gene on their X chromosome and therefore do not make any normal norrin protein. Mothers of such affected males are usually carriers of

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ND; they have one NDP gene with a mutation and one that is normal. As they have one normal copy of the NDP gene, they usually have a sufficient amount of the norrin protein so that they do not show signs of ND. Women that are carriers for ND have a 50% chance of passing the disease gene onto each of their children. If that child is male, he will be affected with ND. If that child is female, she will be a carrier of ND but not affected. Affected males that have children would pass on their disease gene to all of their daughters who would therefore be carriers of ND. Their sons inherit their Y chromosome and, therefore, would not inherit the gene for ND.

Genetic testing for mutations in the NDP gene is clinically available to help confirm a diagnosis of ND. As of the year 2001, this testing is able to identify gene mutations in about 70% of affected males. If such a mutation were found in an affected individual, accurate carrier testing would be available for females in that family. Additionally, diagnosis of a pregnancy could be offered to women who are at risk for having sons with ND.

Demographics

ND has been observed to affect males of many ethnic backgrounds and no ethnic group appears to predominate. The incidence is unknown, however.

K E Y T E R M S

Cataract—A clouding of the eye lens or its surrounding membrane that obstructs the passage of light resulting in blurry vision. Surgery may be performed to remove the cataract.

Cochlea—A bony structure shaped like a snail shell located in the inner ear. It is responsible for changing sound waves from the environment into electrical messages that the brain can understand, so people can hear.

Cornea—The transparent structure of the eye over the lens that is continous with the sclera in forming the outermost, protective, layer of the eye.

Iris—The colored part of the eye, containing pigment and muscle cells that contract and dilate the pupil.

Lens—The transparent, elastic, curved structure behind the iris (colored part of the eye) that helps focus light on the retina.

Retina—The light-sensitive layer of tissue in the back of the eye that receives and transmits visual signals to the brain through the optic nerve.

Signs and symptoms

The first sign of ND is usually the reflection of a white area from within the eye, which gives the appearance of a white pupil. This is caused by a mass or growth behind the lens of the eye that covers the retina. This mass tends to grow and cause total blindness. It may also develop blood vessels that may burst and further damage the eye. At birth the iris, lens, cornea and globe of the eye are generally otherwise normal. The problems in the retina evolve over the first few months and until about ten years of age progressive changes in other parts of the eye develop. Cataracts form and the iris is observed to stick or be attached to the cornea and/or the lens of the eye. The iris will also often decrease in size. Pressure in the fluid within the eye may increase, which can be painful. The retina often becomes detached and may become thickened. Toward the end stages of the disease, the eye globe is seen to shrink considerably in size and appear sunken within the eye socket. The above findings affect both eyes and the changes are usually the same in each eye.

Approximately 50% of affected males have some degree of developmental delay or mental retardation. Some may show behavioral problems or psychosis-like features. Hearing loss may develop in 30–40% of males with ND starting in early childhood. If speech is devel-

oped before the onset of deafness, it is usually preserved. Mental impairment and hearing loss do not necessarily occur together. The role that the norrin protein plays in causing mental impairment and hearing loss is unknown.

Much variability in the expression of ND within a family as well as between families has been observed. On rare occasion, carrier females may show some of the retinal problems, such as retinal detachment, and may have some degree of vision loss.

Diagnosis

The diagnosis of ND is usually made by clinical examination of the eye by a specialist called an ophthalmologist. Gene testing can be pursued as well, keeping in mind that as many as 30% of affected males cannot be identified using current methods.

The symptoms of ND have considerable overlap with a few other eye diseases and ND must be distinguished from the following conditions:

Persistent hyperplastic primary vitreous (PHPV)

Familial exudative vitroeretinopathy (FEVR)

Retinoblastoma (RB)

Retinopathy of prematurity (ROP)

disease Norrie

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Incontinentia pigmenti type 2 (IP2) The first two diseases have been shown to also be associated with mutations in the NDP gene and may represent a more mild condition in the broad spectrum of ND.

Treatment and management

Since the symptoms of ND are often present at birth, little can be done to change them or prevent the disease from progressing. If the retina is still attached to the back of the eye, surgery or laser therapy may be helpful. An ophthalmologist should follow all children with ND to monitor the changes in the disease, including the pressure within the eye. Occasionally, surgery may be necessary. Rarely, the eye is removed because of pain.

The child’s hearing should also be monitored regularly so that deafness can be detected early. For individuals with hearing loss, hearing aids are usually quite successful. Cochlear implants may be considered when hearing aids are not helpful in restoring hearing.

Developmental delays or mental retardation as well as lifelong behavioral problems can be a continuous challenge. Educational intervention and therapies may be helpful and can maximize a person’s educational potential.

Prognosis

The lifespan of an individual with ND may be within the normal range. Risks associated with deafness, blind-

ness, and mental retardation, including injury or illness, might shorten the lifespan. General health, however, is normal.

Resources

ORGANIZATIONS

American Council of the Blind. 1155 15th St. NW, Suite 720, Washington, DC 20005. (202) 467-5081 or (800) 4248666. http://www.acb.org .

American Society for Deaf Children. PO Box 3355, Gettysburg, PA 17325. (800) 942-ASDC or (717) 3347922 v/tty. http://www.deafchildren.org/asdc2k/home/ home.shtml .

National Association of the Deaf. 814 Thayer, Suite 250, Silver Spring, MD 20910-4500. (301) 587-1788. nadinfo @nad.org. http://www.nad.org .

National Federation for the Blind. 1800 Johnson St., Baltimore, MD 21230. (410) 659-9314. epc@roundley.com.http://www.nfb.org .

Norrie Disease Association. Massachusetts General Hospital, E #6217, 149 13th St., Charlestown, MA 02129. (617) 7265718. sims@helix.mgh.harvard.edu.

WEBSITES

Sims, Katherine B., MD. “Norrie Disease.” [July 19, 1999]. GeneClinics. University of Washington, Seattle.http://www.geneclinics.org/profiles/norrie/details

.html .

Jennifer Elizabeth Neil, MS, CGC

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O

Obesity-hypotonia syndrome see Cohen syndrome

Oculo-auriculo-vertebral spectrum see

Goldenhar syndrome

Oculocerebrorenal syndrome of Lowe see

Lowe syndrome

I Oculo-digito-esophago-

duodenal syndrome

Definition

Oculo-digito-esophago-duodenal syndrome (ODED) is a rare genetic disorder characterized by multiple conditions including various hand and foot abnormalities, small head (microcephaly), incompletely formed esophagus and small intestine (esophageal/duodenal atresia), an extra eye fold (short palpebral fissures), and learning disabilities.

Description

Individuals diagnosed with oculo-digito-esophago- duodenal syndrome usually have a small head (microcephaly), fused toes (syndactyly), shortened fingers (mesobrachyphalangy), permanently outwardly curved fingers (clinodactyly), an extra eyelid fold (palpebral fissures), and learning delays. Other features can include backbone abnormalities (vertebral anomalies), an opening between the esophagus and the windpipe (tracheoesophageal fistula), and/or an incompletely formed esophagus or intestines (esophageal or duodenal atresia). The syndrome was first described by Dr. Murray Feingold in 1975. The underlying cause of the different features of ODED is not fully understood. ODED is also

known as Feingold syndrome, Microcephaly, mental retardation, and tracheoesophageal fistula syndrome, and Microcephaly, Mesobrachyphalangy, Microcephaly- oculo-digito-esophago-duodenal (MODED) syndrome, Tracheo-esophagael fistula syndrome (MMT syndrome).

Genetic profile

The genetic cause of oculo-digito-esophago-duode- nal syndrome is not fully understood. One study published in 2000 located an inherited region on the short arm of chromosome 2 that appears to cause ODED when mutated. However, it is still not clear if the features of ODED are caused by a single mutation in one gene or the deletion of several side-by-side genes (contiguous genes). Additionally, since this study is the first published molecular genetic study that has determined a specific location for ODED, it is unknown if most cases of ODED are caused by a mutation in this area or if ODED can be caused by genes at other locations as well.

Although the specific location and cause of ODED is not fully determined, it is known that ODED is inherited in families through a specific autosomal dominant pattern. Every individual has approximately 30,000-35,000 genes which tell their bodies how to form and function. Each gene is present in pairs, since one is inherited from their mother and one is inherited from their father. In an autosomal dominant condition, only one non-working copy of the gene for a particular condition is necessary for a person to experience symptoms of the condition. If a parent has an autosomal dominant condition, there is a 50% chance for each child to have the same or similar condition. Thus, individuals inheriting the same nonworking gene in the same family can have very different symptoms. For example, approximately 28% of individuals affected by ODED have esophageal or duodenal atresia while hand anomalies are present in almost 100% of affected individuals. The difference in physical findings within the same family is known as variable penetrance or intrafamilial variability.

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K E Y T E R M S

Contiguous gene syndrome—A genetic syndrome caused by the deletion of two or more genes located next to each other.

Variable penetrance—A term describing the way in which the same mutated gene can cause symptoms of different severity and type within the same family.

Demographics

Oculo-digito-esophago-duodenal syndrome is a rare genetic condition. As of 2000, only 90 patients affected by ODED have been reported in the literature. However, scientists believe that ODED has not been diagnosed in many affected individuals and suggest that ODED is more common than previously thought. The ethnic origin of individuals affected by ODED is varied and is not specific to any one country or group.

Signs and symptoms

The signs and symptoms of oculo-digito-esophago- duodenal syndrome vary from individual to individual. Most (86-94%) individuals diagnosed with ODED have a small head (microcephaly) and finger anomalies such as shortened fingers (mesobrachyphalangy), permanently curved fingers (clinodactyly), and/or missing fingers. Over half of affected individuals also have fused toes (syndactyly). Between 45% and 85% of individuals affected by ODED have developmental delays and/or mental retardation. Other features can include an extra eyelid fold (palpebral fissures), ear abnormalities/hearing loss, kidney abnormalities, backbone abnormalities (vertebral anomalies), an opening between the esophagus and the windpipe (tracheoesophageal fistula) and/or an incompletely formed esophagus, or intestines (duodenal atresia seen in 20-30%).

Diagnosis

Diagnosis of oculo-digito-esophago-duodenal syndrome is usually made following a physical exam by a medical geneticist using x rays of the hands, feet, and back.

Prenatal diagnosis of ODED can sometimes be made using serial, targeted level II ultrasound imaging, a technique that can provide pictures of the fetal head size, hands, feet, and digestive tract. Ultrasound results indicative of ODED include a “double bubble” sign suggesting incompletely formed intestines (duodenal atresia) and

small head size (microcephaly). Diagnosis by ultrasound before the baby is born is difficult. Prenatal molecular genetic testing is not available as of 2001.

Treatment and management

Since oculo-digito-esophago-duodenal syndrome is a genetic disorder, no specific treatment is available to remove, cure, or fix all conditions associated with the disorder. Treatment for ODED is mainly limited to the treatment of specific symptoms. Individuals with incompletely formed intestinal and esophageal tracts would need immediate surgery to try and extend and open the digestive tract. Individuals with learning difficulties or mental retardation may benefit from special schooling and early intervention programs to help them learn and reach their potential.

Prognosis

Oculo-digito-esophago-duodenal syndrome results in a variety of different physical and mental signs and symptoms. Accordingly, the prognosis for each affected individual is very different.

Individuals who are affected by physical hand, head, or foot anomalies (with no other physical or mental abnormalities) have an excellent prognosis and most live normal lives.

Babies affected by ODED who have incomplete esophageal or intestinal tracts will have many surgeries and prognosis depends on the severity of the defect and survival of the surgeries.

Resources

BOOKS

Children with Hand Differences: A Guide for Families. Area Child Amputee Center Publications. Center for Limb Differences in Grand Rapids, MI, phone: 616-454-4988.

PERIODICALS

Piersall, L. D., et al. “Vertebral anomalies in a new family with ODED syndrome.” Clinical Genetics 57 (2000): 4444448.

ORGANIZATIONS

Cherub Association of Families & Friends of Limb Disorder Children. 8401 Powers Rd., Batavia, NY 14020. (716) 762-9997.

EA/TEF Child and Family Support Connection, Inc. 111 West Jackson Blvd., Suite 1145, Chicago, IL 60604-3502. (312) 987-9085. Fax: (312) 987-9086. eatef2@aol.com.http://www.eatef.org/ .

WEBSITES

OMIM—Online Mendelian Inheritance of Man.

http://www3.ncbi.nlm.nih.gov/Omim/ .

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Reach. http://www.reach.org.uk .

The Family Village. http://www.familyvillage.wisc.edu .

Dawn A. Jacob, MS

Okihiro syndrome see Duane retraction syndrome

Olfactogenitalis of DeMorsier see Kallmann syndrome

I Oligohydramnios sequence

Definition

Oligohydramnios sequence occurs as a result of having very little or no fluid (called amniotic fluid) surrounding a developing fetus during a pregnancy. “Oligohydramnios” means that there is less amniotic fluid present around the fetus than normal. A “sequence” is a chain of events that occurs as a result of a single abnormality or problem. Oligohydramnios sequence is therefore used to describe the features that a fetus develops as a result of very low or absent amount of amniotic fluid. In 1946, Dr. Potter first described the physical features seen in oligohydramnios sequence. Because of his description, oligohydramnios sequence has also been known as Potter syndrome or Potter sequence.

Description

During a pregnancy, the amount of amniotic fluid typically increases through the seventh month and then slightly decreases during the eighth and ninth months. During the first 16 weeks of the pregnancy, the mother’s body produces the amniotic fluid. At approximately 16 weeks, the fetal kidneys begin to function, producing the majority of the amniotic fluid from that point until the end of the pregnancy. The amount of amniotic fluid, as it increases, causes the space around the fetus (amniotic cavity) to expand, allowing enough room for the fetus to grow and develop normally.

Oligohydramnios typically is diagnosed during the second and/or third trimester of a pregnancy. When the oligohydramnios is severe enough and is present for an extended period of time, oligohydramnios sequence tends to develop. There are several problems that can cause oligohydramnios to occur. Severe oligohydramnios can develop when there are abnormalities with the fetal renal system or when there is a constant leakage of amni-

otic fluid. Sometimes, the cause of the severe oligohydramnios is unknown.

Approximately 50% of the time, fetal renal system abnormalities cause the severe oligohydramnios, resulting in the fetus developing oligohydramnios sequence. This is because if there is a problem with the fetal renal system, there is the possibility that not enough amniotic fluid is being produced. Renal system abnormalities that have been associated with the development of oligohydramnios sequence include, the absence of both kidneys (renal agenesis), bilateral cystic kidneys, absence of one kidney with the other kidney being cystic, and obstructions that blocks the urine from exiting the renal system. In a fetus affected with oligohydramnios sequence, sometimes the renal system abnormality is the only abnormality the fetus has. However, approximately 54% of fetuses with oligohydramnios sequence due to a renal system abnormality will have other birth defects or differences with their growth and development. Sometimes the presence of other abnormalities indicates that the fetus may be affected with a syndrome or condition in which a renal system problem can be a feature. Renal system abnormalities in a fetus can also be associated with certain maternal illnesses, such as insulin dependant diabetes mellitus, or the use of certain medications during a pregnancy.

Severe oligohydramnios can also develop even when the fetal renal system appears normal. In this situation, often the oligohydramnios occurs as the result of chronic leakage of amniotic fluid. Chronic leakage of amniotic fluid can result from an infection or prolonged premature rupture of the membranes that surround the fetus (PROM). In chronic leakage of amniotic fluid, the fetus still produces enough amniotic fluid, however, there is an opening in the membrane surrounding the fetus, causing the amniotic fluid to leak out from the amniotic cavity.

Genetic profile

The chance for oligohydramnios sequence to occur again in a future pregnancy or in a family member’s pregnancy is dependant on the underlying problem or syndrome that caused the oligohydramnios sequence to develop. There have been many fetuses affected with oligohydramnios sequence where the underlying cause of the severe oligohydramnios has been a genetic abnormality. However, not all causes of severe oligohydramnios that result in the development of oligohydramnios sequence have a genetic basis. The genetic abnormalities that have caused oligohydramnios developing during a pregnancy include a single gene change, a missing gene, or a chromosome anomaly.

sequence Oligohydramnios

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Oligohydramnios sequence

K E Y T E R M S

Anomaly—Different from the normal or expected. Unusual or irregular structure.

Bilateral—Relating to or affecting both sides of the body or both of a pair of organs.

Fetus—The term used to describe a developing human infant from approximately the third month of pregnancy until delivery. The term embryo is used prior to the third month.

Hypoplasia—Incomplete or underdevelopment of a tissue or organ.

Renal system—The organs involved with the production and output of urine.

Syndrome—A group of signs and symptoms that collectively characterize a disease or disorder.

Teratogen—Any drug, chemical, maternal disease, or exposure that can cause physical or functional defects in an exposed embryo or fetus.

Unilateral—Refers to one side of the body or only one organ in a pair.

Although some fetuses with oligohydramnios sequence have been found to have a chromosome anomaly, the likelihood that a chromosome anomaly is the underlying cause of the renal system anomaly or other problem resulting in the severe oligohydramnios is low. A chromosome anomaly can be a difference in the total number of chromosomes a fetus has (such as having an extra or missing chromosome), a missing piece of a chromosome, an extra piece of a chromosome, or a rearrangement of the chromosomal material. Some of the chromosome anomalies can occur for the first time at the conception of the fetus (sporadic), while other chromosome anomalies can be inherited from a parent. Both sporadic and inherited chromosome anomalies have been seen in fetuses with oligohydramnios sequence. The chance for a chromosome anomaly to occur again in a family is dependent on the specific chromosome anomaly. When the chromosome anomaly is considered to be sporadic, the chance for chromosome anomaly to occur again in a pregnancy is 1% added to the mother’s agerelated risk to have a baby with a chromosome anomaly. If the chromosome anomaly (typically a rearrangement of chromosomal material) was inherited from a parent, the recurrence risk would be based on the specific chromosome arrangement involved. However, even if a chromosome anomaly were to recur in a future pregnancy, it does not necessarily mean that the fetus would develop

oligohydramnios that could cause the development of oligohydramnios sequence.

Many of the genetic conditions that can cause oligohydramnios sequence are inherited in an autosomal recessive manner. An autosomal recessive condition is caused by a difference in a gene. Like chromosomes, the genes also come in pairs. An autosomal recessive condition occurs when both genes in a pair don’t function properly. Typically, genes don’t function properly because there is a change within the gene causing it not to work or because the gene is missing. An individual has an autosomal recessive condition when they inherit one non-working gene from their mother and the same nonworking gene from their father. These parents are called “carriers” for that condition. Carriers of a condition typically do not exhibit any symptoms of that condition. With autosomal recessive inheritance, when two carriers for the same condition have a baby, there is a 25% chance for that baby to inherit the condition. There are several autosomal recessive conditions that can cause fetal renal abnormalities potentially resulting in the fetus to develop oligohydramnios sequence.

Oligohydramnios sequence has also been seen in some fetuses with an autosomal dominant conditions. An autosomal dominant condition occurs when only one gene in a pair does not function properly or is missing. This non-working gene can either be inherited from a parent or occur for the first time at conception. There are many autosomal dominant conditions where affected family members have different features and severity of the same condition. If a fetus is felt to have had oligohydramnios sequence that has been associated with an autosomal dominant condition, it would have to be determined if the condition was inherited from a parent or occurred for the first time. If the condition was inherited from a parent, that parent would have a 50% chance of passing the condition on with each future pregnancy.

Sometimes the fetus with oligohydramnios sequence has a condition or syndrome that is known to occur sporadically. Sporadic conditions are conditions that tend to occur once in a family and the pattern of inheritance is unknown. Since there are some families where a sporadic condition has occurred more than one time, a recurrence risk of approximately 1% or less is often given to families where only one pregnancy has been affected with a sporadic condition.

Sometimes examinations of family members of an affected pregnancy can help determine the exact diagnosis and pattern of inheritance. It is estimated that approximately 9% of first-degree relatives (parent, brother, or sister) of a fetus who developed oligohydramnios sequence as a result of a renal abnormality, will also have renal abnormalities that do not cause any problems or

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