Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 1 - A-L - I

watery stools and fever in a very ill-appearing infant. It is important to diagnose the condition before the intestinal obstruction causes an overgrowth of bacteria that evolves into a medical emergency. Enterocolitis can lead to severe diarrhea and massive fluid loss, which can cause death from dehydration unless surgery is done immediately to relieve the obstruction.

Diagnosis

Hirschsprung’s disease in the newborn must be distinguished from other causes of intestinal obstruction. The diagnosis is suspected by the child’s medical history and physical examination, especially the rectal exam. The diagnosis is confirmed by a barium enema x ray, which shows a picture of the bowel. The x ray will indicate if a segment of bowel is constricted, causing dilation and obstruction. A biopsy of rectal tissue will reveal the absence of the nerve fibers. Adults may also undergo manometry, a balloon study (device used to enlarge the anus for the procedure) of internal anal sphincter pressure and relaxation.

Treatment and management

Hirschsprung’s disease is treated surgically. The goal is to remove the diseased, nonfunctioning segment of the bowel and restore bowel function. This is often done in two stages. The first stage relieves the intestinal obstruction by performing a colostomy. This is the creation of an opening in the abdomen (stoma) through which bowel contents can be discharged into a waste bag. When the child’s weight, age, or condition is deemed appropriate, surgeons close the stoma, remove the diseased portion of bowel, and perform a “pull-through” procedure, which repairs the colon by connecting functional bowel to the anus. This usually establishes fairly normal bowel function.

Prognosis

Overall, prognosis is very good. Most infants with Hirschsprung’s disease achieve good bowel control after surgery, but a small percentage of children may have lingering problems with soilage or constipation. These infants are also at higher risk for an overgrowth of bacteria in the intestines, including subsequent episodes of enterocolitis, and should be closely followed by a physician. Mortality from enterocolitis or surgical complications in infancy is 20%.

Prevention

Hirschsprung’s disease is a congenital abnormality that has no known means of prevention. It is important to diagnose the condition early in order to prevent the

K E Y T E R M S

Anus—The opening at the end of the intestine that carries waste out of the body.

Barium enema x ray—A procedure that involves the administration of barium into the intestines by a tube inserted into the rectum. Barium is a chalky substance that enhances the visualization of the gastrointestinal tract on x-ray.

Colostomy—The creation of an artificial opening into the colon through the skin for the purpose of removing bodily waste. Colostomies are usually required because key portions of the intestine have been removed.

Enterocolitis—Severe inflammation of the intestines that affects the intestinal lining, muscle, nerves and blood vessels.

Manometry—A balloon study of internal anal sphincter pressure and relaxation.

Meconium—The first waste products to be discharged from the body in a newborn infant, usually greenish in color and consisting of mucus, bile and so forth.

Megacolon—Dilation of the colon.

Parasympathetic ganglion cell—Type of nerve cell normally found in the wall of the colon.

development of enterocolitis. Genetic counseling can be offered to a couple with a previous child with the disease or to an affected individual considering pregnancy to discuss recurrence risks and treatment options. Prenatal diagnosis is not available.

Resources

BOOKS

Buyse, Mary Louise, MD., ed. “Colon, Aganglionosis.” In Birth Defects Encyclopedia. Oxford: Blackwell Scientific Publications, 1990.

Phillips, Sidney F., and John H. Pemberton. “Megacolon: Congenital and Acquired.” In Sleisenger & Fordtran’s Gastrointestinal and Liver Disease. Edited by Mark Feldman, et al. Philadelphia: W.B. Saunders Co., 1998.

PERIODICALS

Kusafuka, T., and P. Puri. “Genetic Aspects of Hirschsprung’s Disease.” Seminars in Pediatric Surgery 7 (1998): 148-55.

Martucciello, G., et al. “Pathogenesis of Hirschsprung’s Disease.” Journal of Pediatric Surgery 35 (2000): 101725.

Munnes, M., et al. “Familial Form of Hirschsprung Disease: Nucleotide Sequence Studies Reveal Point Mutations in

disease Hirschsprung’s

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the RET Proto-oncogene in Two of Six Families But Not in Other Candidate Genes.” American Journal of Medical Genetics 94 (2000): 19-27.

Puri, P., K. Ohshiro, and T. Wester. “Hirschsprung’s Disease: A Search for Etiology.” Seminars in Pediatric Surgery 7 (1998): 140-7.

Salomon, R., et al. “From Monogenic to Polygenic: Model of Hirschsprung Disease.” Pathol Biol (Paris) 46 (1998): 705-7.

ORGANIZATIONS

American Pseudo-Obstruction & Hirschsprung’s Society. 158

Pleasant St., North Andover, MA 01845. [phone].

Pull-thru Network. 316 Thomas St., Bessemer, AL 35020. (205)

428-5953.

Amy Vance MS, CGC

HLA region see Major histocompatibility complex

I Holoprosencephaly

Definition

Holoprosencephaly is a disorder in which there is a failure of the front part of the brain to properly separate into what is commonly know as the right and left halves of the brain. This lack of separation is often accompanied by abnormalities of the face and skull. Holoprosencephaly may occur individually or as a component of a larger disorder.

Description

Types of holoprosencephaly

Holoprosencephaly comes in three different types: alobar, semilobar, and lobar. Each of these classifications is based on the amount of separation between what is commonly known as the left and right halves of the brain. Alobar holoprosencephaly is considered to be the most severe form of the disease, in which the separation between the two halves, or hemispheres, completely fails to develop. Semilobar holoprosencephaly represents holoprosencephaly of the moderate type, where some separation between the hemispheres has occurred. Lobar holoprosencephaly represents the least severe type of holoprosencephaly in which the hemispheres are almost, but not completely, divided.

The severity of the effect of the disease on the brain is often reflected in craniofacial abnormalities (abnormalities of the face and skull). This has led to many health

care professionals utilizing the phrase “the face predicts the brain.” This phrase is generally but not always accurate. Children may have severe craniofacial abnormalities with mild (lobar) holoprosencephaly, or children may have severe (alobar) holoprosencephaly with mild facial changes. Since the development of the face, skull, and the front of the brain are interconnected, the changes in the face often, but do not always, correspond with changes in the brain. Finally, the designation of these disorders from least severe to most severe can be mildly misleading, since the best predictor of the severity of the disease, according to Barr and Cohen, is how well the brain functions, not its appearance. However, the alobar, semilobar, and lobar categories are universally utilized and give an indication of the severity of the disease, so knowledge of these categories and what they represent is useful.

Other brain abnormalities in holoprosencephaly

All patients with holoprosencephaly lack a sense of smell through the first cranial nerve (the olfactory nerve). Interestingly enough, one has a partial sense of smell through the sense of taste, which is governed by the seventh cranial nerve. The term “smell” and what it means in a conventional and strictly neurological sense differ, so it may be useful to think of persons with holoprosencephaly as lacking a portion of what is in common usage referred to as smell. This deficiency in smell can be detected by testing. One other important structural abnormality should be mentioned. The corpus callosum, which is the part of the brain that connects the right and left hemispheres with each other, is absent or deficient in persons with holoprosencephaly.

Synonyms for holoprosencephaly

Arrhinencephaly and familial alobar holoprosencephaly are synonyms for this disorder.

Genetic profile

Genetic causes of holoprosencephaly

Holoprosencephaly is a feature frequently found in many different syndromes including, but not limited to: trisomy 13, trisomy 18, tripoloidy, pseudotrisomy 13,

Smith-Lemli-Opitz syndrome, Pallister-Hall syndrome, Fryns syndrome, CHARGE association, Goldenhar syndrome, frontonasal dysplasia, MeckelGruber syndrome, velocardiofacial syndrome, Genoa syndrome, Lambotte syndrome, Martin syndrome, and Steinfeld syndrome, as well as several teratogenic syndromes such as diabetic embryopathy, accutane embryopathy, and fetal alcohol syndrome. Holoprosencephaly has been linked to at least 12 different loci on 11 different chromosomes. Some candidate genes are Sonic hedge-

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hog (abbreviated Shh, and located at 7q36), SIX3 (located at 2p21), and the ZIC2 gene (located on chromosome 13). The gene causing Smith-Lemli-Opitz syndrome, which affects cholesterol synthesis, also is interesting, since it is also obviously a candidate to cause holoprosencephaly.

Shh, cholesterol, the prechordal plate, and the cause of holoprosencephaly

Holoprosencephaly probably arises in one of two ways (suggested by experiments in animal models). Early in the life of an embryo, an area called the prechordal plate forms. The prechordal plate is an area of the embryo which is important for the formation of the brain. The prechordal plate is said to induce brain formation. One can think of the induction process in the following way. If you take a sponge, wet it, and then place a paper towel on top of it, the paper towel will absorb some of the water. In the same way, a signal (the water) goes from the sponge (prechordal plate) to the paper towel (future brain tissue). If the water doesn’t hit the paper towel, brain tissue will not form. This is an extremely simplified version of how the process works, for many reasons. One is that the prechordal plate is not the only “sponge.” The notochord is another sponge, which sends out the signal (water) of Shh to form brain and spinal cord and other nervous tissue. Of course, Shh has already been mentioned as a candidate for a gene which causes holoprosencephaly. It turns out it is better than a candidate, because mutations in Shh have been found in some familial forms of holoprosencephaly. Further evidence that Shh plays a role in holoprosencephaly comes from Shh in mice and fish, which both result in holoprosencephaly. Thus, it would be a nice, clear-cut picture if mutations in Shh and Shh alone led to holoprosencephaly, because Shh mutations lead to holoprosencephaly in other animals and Shh is already known to be involved in the formation of neural tissue.

However, Shh is not the only answer. Many persons with holoprosencephaly have perfectly normal Shh genes, and, as previously mentioned, a number of genes have been linked to holoprosencephaly, including genes involved in cholesterol synthesis. So why are so many genes involved?

One possible answer stems from the connection between cholesterol and the Shh signaling pathway. When Shh travels from one tissue to another tissue, there are a number of other genes involved before Shh has its final effect. This process is called signal transduction, and the genes that make it up are part of a signaling pathway. Signal transduction can be compared to a shot in the game of pool. When shooting pool, one must take the cue (Shh), hit the cue ball (another gene; for Shh this would be the gene Patched), and the cue ball goes on to hit the

K E Y T E R M S

Corpus callosum—A thick bundle of nerve fibers deep in the center of the forebrain that provides communications between the right and left cerebral hemispheres.

Craniofacial—Relating to or involving both the head and the face.

Induction—Process where one tissue (the prechordal plate, for example) changes another tissue (for example, changes tissue into neural tissue).

Neural—Regarding any tissue with nerves, including the brain, the spinal cord, and other nerves.

ball that one is interested in sinking (in this case sinking the ball means making a normal brain). Thus, each step depends on the last step and the next step. If one doesn’t have the stick or the cue ball one cannot sink the ball in the pocket. Thus, a number of mutations in genes in the Shh signaling pathway, and not just Shh, could cause holoprosencephaly. Not just that, but other genes involved in cholesterol biosynthesis can have effects on genes in the Shh signaling pathway. Cholesterol appears to affect the function of the gene Patched. In the pool example, a lack of cholesterol would not mean the cue ball is gone, but maybe that the cue ball has a big lump on one side, so the shot is likely to miss.

Another possible answer comes from studies on bone morphogenetic proteins (BMPs) in chickens. Up until now, the problem of holoprosencephaly has been addressed as if it occurs when neural tissue is formed. However, the presence of too much BMP in a chick embryo after the time neural tissue is formed can cause holoprosencephaly. It appears there are two stages that can be interfered with: one that occurs at the time of neural tissue formation involving Shh, and another that occurs later involving BMPs. Increased levels of BMPs may cause important neural cells to die. It has been speculated that holoprosencephaly is either a failure to grow neural cells due to failure in Shh pathway, or an excess of neural cells dying possibly due to increased levels of BMPs. Both may end up being true, with some Shh signaling defects early, and BMP mutations later.

Teratogens also cause holoprosencephaly

A teratogen is any environmental influence that adversely affects the normal development of the fetus. Teratogens can be skin creams, drugs, or alcohol. Alcohol, when ingested in sufficient amounts during the second week of pregnancy, is thought to lead to some

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The most severe form of holoprosencephaly, alobar holoprosencephaly, results when the brain fails to separate into the right and left lobes. (Greenwood Genetic Center)

cases of holoprosencephaly. Cytomegalovirus infections in the mother during pregnancy have also been associated with holoprosencephaly. Additionally, in animals, drugs inhibiting cholesterol synthesis have been shown to cause cases of holoprosencephaly. Finally, the drug cyclopamine, which affects the Shh pathway, also causes holoprosencephaly in animals. Cyclopamine was discovered when an abnormally large number of sheep were found to have holoprosencephaly. A local shepherd and scientists determined the drug was found in a fungus called Veratrum californicum.

Demographics

Holoprosencephaly affects males and females at the same rate. Estimates vary on the frequency of the disorder in children with normal chromosomes. The estimates range from one case in every 11,363 births to one case in 53,394 births. It is important to note that this rate of incidence excludes those cases which are caused by chromosomal abnormalities, like trisomy 13.

Signs and symptoms

In holoprosencephaly alone, symptoms involve the brain and/or the face and bones of the face and skull. Facial abnormalities exhibit a wide range. In the most severe cases, persons with holoprosencephaly lack eyes and may lack a nose. Less severe is cyclopia, or the presence of a single eye in the middle of the face above the possibly deformed or absent nose. Even less severe are

ethmocephaly and cebocephaly, in which the eyes are set close together and the nose is abnormal. In premaxillary agenesis the patient has a midline cleft lip and cleft palate and close-set eyes. If the face is very abnormal, the patient is likely to have alobar holoprosencephaly, the most severe type. In addition to abnormalities of the face, children with alobar holoprosencephaly also have small brains (less than 100g). These children also have small heads unless they have excess cerebrospinal fluid. Excess cerebrospinal fluid can cause the head to be abnormally large.

Persons with holoprosencephaly experience many problems due to brain malformations including in utero or neonatal death. Survivors may experience seizures, problems with muscle control and muscle tone, a delay in growth, problems feeding (choking and gagging or slowness, pauses, and a lack of interest), intestinal gas, constipation, hormone deficiencies from the pituitary, breathing irregularities, and heart rhythm and heart rate abnormalities. These problems are usually least severe in lobar holoprosencephaly and most severe in alobar. Children with holoprosencephaly also experience severe deficiencies in their ability to speak and in their motor skills. An ominous sign that children with holoprosencephaly may exhibit is a sustained (lasting many hours or days) period of irregular breathing and heart rate. This may precede death. However, episodes lasting only minutes are usually followed by a full recovery.

Diagnosis

Prenatal ultrasound and computerized tomography can be used to determine whether the fetus has holoprosencephaly and its severity. After birth, physical appearance and/or imaging of the brain can determine a diagnosis of holoprosencephaly. Once a diagnosis of holoprosencephaly has been made, syndromes of which holoprosencephaly is a part must be considered. Fortyone percent of holoprosencephaly cases are thought to have a chromosomal abnormality as the primary cause. Holoprosencephaly is estimated to be found in the context of a larger syndrome in 25% of the remaining cases.

Treatment and management

Although no treatment exists for the underlying disease, symptomatic treatment can reduce the amount of fluid surrounding the brain and assist in feeding. Medical intervention can reduce or eliminate seizures and hormonal deficiencies. However, few treatments exist for the most serious aspects of the disease—breathing and heart arrhythmias (irregular heart rate)—or for the problems associated with developmental delay and poor muscle control. One important aspect of treatment is to help parents understand the effects of the disease and what may

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be expected from the child. Support groups, like the one listed at the end of this entry, may be important for this purpose. Parents should also be prepared to deal with a large number of health care professionals based on their child’s particular needs.

Prognosis

About half of the children born with alobar holoprosencephaly die before the age of four to five months, but a much longer survival time is possible, up to at least 11 years. Children with semilobar and lobar holoprosencephaly may live for any length of time. Depending on the severity of the holoprosencephaly, however, parents should be prepared for differences in their child. For example, children with alobar holoprosencephaly and semilobar holoprosencephaly learn to speak very little, if at all, and children with alobar holoprosencephaly have difficulty even mastering the simple task of reaching and grasping an object. On the other end of the spectrum, children may develop much more normally. It is very important to understand the severity of the disorder to understand the child’s abilities and possibilities.

Resources

BOOKS

Sadler, T. W. Langman’s Medical Embryology. Baltimore: Williams and Williams, 1995, pp. 53-60.

PERIODICALS

Barr, M., and M. Cohen. “Holoprosencephaly survival and performance.” American Journal of Medical Genetics 89 (1999): 116-120.

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. [phone] or [phone]. Fax: [phone]. http://www

.rarediseases.org .

Michael V. Zuck, PhD

I Holt-Oram syndrome

Definition

Holt-Oram syndrome (HOS) is one of several hereditary conditions characterized by abnormalities of the heart and hands at birth.

Description

HOS involves variable abnormalities of the heart and the hands, or hands and arms. The heart abnormalities

may range from disturbances in the electrical conduction pattern of the heart to severe structural defects requiring surgical intervention for survival. The abnormalities of the upper limbs are usually bilateral (occurring on both sides) and asymmetric (not identical from side to side). The severity of the upper limb changes may range from minor signs, such as clinodactyly (inward curvature of the fingers) to disabling defects, such as small or missing bones resulting in very short arms.

Some individuals with HOS are so mildly affected, they do not require any special care or treatment. Other individuals are severely affected and may have significant disability resulting from abnormalities of the arms, or may have limited lifespans due to serious heart abnormalities. The signs of HOS are usually limited to the heart and skeleton. HOS does not cause mental retardation.

Some references may use the alternative name of hand-heart syndrome. However, Holt-Oram syndrome is one of many hereditary hand-heart syndromes, so the two names are not truly interchangeable.

Genetic profile

HOS is inherited as an autosomal dominant condition, with variable expressivity (meaning that different individuals with HOS may have very different signs of the condition) and complete penetrance (meaning that every individual that has the genetic change causing the condition has some physical symptoms). An autosomal dominant condition only requires the presence of one abnormal gene on a non-sex-linked chromosome for the disorder to occur. Some researchers have observed families with incomplete penetrance (meaning that not every individual with the gene abnormality shows symptoms) as well.

In some individuals and families, HOS is caused by mutations in the TBX5 gene located on the long arm of chromosome 12. The TBX5 gene encodes a transcription factor that helps regulate DNA expression. Other families with HOS do not show mutations in the TBX5 gene, indicating that mutations in other genes can also cause HOS. HOS families that have TBX5 mutations do not appear to differ significantly from those which do not.

Some patients with HOS have inherited it from an affected parent, whereas others have it as the result of a new change in a gene. The proportion of patients with HOS resulting from new mutations ranges from 8% to 85%. Regardless of where the gene came from, an affected individual has a 50% chance of passing on the gene and the condition to each child. It is difficult to predetermine the severity of symptoms a child may have.

syndrome Oram-Holt

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Demographics

Since HOS was first described in 1960, more than 200 cases have been reported in individuals of diverse ethnicity. The incidence of the condition has been estimated as 1/100,000 live births.

Signs and symptoms

All individuals with HOS have some degree of upper limb abnormality, and most (approximately 95% in familial cases) have defects or dysfunction of the heart. Other body parts and systems are usually not significantly affected by HOS.

Defects of the upper limbs

The limb abnormalities in HOS primarily affect the radial side (the inner or thumb side of the arm/hand). Involvement of the ulnar side (the outer side of the arm/hand, opposite the thumb) may also occur to a lesser degree. In some individuals, the abnormality of the upper limb may be very mild, such as hypoplasia (underdevelopment) of the muscle at the base of the thumb, limited rotation of the arm, or narrow, sloping shoulders. Rarely, severe abnormalities of the upper limbs may be present, resulting in extremely short, “flipper-like” arms. Abnormalities of the upper limb are always bilateral and usually asymmetric. In 90% of patients, the left side is more severely affected.

The thumb is the most commonly affected part of the upper limb in HOS, and is affected in some way in 84% of patients. Some individuals have three phalanges (or bones) in the thumb, resulting in a thumb that can bend in three places, like a finger. In other cases, the thumb may be hypoplastic (underdeveloped). Syndactyly (or skin webbing) may occur between the thumb and index finger.

Abnormalities of the fingers may include hypoplasia, underdevelopment, or absence of one or more fingers. Clinodactyly (inward curvature) of the fifth or “pinky” finger is also common. In some patients, polydactyly (extra fingers) has been reported.

The bones of the arms may also be affected by HOS. The radius (the inner bone of the forearm, adjacent to the thumb) may be hypoplastic or even missing. Such patients may have a lesser degree of hypoplasia of the ulna (outer bone of the forearm, opposite the thumb). The upper arm may be short. In rare cases, as noted above, the bones of the arm are dramatically shortened, resulting in a tiny arm.

Individuals with HOS often appear to have narrow, sloping shoulders. This likely results from some degree of hypoplasia of the clavicles (collarbones), as well as

decreased musculature which occurs secondarily to bone hypoplasia.

Defects and dysfunction of the heart

The vast majority (95%) of individuals with HOS who have inherited it from an affected parent have heart involvement. Most have a defect in the structure of the heart. In some patients, there is no structural defect in the heart, but abnormalities are present in the pattern of electrical conduction in the heart.

The most common heart abnormalities in people with HOS are septal defects, or holes in the heart. A hole may occur in the wall separating the atria of the heart (atrioseptal defect or ASD), or the wall separating the ventricles of the heart (ventriculoseptal defect or VSD). In rare cases, more severe and complex heart defects may occur, such as hypoplastic left heart (in which the chambers of the left side of the heart are too small to function normally) or tetralogy of fallot (a specific combination of four heart defects). In the case of severe defects, surgical correction is necessary for survival. However, most persons with HOS do not require surgical intervention.

Some individuals with HOS have a cardiac conduction defect, or an abnormal electrical pattern in the heart. The complex motion of the heart requires a system of electrical impulses for coordinated contraction of the muscle fibers. In people with cardiac conduction defects, these electrical impulses may not occur in the normal pattern, resulting in an abnormal heartbeat. In rare cases, this can result in sudden death.

Other defects

Additional skeletal abnormalities occasionally reported in patients with HOS include scoliosis, vertebral abnormalities, and minor deformities of the rib cage. Some patients may have abnormalities unrelated to the cardiac or skeletal systems, such as minor eye defects and various birthmarks. It is not clear whether these additional findings are coincidental or part of HOS.

Diagnosis

The diagnosis of HOS is made on the basis of the clinical judgment by a specialist physician, usually a geneticist, following physical examination and review of pertinent tests or studies. Diagnostic criteria may be employed to guide this decision. One commonly used set of criteria for the diagnosis of HOS require that there be

1)defect(s) of the radial side of the hand/arm, as well as

2)septal defect(s) or conduction abnormality of the heart, within one individual or family.

X rays may be necessary to determine involvement of the bones of the upper limb. Diagnosis of structural

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defects of the heart requires echocardiography, or ultrasound visualization of the heart. Conduction defects of the heart are identified via electrocardiography (EKG). This test involves measuring the electrical activity of the heart and charting the electrical impulses associated with each heartbeat.

Testing to identify changes in the TBX5 gene may be offered, but is not necessary for a diagnosis of HOS. Identification of a change or alteration in the TBX5 gene could provide confirmation of the clinical diagnosis, prenatal diagnosis, or assist in the diagnosis of at-risk family members who are minimally affected. Prenatal screening in a pregnancy at risk for HOS may also be attempted by fetal ultrasonography targeted toward the fetal arms and heart. However, a normal ultrasound examination does not eliminate the possibility of HOS in the unborn baby.

Treatment and management

There is no specific treatment for HOS. Surgery or other treatment may be recommended for cardiac abnormalities. Referral for genetic counseling should be considered for families in which HOS has been diagnosed.

Some patients with HOS have life-threatening heart defects that require surgical correction for survival. The most complex heart defects may require multiple surgeries. However, many individuals have asymptomatic or no heart abnormalities. When life-threatening irregularities are present in the heartbeat, a pacemaker device is inserted. These devices correct the abnormal electrical patterns which cause the irregularities and stimulate the heart to beat normally.

Because eye abnormalities have been occasionally reported in HOS, an eye examination may be recommended at the time of diagnosis.

Prognosis

The prognosis for individuals with HOS depends on the severity of associated birth defects, which varies considerably. Positive correlation has been reported between the severity of upper limb and heart defects. In other words, individuals who have more severe hand or arm involvement may be more likely to have a symptomatic heart defect. People who have HOS resulting from new mutations are more likely to have severe defects than those who have inherited it from a parent.

In some cases, HOS may lead to death in early infancy due to multiple septal defects or other complex structural abnormalities of the heart. Severe and unrecognized disturbances of the cardiac conduction system can lead to sudden death. In other cases, heart involvement is limited to asymptomatic irregular heartbeat requiring no treatment.

K E Y T E R M S

Atria—The two chambers at the top of the heart, where blood from the lungs or body pools before entering one of the ventricles.

Polydactyly—The presence of extra fingers or toes.

Radius—One of the two bones of the forearm, the one adjacent to the base of the thumb.

Septal defect—A hole in the heart.

Syndactyly—Abnormal webbing of the skin between the fingers or toes.

Ulna—One of the two bones of the forearm, the one opposite the thumb.

Ventricles—One of the chambers (small cavities) of the heart through which blood circulates. The heart is divided into the right and left ventricles.

Several unusual findings have been described with respect to the severity of HOS in families. Affected women have been reported to have a higher chance of having a severely affected child than do affected men. The severity of defects associated with HOS has also been reported to increase with successive generations. The possible explanations for these observations are not known.

Resources

BOOKS

Jones, Kenneth L. Smith’s Recognizable Patterns of Human

Malformation. Philadelphia, PA: W.B. Saunders

Company, 1997.

PERIODICALS

Newbury, R.A., R. Leanage, J.A. Raeburn, and I.D. Young. “Holt-Oram Syndrome: A clinical genetic study.” Journal of Medical Genetics (April 1996): 300-307.

Jennifer A. Roggenbuck, MS, CGC

I Homocystinuria

Definition

The term homocystinuria is actually a description of a biochemical abnormality, as opposed to the name of a particular disease, although many refer to homocystinuria as a disease. Homocystinuria refers to elevated levels of homocysteine in the urine. This can be caused by different biochemical abnormalities and in fact there are

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K E Y T E R M S

Anabolism—The energy-using process of building up complex chemical compounds from simpler ones in the body.

Catabolism—The energy-releasing process of breaking down complex chemical compounds into simpler ones in the body.

Marfan syndrome—A syndrome characterized by skeletal changes (arachnodactyly, long limbs, lax joints), ectopia lentis, and vascular defects.

Thrombophilia—A disorder in which there is a greater tendency for thrombosis (clot in blood vessel).

at least eight different gene changes that are known to cause excretion of too much homocysteine in the urine. The best known and most common cause of homocystinuria is the lack of cystathionine b-synthase. For the purpose of this entry we will be referring to “classical homocystinuria” that is caused by cystathionine b-syn- thase deficiency (CBS deficiency).

Description

In Northern Ireland in the early 1960s, homocystinuria was described in individuals who were mentally retarded. Soon after that, it was shown that the cause of the homocystinuria was a deficiency of the enzyme cystathionine b-synthase. This condition is an inborn error of metabolism, meaning that the cause for this condition is present from birth and it affects metabolism.

Metabolism is the sum of all of the chemical processes that take place in the body. Metabolism includes both construction (anabolism) and break down (catabolism) of important components. For example, amino acids are the building blocks for proteins and are converted to proteins through many steps in the process of anabolism. In contrast, proteins can also be broken down into amino acids through many steps in the process of catabolism. These processes require multiple steps that involve different substances called enzymes. These enzymes are proteins that temporarily combine with reactants and in the process, allow these chemical processes to occur quickly. Since practically all of the reactions in the body use enzymes, they are essential for life. At any point along the way, if an enzyme is missing, the particular process that requires that enzyme would not be able to be completed as usual. Such a situation can lead to disease.

Homocysteine is involved with the catabolism of methionine. Methionine is an essential amino acid. Amino acids are the building blocks of proteins. Over 100 amino acids are found in nature, but only 22 are found in humans. Of these 22 amino acids, eight are essential for human life, including methionine. Methionine comes from dietary protein. Generally, the amount of methionine that is consumed is more than the body needs. Excess methionine is converted to homocysteine, which is then metabolized into cystathionine; cystathionine is then converted to cysteine. The cysteine is excreted in the urine. Each step along this pathway is carried out by a specific enzyme and that enzyme may even require help from vitamin co-factors to be able to complete the job. For example, the conversion of homocysteine to cystathionine by cystathionine b-synthase requires vitamin B6 (pyridoxine). If cystathionine b-synthase is missing, then homocysteine cannot be broken down into cystathionine and cysteine, and instead, homocysteine accumulates and the elevated levels of homocysteine and methionine can be found in the blood. Also, decreased levels of cysteine can be found in the blood. Elevated levels of homocysteine lead to a disease state that, if untreated, affects multiple systems, including the central nervous system, the eyes, the skeleton, and the vascular system.

Genetic profile

Classical homocystinuria or cystathionine b-syn- thase (CBS) deficiency is an autosomal recessive condition. This means that in order to have the condition, an individual must inherit one copy of the gene for CBS deficiency from each parent. An individual who has only one copy of the gene is called a carrier for the condition. In most cases of autosomal recessive inheritance a carrier for a condition does not have any signs, symptoms, or effects of the condition. This is not necessarily the case with CBS deficiency. Individuals who are carriers for CBS deficiency may have levels of homocysteine that are elevated enough to increase the risk for thromboembolic events. So, although carriers may not exhibit obvious physical signs or symptoms of the condition, they may have clinical effects of elevated levels of homocysteine, such as vascular or cardiovascular disease. A carrier for CBS deficiency can have vascular complications, especially if they are also carriers for other clotting disorders such as factor V Leiden thrombophilia.

When two parents are carriers for CBS deficiency, there is a one in four or 25% chance, with each pregnancy, for having a child with CBS deficiency. They have a one in two or 50% chance for having a child who is a carrier for the condition and a one in four or 25% chance for having a child who is neither affected nor a carrier for CBS deficiency.

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Homocystinuria	Homocystinuria

(Gale Group)

The gene for CBS has been mapped to the long arm of chromosome 21, specifically at 21q22.3. Approximately 100 different disease-associated gene changes or alterations of the CBS gene have been identified. The two most frequently encountered gene changes are 1278T and G307S. G307S is the most common cause of CBS deficiency in Irish patients and the 1278T gene is the most common cause of CBS deficiency in Italian patients.

Demographics

The worldwide frequency of individuals with CBS deficiency who are identified through newborn screening and clinical detection is approximately one in 350,000; however, newborn screening may be missing half of affected patients and thus the worldwide incidence may be as high as one in 180,000. One study showed that by lowering the cutoff level of methionine from 2 mg per deciliter to 1 mg per deciliter in newborn screening, detection of the deficiency increased from 1 in 275,000 to 1 in 157,000. The incidence of CBS deficiency in the United States population is 1 in 58,000; in the Irish population it is estimated to be 1 in 65,000; in the Italian population it is 1 in 55,000 and in the Japanese population it is 1 in 889,000. CBS deficiency has been seen in persons of many different ethnic origins living in the United States.

Signs and symptoms

Individuals who have CBS deficiency tend to be tall and thin with thinning and lengthening of the bones. They tend to have a long, narrow face and high arched palate (roof of the mouth). The thinning and lengthening of the long bones causes individuals to be tall and thin by the time they reach late childhood. Their fingers tend to be long and thin as well (referred to as arachnodactyly). They can have curvature of the spine, called scoliosis. Their chest can be sunken in (pectus excavatum) or it

may protrude out (pectus carinatum). Osteoporosis may occur. Also, they tend to have stiff joints. CBS deficiency affects the eyes, causing dislocated lenses and nearsightedness (myopia). Untreated individuals or those individuals who do not respond to treatment develop mental retardation or learning disabilities. Affected individuals may also develop psychiatric problems. These psychiatric problems may include depression, chronic behavior problems, chronic obsessive-compulsive disorder, and personality disorders. The most frequent cause of death associated with CBS deficiency is blood clots that form in veins and arteries. These are known as thromboembolisms, and include deep vein thrombosis (blood clots that form in the deep veins of the legs, etc.), pulmonary embolus (blood clots that form in the lungs), and strokes. Thromboembolism can occur even in childhood. When thromboembolism does occur in childhood, CBS deficiency should always be considered as a cause for the thromboembolic events. These thromboembolic events can occur in any part of the body. Lastly, another complication of CBS deficiency is severe premature arteriosclerosis (hardening of the arteries).

Diagnosis

Approximately 50% of individuals who have CBS deficiency are diagnosed by newborn screening because they have an elevated level of methionine in their blood. The reason for performing newborn screening is so that infants affected with genetic disorders can be identified early enough to be treated. The screening is done by collecting blood from a pin-prick on the baby’s heel prior to leaving the hospital, but at least 24 hours after birth. For CBS deficiency, the screening test checks for elevated levels of methionine. If the levels are elevated then fol- low-up testing to verify the diagnosis is performed. There are other disorders of methionine metabolism, and fol- low-up testing determines the underlying cause of the positive newborn screen.

G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

563

Homocystinuria

Pyridoxine (vitamin B6) (co-factor)

+

Cystathionine b-synthase

acts

here

dietary intake of

Methionine Homocysteine Cystathionine Cysteine

(found in dietary protein)							(excreted in urine)
			Betaine
			acts here
Methionine
synthase
Methyl-B12
H4-folate		acts	Methyl-H4-folate				Methylene H4-folate
		here				acts	acts dietary folic acid or folate
Dietary cobalamin						here	here
				Methylene H4-folate reductase

Flow chart for the chemical processes involved in the breakdown of methionine, an essential amino acid found in dietary protien. Homocystinuria results when the enzyme cystathionine b-synthase is missing and does not break down homocystine, a converted form of excess methionine. The elevated levels of methionine and homocystein that result from the failure of homocysteine to break down into cystathionine and cysteine causes a disease state that affects multiple body systems. (Gale Group)

If not identified at newborn screening, diagnosis is made by identifying low levels of cysteine in blood and urine. Measurements of the amount of methionine and homocysteine produced by cultured blood cells (lymphoblasts) or cultured skin cells (fibroblasts) also can confirm the diagnosis of CBS deficiency.

DNA testing is available for families in which a gene alteration is identified. Potentially, this makes prenatal diagnosis by chorionic villus sampling (CVS) and amniocentesis available for families who have had a previously affected child and in which two identifiable gene alterations for CBS deficiency have been detected. Prenatal diagnosis is also possible by measuring the amount of enzyme activity in cultured cells grown from amniotic fluid.

CBS deficiency has several features in common with Marfan syndrome, including the tall, thin build with long limbs and long, thin fingers (arachnodactyly), a sunken-in chest (pectus excavatum), and dislocated lenses. The dislocated lens in Marfan syndrome tends to be dislocated upward; the tendency for the lens dislocation is to be downward in CBS deficiency. Also, individuals who have Marfan syndrome tend to have lens dislocation from birth (congenital) whereas individuals

who have CBS deficiency have not been identified to have lens dislocation before 2 years of age.

Treatment and management

The first choice of therapy for patients with CBS deficiency is administration of pyridoxine (vitamin B6). Vitamin B6 is the cofactor for the cystathionine b-syn- thase reaction. Potentially, some individuals who have CBS deficiency are not missing the enzyme, but rather have an enzyme that is unable to perform its job. The addition of pyridoxine can help to push the reaction along and thus help to reduce the levels of homocysteine and methionine in the blood. Information suggests that approximately 50% of patients with CBS deficiency respond to high doses of pyridoxine (pyridoxine responsive) and show a significant reduction in levels of homocysteine in the blood. Patients who do not respond to pyridoxine treatment (pyridoxine non-responsive) tend to be more severely affected than the patients who do respond. Those non-responding patients are treated with combinations of folic acid, hydroxycobalamin, and betaine, which stimulate the conversion of homocysteine back to methionine. The reason that the addition of folic acid can help is because within the methylene H4-folate

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