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

brain cells. Therefore, an enzyme substitute injected into the blood would not prevent or reduce the brain damage caused by Hurler syndrome. The substitute might, however, reduce damage to other tissues of the body.

Gene therapy attempts to introduce a normal gene into the patient’s cells. In theory, the cells would then incorporate the gene, copy it, and produce enough enzyme to break down complex molecules.

Until these or other therapies become available, patients who cannot undergo BMT can receive treatment for individual Hurler syndrome symptoms. While treatment provides temporary relief, it cannot prevent the progressive damage caused by accumulation of dermatan sulfate and heparan sulfate. Death due to respiratory complications or heart failure usually occurs by age 12.

Resources

BOOKS

Beighton, Peter, ed. McKusick’s Heritable Disorders of

Connective Tissue. Fifth Edition. St. Louis: Mosby, 1993. Jones, Kenneth L. “Hurler Syndrome.” In Smith’s Recognizable

Patterns of Human Malformation. Fifth Edition. Philadelphia: W.B. Saunders Company, 1997, pp. 456-457.

Jorde, Lynn, et al. Medical Genetics. Second Edition. St. Louis: Mosby, 2000, pp. 147-149.

Scriver, Charles, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. Seventh Edition. New York: McGraw-Hill, 1995.

PERIODICALS

Peters, Charles, et al. “Hurler Syndrome: II. Outcome of HLAGenotypically Identical Sibling and HLA-Haploidentical Related Donor Bone Marrow Transplantation in FiftyFour Children.” Blood 91, no. 7 (April 1998): 2601-2608.

ORGANIZATIONS

Genetic Alliance. 4301 Connecticut Ave. NW, #404, Washington, DC 20008-2304. (800) 336-GENE (Helpline) or (202) 966-5557. Fax: (888) 394-3937 info@geneticalliance. http://www.geneticalliance.org .

National MPS Society. 102 Aspen Dr., Downingtown, PA 19335. (610) 942-0100. Fax: (610) 942-7188. info @mpssociety.org. http://www.mpssociety.org .

WEBSITES

GeneClinics. http://www.geneclinics.org 2001.

GeneTests. http://www.genetests.org 2001.

New York University School of Medicine.

http://www.med.nyu.edu 2001.

Avis L. Gibons

Hutchinson-Gilford progeria syndrome see

Progeria

I Hydrocephalus

Definition

Hydrocephalus is an abnormal expansion of cavities (ventricles) within the brain that is caused by the accumulation of cerebrospinal fluid. Hydrocephalus comes from two Greek words: hydros means water and cephalus means head.

There are two main varieties of hydrocephalus: congenital and acquired. An obstruction of the cerebral aqueduct (aqueductal stenosis) is the most frequent cause of congenital hydrocephalus. Acquired hydrocephalus may result from spina bifida, intraventricular hemorrhage, meningitis, head trauma, tumors, and cysts.

Description

Hydrocephalus is the result of an imbalance between the formation and drainage of cerebrospinal fluid (CSF). Approximately 500 milliliters (about a pint) of CSF is formed within the brain each day, by epidermal cells in structures collectively called the choroid plexus. These cells line chambers called ventricles that are located within the brain. There are four ventricles in a human brain. Once formed, CSF usually circulates among all the ventricles before it is absorbed and returned to the circulatory system. The normal adult volume of circulating CSF is 150 ml. The CSF turnover rate is more than three times per day. Because production is independent of absorption, reduced absorption causes CSF to accumulate within the ventricles.

There are three different types of hydrocephalus. In the most common variety, reduced absorption occurs when one or more passages connecting the ventricles become blocked. This prevents the movement of CSF to its drainage sites in the subarachnoid space just inside the skull. This type of hydrocephalus is called “noncommunicating.” In a second type, a reduction in the absorption rate is caused by damage to the absorptive tissue. This variety is called “communicating hydrocephalus.”

Both of these types lead to an elevation of the CSF pressure within the brain. This increased pressure pushes aside the soft tissues of the brain. This squeezes and distorts them. This process also results in damage to these tissues. In infants whose skull bones have not yet fused, the intracranial pressure is partly relieved by expansion of the skull, so that symptoms may not be as dramatic. Both types of elevated-pressure hydrocephalus may occur from infancy to adulthood.

A third type of hydrocephalus, called “normal pressure hydrocephalus,” is marked by ventricle enlargement

Hydrocephalus

Hydrocephalus

K E Y T E R M S

Cerebral ventricles—Spaces in the brain that are located between portions of the brain and filled with cerebrospinal fluid.

Cerebrospinal fluid—Fluid that circulates throughout the cerebral ventricles and around the spinal cord within the spinal canal.

Choroid plexus—Specialized cells located in the ventricles of the brain that produce cerebrospinal fluid.

Fontanelle—One of several “soft spots” on the skull where the developing bones of the skull have yet to fuse.

Shunt—A small tube placed in a ventricle of the brain to direct cerebrospinal fluid away from the blockage into another part of the body.

Stenosis—The constricting or narrowing of an opening or passageway.

Subarachnoid space—The space between two membranes surrounding the brain, the arachnoid and pia mater.

without an apparent increase in CSF pressure. This type affects mainly the elderly.

Hydrocephalus has a variety of causes including:

•congenital brain defects

•hemorrhage, either into the ventricles or the subarachnoid space

•infection of the central nervous system (syphilis, herpes, meningitis, encephalitis, or mumps)

•tumor

Genetic profile

Hydrocephalus that is congenital (present at birth) is thought to be caused by a complex interaction of genetic and environmental factors. Aqueductal stenosis, an obstruction of the cerebral aqueduct, is the most frequent cause of congenital hydrocephalus. As of 2001, the genetic factors are not well understood. According to the British Association for Spina Bifida and Hydrocephalus, in very rare circumstances, hydrocephalus is due to hereditary factors, which might affect future generations.

Demographics

Hydrocephalus is believed to occur in approximately 1–2 of every 1,000 live births. The incidence of adult

onset hydrocephalus is not known. There is no known way to prevent hydrocephalus.

Signs and symptoms

Signs and symptoms of elevated-pressure hydrocephalus include:

•headache

•nausea and vomiting, especially in the morning

•lethargy

•disturbances in walking (gait)

•double vision

•subtle difficulties in learning and memory

•delay in children achieving developmental milestones

Irritability is the most common sign of hydrocephalus in infants. If this is not treated, it may lead to lethargy. Bulging of the fontanelles, or the soft spots between the skull bones, may also be an early sign. When hydrocephalus occurs in infants, fusion of the skull bones is prevented. This leads to abnormal expansion of the skull.

Symptoms of normal pressure hydrocephalus include dementia, gait abnormalities, and incontinence (involuntary urination or bowel movements).

Diagnosis

Imaging studies—x ray, computed tomography scan (CT scan), ultrasound, and especially magnetic resonance imaging (MRI)—are used to assess the presence and location of obstructions, as well as changes in brain tissue that have occurred as a result of the hydrocephalus. Lumbar puncture (spinal tap) may be performed to aid in determining the cause when infection is suspected.

Treatment and management

The primary method of treatment for both elevated and normal pressure hydrocephalus is surgical installation of a shunt. A shunt is a tube connecting the ventricles of the brain to an alternative drainage site, usually the abdominal cavity. A shunt contains a one-way valve to prevent reverse flow of fluid. In some cases of noncommunicating hydrocephalus, a direct connection can be made between one of the ventricles and the subarachnoid space, allowing drainage without a shunt.

Installation of a shunt requires lifelong monitoring by the recipient or family members for signs of recurring hydrocephalus due to obstruction or failure of the shunt. Other than monitoring, no other management activity is usually required.

Some drugs may postpone the need for surgery by inhibiting the production of CSF. These include acetazo-

lamide and furosemide. Other drugs that are used to delay surgery include glycerol, digoxin, and isosorbide.

Some cases of elevated pressure hydrocephalus may be avoided by preventing or treating the infectious diseases which precede them. Prenatal diagnosis of congenital brain malformation is often possible.

Prognosis

The prognosis for elevated-pressure hydrocephalus depends on a wide variety of factors, including the cause, age of onset, and the timing of surgery. Studies indicate that about half of all children who receive appropriate treatment and follow-up will develop IQs greater than 85. Those with hydrocephalus at birth do better than those with later onset due to meningitis. For individuals with normal pressure hydrocephalus, approximately half will benefit by the installation of a shunt.

Resources

BOOKS

Drake, James M., and Christian Sainte-Rose. Shunt Book. Boston: Blackwell Science Inc., 1995.

Toporek, Chuck, and Kellie Robinson. Hydrocephalus: A Guide for Patients, Families & Friends. Cambridge, Mass.: O’Reilly & Associates, 1999.

PERIODICALS

Grant, Beth. “Hydrocephalus: diagnosis and treatment.” Radiologic Technology 69, no. 2 (Nov–Dec 1997): 173–5.

“Hydrocephalus.” Review of Optometry 137, no. 8 (August 15, 2000): 56A.

ORGANIZATIONS

Association for Spina Bifida and Hydrocephalus. 42 Park Rd., Peterborough, PE1 2UQ UK. 0173 355 5988. Fax: 017 3355 5985. postmaster@asbah.org. http://www.asbah

.demon.co.uk .

Columbia Presbyterian Medical Center. Dept. of Neurological Surgery, 710 West 168 St., New York, NY 10032. (212) 305-0378. Fax: (212) 305-3629. http://cpmcnet.columbia

.edu/dept/nsg/PNS/Hydrocephalus.html . Hydrocephalus Association. 870 Market St., Suite 705, San

Francisco, CA 94102. (415) 732-7040 or (888) 598-3789. (415) 732-7044. hydroassoc@aol.com. http://neurosurgery

.mgh.harvard.edu/ha .

Hydrocephalus Foundation, Inc. (HyFI), 910 Rear Broadway, Saugus, MA 01906. (781) 942-1161. HyFI1@netscape

.net. http://www.hydrocephalus.org .

Hydrolethalus syndrome

WEBSITES

“Hydrocephalus.” American Association of Neurological Surgeons/Congress of Neurological Surgeons. http:// www.neurosurgery.org/pubpages/patres/hydrobroch

.html .

“Hydrocephalus.” Beth Israel Medical Center, New York, NY.

Institute for Neurology and Neurosurgery. http://nyneurosurgery.org/child/hydrocephalus/hydrocephalus.htm .

“Hydrocephalus.” National Library of Medicine. MEDLINEplus. http://www.nlm.nih.gov/medlineplus/ hydrocephalus.html .

L. Fleming Fallon, Jr., MD, DrPH

I Hydrolethalus syndrome

Definition

Hydrolethalus syndrome is a rare disorder that results in severe birth defects and often, stillbirth.

Description

Hydrolethalus syndrome is a condition that causes improper fetal development. Multiple malformations along the body’s midline, such as heart and brain defects, a cleft lip or palate, an abnormally shaped nose or jaw, and incomplete lung development result from this syndrome. The birth defects are typically extreme enough to cause stillbirth or death within a few days of birth. A less common name for hydrolethalus syndrome is Salonen- Herva-Norio syndrome, after the Finnish researchers who first described it in 1981.

Genetic profile

Hydrolethalus syndrome is passed on through an autosomal recessive pattern of inheritance. Autosomal means that the syndrome is not carried on a sex chromosome, while recessive means that both parents must carry the gene mutation in order for their child to have the disorder. Some cases of hydrolethalus syndrome have been observed in cases where the parents are related by blood (consanguineous). Parents with one child affected by hydrolethalus syndrome have a 25% chance that their next child will also be affected with the disease.

Each parent passes 23 chromosomes, or units of genetic information, to the infant. Structurally, each chromosome has a short segment or “arm,” called the p arm, and a long arm, called the q arm, extending from a central region called the centromere. Along each arm the chromosome is further divided by numbering the bands down the arm according to their appearance under a

microscope. Each band corresponds to specific genes. Based on studies of genetic material from affected and non-affected families, studies in 1999 assigned the gene location for hydrolethalus syndrome to 11q23-25, or somewhere between the 23rd and 25th band of the q arm of chromosome 11.

Demographics

The majority of cases of hydrolethalus syndrome have been reported in people of Finnish ancestry. In Finland the incidence of hydrolethalus syndrome is estimated at one in every 20,000. Less than twenty cases have been reported outside of Finland.

Hydrolethalus syndrome affects fetal development in the womb and is a syndrome of infants only, due to the extremely serious birth defects caused by the disorder. No cases of survival into childhood or adulthood have been reported. The syndrome appears to affect both males and females with equal probability.

Signs and symptoms

Prenatal symptoms include an excess of amniotic fluid in the womb (hydramnios). Babies with hydrolethalus syndrome are often delivered pre-term and may be stillborn.

After birth, the following conditions may be observed as a result of hydrolethalus syndrome:

•fluid in the skull and swelling leading to an abnormally large head (hydrocephalus)

•defects in the structure of the heart

•incomplete development of the lungs

•the presence of extra fingers and toes (polydactyly), especially an extra big toe or little finger

•clubfoot

•a cleft lip or palate

•a small lower jaw (micrognathia)

•abnormal eye and nose formation

•a keyhole-shaped defect at the back of the head

•abnormal genitalia

Diagnosis

Hydrolethalus syndrome can be diagnosed prenatally by ultrasound scanning in as early as the eleventh week of gestation. After birth, the presence of multiple malformations, especially the extreme swelling of the skull and other brain and spinal cord defects, can confirm the diagnosis. A family history and genetic testing may be useful in making the diagnosis certain.

K E Y T E R M S

Hydramnios—A condition in which there is too much amniotic fluid in the womb during pregnancy.

Hydrocephalus—The excess accumulation of cerebrospinal fluid around the brain, often causing enlargement of the head.

Micrognathy—Having a very small and receding jaw.

Polydactyly—The presence of extra fingers or toes.

Treatment and management

There is no treatment for hydrolethalus syndrome other than management of the specific medical conditions of the infant. Genetic counseling is particularly important in the prenatal treatment and management of hydrolethalus syndrome. This is because the severity of symptoms almost always causes death of the infant within a few days of birth, even if the fetus survives to full term.

Prognosis

The prognosis for infants with hydrolethalus syndrome is extremely poor. Most affected infants are stillborn or die within the first day of life. Only a handful of cases of survival past the neonatal period have been reported and the longest survival period was 44 days.

Resources

PERIODICALS

Visapaa, Ilona, et al. “Assignment of the locus for hydrolethalus syndrome to a highly restricted region on 11q23-25.”

American Journal of Human Genetics (September 1999): 1086-95.

ORGANIZATIONS

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. http://www.modimes

.org .

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 http://www

.rarediseases.org .

WEBSITES

“Entry 236680: Hydrolethalus syndrome.” OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm

.nih.gov/htbin-post/Omim/dispmim?236680 (April 20, 2001).

Jeanty, Philippe, and Sandra Silva. “Hydrolethalus syndrome.” TheFetus.Net. http://www.thefetus.net (April 20, 2001).

Paul A. Johnson

Hydrometrocolpos syndrome see

McKusick-Kaufman syndrome

I Hydrops fetalis

Definition

Refers to the abnormal accumulation of fluid in the skin, body cavities, umbilical cord, and placenta of an unborn baby. Hydrops fetalis (HF) can result from many different diseases and structural defects. HF is traditionally divided into two major categories: immune HF and nonimmune HF. Immune hydrops fetalis is caused by Rh incompatibility, and was the most common cause of HF until the advent of anti-Rh antibody treatment (RhoGAM®) during pregnancy. All other causes of HF are termed nonimmune HF. Nonimmune hydrops fetalis may be caused by chromosomal aberrations, other genetic disorders, infections, anemias, structural birth defects such as congenital heart disease, and many other conditions. Currently in the United States nonimmune HF consists of about 90% and immune HF consists of about 10% of cases.

Description

HF occurs when a baby has a condition or birth defect that causes accumulation of excess fluid, known as edema, in the skin and other body cavities. Immune HF occurs when a mother’s blood group is Rh negative (this means that she does not have the Rh protein on the surface of her blood cells) and her baby’s blood group is Rh positive (the baby has the Rh protein on its blood cells). During the pregnancy a small amount of the baby’s blood crosses into the mother’s circulatory system. When this happens, the mother’s immune system recognizes the Rh protein on the baby’s blood cells as foreign and makes antibodies to the Rh protein. The antibodies can then cross back over to the baby and attack its blood cells, destroying them and causing anemia. The anemia causes heart failure, subsequent edema, and, ultimately, HF. The mother’s immune response becomes greater with each subsequent pregnancy in which the baby has Rh-positive blood and thus the HF becomes worse. Administration of anti-Rh antibodies during all of an Rh-negative mother’s

fetalis Hydrops

Hydrops fetalis

K E Y T E R M S

Alpha-thalassemia—Autosomal recessive disorder where no functional hemoglobin is produced. Leads to severe untreatable anemia.

Arrhythmia—Abnormal heart rhythm, examples are a slow, fast, or irregular heart rate.

Congenital heart disease—Structural abnormality of the heart at birth. Examples include a ventricular septal defect and atrial septal defect.

Down syndrome—A genetic condition characterized by moderate to severe mental retardation, a characteristic facial appearance, and, in some individuals, abnormalities of some internal organs. Down syndrome is always caused by an extra copy of chromosome 21, or three rather than the normal two. For this reason, Down syndrome is also known as trisomy 21.

Gaucher disease—Autosomal recessive metabolic disorder caused by dysfunction of the lysosomal enzyme beta-glucosidase.

Lymphedema distichiasis—Autosomal dominant condition with abnormal or absent lymph vessels. Common signs include a double row of eyelashes (distichiasis) and edema of the limbs beginning around puberty.

Myotonic dystrophy—A form of muscular dystrophy, also known as Steinert’s condition, characterized by delay in the ability to relax muscles after forceful contraction, wasting of muscles, as well as other abnormalities.

Pericardial cavity—Space occupied by the heart.

Pleural cavity—Area of the chest occupied by the lungs.

Sly disease—Autosomal recessive metabolic disorder caused by dysfunction of the lysosomal enzyme beta-glucuronidase.

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

pregnancies will prevent her from ever developing an immune response to Rh-positive blood and thus will prevent HF.

The most common causes of nonimmune HF include heart disease (congenital malformations and arrhythmia), chromosome aberrations (Turner syndrome and Down

syndrome), and anemia (alpha-thalassemia, fetomaternal transfusion, and twin-twin transfusion). Other causes include infections, metabolic disorders, and tumors. In all there are over 100 separate causes of nonimmune HF.

All disorders that cause HF do so by three common mechanisms that include heart failure, hypoproteinemia (low levels of protein in the blood stream), and vascular or lymphatic obstruction. Some disorders combine two or more of these mechanisms to cause HF. Most disorders cause some degree of heart failure. Anemia causes heart failure by increasing the work of the heart so much that it fails (this is termed high output heart failure). Isolated congenital heart disease or conditions that have congenital heart disease as a feature often will develop heart failure due to a poorly functioning heart (this is termed low output heart failure). Conditions that block the flow of blood or lymph can cause edema and HF. Examples include tumors and congenital malformations of the blood and lymphatic vessels. Conditions that lower that amount of protein in the blood can cause edema and HF by allowing fluid to easily leak out of the vessels and collect in the soft tissues and body cavities. Examples include metabolic conditions that damage the liver and prevent it from producing enough protein such as

Gaucher disease and Sly disease.

Genetic profile

Many causes of hydrops fetalis do not have a genetic etiology. Because the recurrence risk can range from 0–100% depending on the underlying cause, an accurate diagnosis is important. Infectious causes are not genetic and should not recur in subsequent pregnancies. Other causes of HF have a specific genetic profile. Immune causes are due to a difference in the antigens on the mother and baby’s blood cells. This can recur in subsequent pregnancies if anti-Rh antibodies are not given to the mother. Recurrence can either be 50% or 100% depending on the father’s Rh-antigen status.

If hydrops fetalis is caused by a chromosome aberration, the risk of recurrence is about 1%, as most of these conditions occur sporadically and are not inherited. Malformations causing HF, such as congenital heart disease, are most commonly inherited as multifactorial traits. This type of inheritance pattern is caused by multiple genes and environmental factors working in combination. The recurrence risk for a multifactorial trait is about 3–5% with each subsequent pregnancy.

Higher risk for recurrence occurs when a single gene condition is the cause of HF. Autosomal recessive conditions such as alpha-thalassemia, Gaucher disease, and Sly disease have a recurrence risk of 25% with each subsequent pregnancy. The X-linked recessive disorder

G-6-P-deficiency has a recurrence risk of 50% with each additional male child and 0% for each additional female child.

Some dominant conditions can cause HF; these are often lethal and usually represent a new mutation in that child. In these cases the recurrence risk is about 1%. Other dominant conditions such as myotonic dystrophy and lymphedema distichiasis are variable and recurrence may be 50% with each child.

Demographics

The incidence of HF in the United States is 1 in 3,000 pregnancies in all populations. In developing countries where Rh antibodies are not used, the rate can be much higher, due to a higher rate of immune HF cases. In Southeast Asia the most common cause is alpha-tha- lassemia. Alpha-thalassemia is so common in Southeast Asia that it remains as the most common cause of HF in the world today.

Signs and symptoms

All babies with HF have edema of the skin, soft tissues, and placenta. Often the body cavities will show fluid collections including the abdominal cavity (ascites), pleural cavity, and pericardial cavity. The back of the neck is particularly prone to fluid collections and can sometimes contain so much fluid that it appears as a large cystic mass called a cystic hygroma. Internal organs such as the liver, spleen, and heart can become enlarged with accumulated fluid. All of these signs may be seen in the newborn or before birth using ultrasonography.

Other signs of hydrops fetalis are variable and often depend on the underlying cause. Common to most causes of HF are decreased movements during the pregnancy, respiratory distress from poor lung development due to compression of the lungs by accumulated fluid, and heart failure.

Diagnosis

HF is easily diagnosed at birth by the swollen appearance of an affected baby, but the diagnosis is often made during the pregnancy by ultrasonography. Determining the cause of the HF is more challenging, but necessary for possible treatment and recurrence risk assessment. Testing the mother for infections such as toxoplasmosis, rubella, cytomegalovirus (CMV), herpes, syphilis, and parvovirus B19 can rule out most infectious causes of HF. A high-resolution ultrasound will help determine if a baby has any major structural malformations or tumors that could cause HF. At the same time as the ultrasound a percutaneous umbilical artery blood

sampling (PUBS) procedure can be done. This procedure consists of passing a needle through the mother’s abdomen into the uterine cavity and then into the baby’s umbilical cord to withdraw a small amount of blood. This blood is then used to test for Rh antibodies, anemia, chromosome aberrations, and other suspected conditions. These diagnostic steps will determine the cause for the HF in many cases, but sometimes the cause remains unknown.

Treatment and management

As discussed in the description section, immune HF is easily prevented by administration of anti-Rh antibodies to Rh negative pregnant women. Most nonimmune HF causes have no specific treatment other than early delivery and supportive care. HF caused by some types of anemia can be treated by a blood transfusion via a PUBS procedure. Fetal arrhythmia can often be treated by antiarrhythmia medications taken by the mother. Fetal operations are indicated for HF caused by sacrococcygeal teratomas (tumor seen in newborns) and some other structural malformations.

Prognosis

The prognosis is poor. A baby who is diagnosed by ultrasonography before birth has a less than 30% chance of survival. Babies who are born alive have a 50% chance of survival. The specific cause of HF influences the chances of survival with chromosome aberrations having a higher mortality rate and infectious etiologies having a lower mortality rate.

Resources

BOOKS

Machin, Geoffrey A. “Hydrops, Cystic Hygroma, Hydrothorax, Pericardial Effusion, and Fetal Ascites.” In Potter’s Pathology of the Fetus and Infant. Ed. Enid GilbertBarness. St. Louis: Mosby, 1997, pp. 163–77.

PERIODICALS

Norton, Mary E. “Nonimmune Hydrops Fetalis.” Seminars in Perinatology 18 (August 1994): 321–332.

Steiner, Robert D. “Hydrops Fetalis: Role of the Geneticist.” Seminars in Perinatology 18 (August 1994): 516–524.

WEBSITES

“Hydrops Fetalis.” Lucile Packard Children’s Hospital. Stanford University Medical Center. http://www.packardchildrenshospital.org/health/hrnewborn/hydrops_lh.htm (2000).

Premer, Danna, M.D. “Hydrops Fetalis.” http://www.peds

.umn.edu/divisions/neonatology/hydrops.html .

Randall Stuart Colby, MD

fetalis Hydrops

Hyperlipoproteinemia

Hyperactivity of childhood see Attention deficit hyperactivity disorder (ADHD)

Hyperglycinemia with ketoacidosis and lactic acidosis (propionic type) see

Propionic acidemia

I Hyperlipoproteinemia

Definition

Hyperlipoproteinemia refers to a group of acquired and inherited disorders whose common denominator is excessive levels of lipids (fats) in the blood, caused by a metabolic disorder. It is also referred to as hyperlipidemia. The condition is a major cause of coronary heart disease (CHD).

Description

The acquired form of hyperlipoproteinemia occurs as a condition secondary to another disease, such as diabetes mellitus, hypothyroidism, or nephrosis. The hereditary, or inherited, form of hyperlipoproteinemia is classified into five major types.

Lipids are an essential part of human metabolism and are a primary source of energy for the body. Lipids are produced by cells in the body and along with carbohydrates and proteins, are components of all life. But lipids are essentially oil-based and as such do not mix with a water-based liquid such as blood. Yet both must be carried through the body’s circulatory system. So to get around this obstacle, lipids attach themselves to proteins. This combination of lipids and proteins is called lipoproteins, which are water-soluble particles that can be carried through the blood stream.

Some of the chemicals in the lipoproteins are fatty nutrients that are absorbed by the intestines for use in other parts of the body. Cholesterol is carried by lipoproteins through the blood stream to the liver and ultimately to the bowel for excretion. If the substances in the lipoproteins are not properly balanced, cholesterol will stay in the tissues instead of being excreted. It can also build up in blood vessels, eventually restricting and even blocking blood flow.

There are five different densities of lipoproteins, each containing triglycerides, cholesterol, phospholipids (lipids with phosphorus attached), and special proteins. The lipoproteins are high-density lipoproteins (HDL), low-density lipoproteins (LDL), intermediate-density

lipoproteins, very low-density lipoproteins (VLDL), and chylomicrons. HDL is commonly called “good” cholesterol and LDL “bad” cholesterol. The two major lipoprotein groups are HDL and LDL.

HDL helps prevent fat buildup throughout the body by carrying cholesterol from the arteries to the liver, where it is disposed of. Abnormally low levels of HDL, fewer than 30 milligrams per deciliter (mg/dL) of blood, are associated with a greater risk for coronary heart disease and stroke. LDL carries most of the cholesterol in the body, so an excess of LDL, usually 160 mg/dL of blood, can clog the arteries with cholesterol buildup. This can lead to atherosclerosis, commonly referred to as hardening of the arteries, or acute myocardial infarction (heart attack).

The five types of inherited hyperlipoproteinemia are:

•Type I, characterized by high levels of chylomicrons and triglycerides and a deficiency of lipoprotein lipase, an enzyme that accelerates the breakdown of lipoproteins. Disease onset is usually in infancy.

•Type II, broken into two subtypes, type II-a and type II- b. Both subtypes display high levels of blood cholesterol. People with type II-b also have high levels of triglycerides in their blood. Disease onset is usually after age 20.

•Type III, also called broad beta disease, is characterized by high blood levels of cholesterol and triglycerides, and the presence of a lipoprotein called apolipoprotein E (apo E) genotype E2/E2. Disease onset is usually in adults.

•Type IV, characterized only by high triglyceride levels in the blood. Disease onset is usually during puberty or early adulthood.

•Type V, characterized by increased blood levels of chylomicrons and triglycerides and low levels of LDL and HDL. Disease onset is usually in children or adults.

Genetic profile

Type III hyperlipoproteinemia is an autosomal recessive disorder that affects males and females. Autosomal means that the gene does not reside on the sex chromosome. People with only one abnormal gene are carriers but since the gene is recessive, they do not have the disorder. Their children could be carriers of the disorder but not show symptoms of the disease. Both parents must have one of the abnormal genes for a child to have symptoms of type III hyperlipoproteinemia. When both parents have the abnormal gene, there is a 25% chance each child will inherit both abnormal genes and have the disease. There is a 50% chance each child will inherit one abnormal gene and become a carrier of the

disorder but not have the disease itself. There is a 25% chance each child will inherit neither abnormal gene and not have the disease nor be a carrier.

The other types of hyperlipoproteinemia are autosomal dominant. This means they occur when an abnormal gene from one parent is capable of causing the disease even though the matching gene from the other parent is normal. The abnormal gene dominates the outcome of the gene pair. This means that there is a 50% chance that each child of the couple will have the disease. Consequently, there is a 50% chance each child will not inherit the defective gene and will not have the disease.

Demographics

Hyperlipoproteinemia can affect people regardless of age, gender, race, or ethnicity. All adults, starting at age 20, should be tested for hyperlipoproteinemia at least once every five years, recommends the National Cholesterol Education Program (NCEP) of the National Institutes of Health (NIH). People considered at high risk for hyperlipoproteinemia should be tested more often and include those with a diet high in fat and cholesterol, have a family history of the disorder, use oral contraceptive or take estrogen, or who have diabetes mellitus, hypothyroidism, nephrosis, or alcoholism. Ethnic groups that have a higher risk of developing hyperlipoproteinemia include Latinos, Native Americans, African-Americans, and Pacific Islanders.

Signs and symptoms

It is very common for people with hyperlipoproteinemia to show no outward signs of the disorder. But there are several general signs that may indicate a person has the disorder, including obesity, yellowish skin, fatty yellow patches or nodules on the skin, especially the eyelids, neck, and back, inflamed tendons, an enlarged spleen, inflamed pancreas, nausea and vomiting, or abdominal pain. However, these are also symptoms of a variety of other conditions so for hyperlipoproteinemia to be diagnosed, blood tests are needed.

Diagnosis

Diagnosis involves a series of blood tests to measure lipid levels and determine the type of hyperlipoproteinemia. Blood tests, usually taken after a 12-hour fast, include measurement of total serum cholesterol, HDL, LDL, VLDL, triglycerides, and for the presence of apolipoprotein E. When hyperlipoproteinemia secondary to another disorder has been excluded and inherited hyperlipoproteinemia seems likely, first-degree relatives

K E Y T E R M S

Atherosclerosis—Hardening of the arteries caused by cholesterol and fat deposits. Increases risk of heart disease, stroke, and other complications.

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.

Chylomicrons—Microscopic lipid particles common in the blood during fat digestion and assimilation.

Diabetes mellitus—The clinical name for common diabetes. It is a chronic disease characterized by inadequate production or use of insulin.

Genetic—Referring to genes and characteristics inherited from parents.

Inflammation—Swelling and reddening of tissue; usually caused by immune system’s response to the body’s contact with an allergen.

Isotope—Any of two or more species of atoms of a chemical element with the same atomic number and nearly identical chemical behavior but with differing atomic mass and physical properties.

Nephrosis—A non-inflammatory disease of the kidneys.

Serum—The liquid part of blood, from which all the cells have been removed.

should be tested. These include parents, children, and siblings.

Treatment and management

Hyperlipoproteinemia treatment is usually based on a three-fold attack: diet, exercise, and lipid-lowering medications. People who are overweight should begin a program to slowly but consistently lose weight until they are at or near the recommended weight for their height and body frame. It is essential to eat a diet low in fat. Exercise also plays a vital role. A minimum of 20 minutes of aerobic exercise three times a week is beneficial and 30 minutes or more daily is ideal. The exercise can take the form of running, jogging, cycling, swimming, cardiovascular machines, or even walking briskly.

Eating healthy and exercising regularly, while extremely beneficial, are not always enough to bring lipid levels to the desired range. Prescription medications are often required. There is a wide range of medications

Hyperlipoproteinemia

Hypochondroplasia

available to manage lipid levels. The most prescribed are HMG-CoA-reductase inhibitors, commonly called “statins,” which hinder the body’s production of cholesterol. Statins include cerivstatin (Baycol), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravacol), atorvastatin (Lipitor), and simvastatin (Zocor). Other first-line medications include bile acid sequestrants, cholestyramine (Questran), colesevelan (Welchol), and colestipol (Colestid). Also, probucol (Lorelco) is sometimes used.

The type of drug prescribed may vary, depending on the lipid test results and the type of hyperlipoproteinemia that is diagnosed. For example, people with type III of the disorder respond better when prescribed fibric acid derivatives such as gemfibrozil (Lopid), clofibrate (Atromid-S), and fenofibrate (Tricor) or nicotinic acid (niacin).

Other factors which have a negative effect on hyperlipoproteinemia include smoking, excessive alcohol consumption, and stress. It is also important to treat underlying conditions, such as diabetes, heart disease, pancreatitis (inflamed pancreas), and thyroid problems.

Prognosis

The prognosis is good for type I hyperlipoproteinemia with treatment. For type II, the prognosis is good for II-b and fair for II-a with early diagnosis and treatment. The prognosis for type III is good when the prescribed diet is strictly followed. The prognosis is uncertain for types IV and V, due to the risk of developing premature coronary artery disease in type IV and pancreatitis in type V.

Resources

BOOKS

Carlson, Lars., et al. Treatment of Hyperlipoproteinemia. New York: Lippincott-Raven Publishers, 1984.

Rifkind, Basil M., ed. Drug Treatment of Hyperlipidemia. New York: Marcel Dekker, 1991.

PERIODICALS

Abel, Allen. “The Tumblebrutus Solution.” Saturday Night (February 1997): 26-29.

Baer, Daniel. “Lipid Tests.” Medical Laboratory Observer (May 1992): 11-14.

Gotto, Antonio M. Jr., et al. “Hyperlipidemia: A Complete Approach.” Patient Care (February 15, 1989): 34-48.

ORGANIZATIONS

Inherited High Cholesterol Foundation. University of Utah School of Medicine, 410 Chipeta Way, Room 167, Salt Lake City, UT 84104. (888) 244-2465.

National Cholesterol Education Program. National Heart, Lung and Blood Institute. PO Box 30105, Bethesda, MD 20824. (301) 592-8573. http://www.nhlbi.nih.gov .

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. http://www

.rarediseases.org .

WEBSITES

“Hyperlipidemia Types I, II, III, IV, V (Hyperlipoproteinemia).” HealthGate. http://www.healthgate.com/ped/sym204

.html .

Ken R. Wells

Hypermobility syndrome see Larsen syndrome

I Hypochondroplasia

Definition

Hypochondroplasia is an autosomal dominant mutation that results in short stature with disproportionately short arms and legs, but normal head size.

Description

Hypochondroplasia is a genetic form of short stature (dwarfism) due to a problem of bone growth and development. There are many causes for short stature including hormone imbalances, metabolic problems, and problems with bone growth. Hypochondroplasia is a common form of short stature and belongs to a class of dwarfism referred to as a chrondrodystrophy or skeletal dysplasia. All skeletal dysplasias are the result of a problem with bone formation or growth. There are over 100 different types of skeletal dysplasia.

Because the features of hypochondroplasia are so mild, the disorder may go undiagnosed. Although infants with hypochondroplasia may have low birth weight, hypochondroplasia is often not evident until between two and six years of age. In general, individuals with hypochondroplasia have disproportionate short stature with an average height of 51-57 in (130-145 cm). The degree of disproportion of the limbs to the body is variable.

Most individuals with hypochondroplasia have a normal IQ although some studies suggest that up to 10% of individuals with hypochondroplasia may have mild mental retardation or learning disabilities. This finding is controversial and more studies are currently underway to verify it. The motor development of infants with hypochondroplasia is normal. In rare cases, individuals with hypochondroplasia may experience neurologic problems due to spinal cord compression. The spinal