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

Inheritance

PERIODICALS

Bader, P. I., et al. “Infantile refsum disease in four Amish sibs.”

American Journal of Medical Genetics 90 (January 2000): 110-114.

Naidu, S., and H. Moser. “Infantile refsum disease.” American Journal of Neuroradiology. 12 (November 1991): 11611163.

Torvik A., et al. “Infantile Refsum’s disease: a generalized peroxisomal disorder.” Journal of Neurological Science 85 (May 1988): 39-53.

ORGANIZATIONS

Infantile Refsum disease support and information. 6004 NE 108th Avenue, Vancouver, WA, 98662. (360) 891-5878.http://home.pacifier.com/~mstephe/ .

WEBSITES

Infantile Refsum’s Disease Webring. http://www.angelfire

.com/nc/homefireplace/IRDring.html .

National Center for Biotechnology Information. OMIM— Online Mendelian Inheritance in Man. http://www3

.ncbi.nlm.nih.gov/htbinpost/Omim .

NINDS Infantile Refsum Disease Information Page.

http://www.ninds.nih.gov/health_and_medical/disorders/ refsum_infantile_doc.htm .

Oren Traub, MD, PhD

I Inheritance

Definition

Inheritance refers to the transmission of genetic information across generations. There are two types of inheritance patterns in humans: Mendelian nuclear inheritance and non-Mendelian mitochondrial inheritance. The 23 pairs of human chromosomes located in the nucleus of the cells make up the human nuclear genome. This genome contains an estimated 30 to 40 thousand genes that we inherit in combination from our parents. These genes are called Mendelian-inherited nuclear genes, after Gregor Mendel, the Austrian monk who first established the laws of inheritance in the late 1800s. There is also DNA, called mitochondrial DNA, or the mitochondrial human genome, in the cytoplasm that we inherit almost exclusively from our mothers. These mitochondrial genes are called non-Mendelian-inherited mitochondrial genes.

Mendelian inheritance

Mendelian type inheritance is the more familiar form of genetic inheritance. During reproduction, genetic material is passed from the mother and the father to the offspring. These genes are inherited according to the laws

of segregation established by Gregor Mendel, and are called Mendelian-inherited nuclear genes.

A chromosomally normal human carries 23 pairs of chromosomes in the nucleus of each cell: 22 pairs of autosomes and one pair of sex chromosomes. An individual inherits one of each paired chromosome from each parent. Each of these chromosomes is made up of thousands of genes. Genes are the chemical sequences which together control all characteristics and functions of the body. A particular characteristic controlled by a single gene is called a trait.

Almost all genes are located on each of the two copies of the paired chromosomes. The two copies of these genes, taken together, are called an allele. If the two copies of this gene are identical to each other, this person is said to have a homozygous allele for that gene. If the two copies of this gene are not the same, this person is said to have a heterozygous allele for that gene.

The only genes that are not located on two copies of paired chromosomes occur when there is not a matching pair of chromosomes, such as those genes on the single X chromosome in an XY male. When only one chromosome carries a gene, this gene is called a hemizygous allele. A hemizygous allele is made up of only the one copy that is present.

There are three modes of Mendelian inheritance: dominant, semi-dominant, and recessive. Additionally, a trait may be sex-linked, or non-sex-linked (autosomal). A sex-linked trait is conferred from parents to their child on the X or Y chromosome. An autosomal trait is transmitted from parents to their child on one of the other 22 pairs of chromosomes (the autosomes).

Recent advances in molecular genetics have tended to blur the line between dominant and semi-dominant inheritance. It is now believed that semi-dominant inheritance is almost always observed in traits once felt to be strictly dominant traits. These research findings are in direct opposition to current clinical practice. Genetic counselors and other health care professionals prefer not to confuse their patients by referring to semi-dominant inheritance of a particular trait. Therefore, in a research setting, one is unlikely to discuss true dominance of a trait, while in a clinical setting, one is unlikely to encounter the usage of semi-dominance.

Autosomal Mendelian inheritance

AUTOSOMAL DOMINANT In autosomal dominant inheritance, only one copy of the gene that causes a specific trait must be present in order for the person to display (express) the trait. The gene is said to dominate the expression of the trait because its effects outweigh that of

the corresponding gene on the other half of the chromosome pair. Thus, in the case of a genetic mutation, one parent may pass the mutation to his or her offspring. Homozygous and heterozygous individuals will be affected equally by the mutation and both will express identical forms of the trait. The second copy of the mutated gene in the homozygous individual does not affect them more severely than the single copy of the mutated gene affects the heterozygous individual.

By definition, parents who pass on an autosomal dominant mutation to their offspring express the characteristics of that mutation. These parents are not called carriers because they are already fully affected with the trait. In the case of one heterozygous affected parent, the probability that a child will inherit this trait is 50%. In the case of two heterozygous affected parents, the probability that a child will inherit this trait is 75%. In the case of one homozygous affected parent, regardless of whether or not the other parent is affected, the probability that a child will inherit this trait is 100%.

AUTOSOMAL SEMI-DOMINANT If a particular trait is an autosomal semi-dominant trait, homozygous and heterozygous individuals will both experience characteristics of the trait. The gene for this trait still dominates the expression of the trait, but the effect of the corresponding gene on the other chromosome is noticeable. In diseases caused by a genetic mutation, the homozygous individual will experience more severe characteristics of that disease than the heterozygous individual because of the extra copy of the mutated gene that the homozygous individual possesses. Heterozygous individuals are carriers of the trait. Because these heterozygous individuals will exhibit some symptoms of the trait, they are also called symptomatic carriers.

In the case of one carrier parent and one non-carrier parent, the probability that a child of these parents will be a carrier of the trait is 50%, but their child cannot be homozygous for the trait. In the case of a homozygous affected parent and a non-carrier parent, the probability of a child being homozygous for the trait is also zero. The probability that this child will be a carrier of the trait is, however, 100%. In the case of two carrier parents, the probability that a child will be homozygous for the trait is 25%. The probability that this child will be a symptomatic carrier is 50%. In the case of one carrier parent and one affected parent, the probability that a child will be affected is 50%. The probability that this child will be a symptomatic carrier is also 50%. In the case of two affected parents, the probability that a child will be affected is 100%.

AUTOSOMAL RECESSIVE If a particular trait is an autosomal recessive trait, two copies of the mutated gene that causes this trait must be present in order for the per-

son to possess the trait. The effect of the recessive gene is less than that of the corresponding gene on the other half of the chromosome pair. Therefore, only homozygous individuals will be affected with the trait. Heterozygous individuals will not exhibit characteristics of the trait. These heterozygous individuals are called carriers because they carry the trait and can pass it on to their children. Because these heterozygous individuals do not show characteristics of the trait that they carry, they are also called asymptomatic carriers.

A child cannot exhibit the symptoms of a recessive trait unless her or his parents are either both carriers of the trait or one is a carrier of the trait and the other is affected with the trait. In the case of one carrier parent and one non-carrier parent, the probability of a child being affected with the trait is zero. However, the probability that a child of these parents will be a carrier of the trait is 50%. In the case of an affected parent and a noncarrier parent, the probability of a child being affected with the trait is also zero. The probability that this child will be a carrier of the trait is, however, 100%. In the case of two carrier parents, the probability that a child will be affected with the trait is 25%. The probability that this child will be an asymptomatic carrier is 50%. In the case of one carrier parent and one affected parent, the probability that a child will be affected is 50%. The probability that this child will be an asymptomatic carrier is also 50%. In the case of two affected parents, the probability that a child will be affected is 100%. The probability that an autosomal recessive trait will be passed to the child of consanguineous parents is much higher than it is in nonconsanguineous parents.

Sex-linked Mendelian inheritance

Sex-linked traits are carried on the X and Y, or sex, chromosomes. Sex-linked traits may be linked to either the X or the Y chromosome and may also be either dominant, semi-dominant, or recessive. Many more X-linked traits have been identified than Y-linked traits.

The sex chromosomes control the biological sex of an individual. Individuals with XY chromosomes are male, and individuals with XX chromosomes are female. The chromosome inherited from the mother is always the X chromosome, while the chromosome carried by the father’s sperm may be either an X or Y chromosome.

X-LINKED DOMINANT Chromosomally normal females possess two X chromosomes; therefore, they can be homozygous or heterozygous in a trait that is caused by a gene mutation on the X chromosome. In the case of X-linked dominant traits, only one copy of the mutant gene must be present for the trait to be fully expressed. A female child affected with an X-linked trait may inherit this trait from either her mother or her father. In cases of

Inheritance

Inheritance

Inheritance

Inheritance

A scanning electron micrograph (SEM) of the female X chromosome (left) and male Y chromosome (right). (Photo Researchers, Inc.)

hereditary mental retardation called fragile X syndrome, and both Duchenne type and Becker type muscular dystrophies.

Mitochondrial inheritance

A human being is conceived by the joining of the egg from the mother and the sperm from the father. Relative to the egg, the sperm is extremely small. It contains almost no cellular material outside the nucleus (cytoplasm) and very few mitochondria. In the cytoplasm of the egg, cellular components called mitochrondria are present. These mitochondria carry mitochondrial DNA, which is circular and contains 16,569 base pairs. Each mitochondrion contains between two and ten copies of this mitochondrial DNA. This separate genome codes for two ribosomal RNAs, 22 transfer RNAs, and 13 proteins that are used as enzymes in oxidative phosphorylation (cellular metabolism). Almost all the mitochondria in a person are derived from maternal mitochondria.

Therefore, traits that result from mutations in mitochondrial DNA are exclusively inherited from the mother. These traits are not characterized by dominant, recessive, or semi-dominant patterns.

Most often, mitochondrial DNA is mosaic for a particular trait. That is to say, the trait exists on some, but not all, of the mitochondrial DNA in each cell. There can be as few as two or as many as ten copies of this mitochondrial DNA in a single cell. When cell division occurs, these mitochondrial DNA are randomly distributed into the newly formed mitochondria of the daughter cells. In most cases this mosaicism is such that only certain cells of the body contain the mutant DNA forms while other cells of the body are normal.

Human pedigree analysis

A pedigree analysis is the inspection of a family tree to look for the inheritance pattern of a trait associated with a mutant gene or a chromosomal aberration. Because the size of human families is usually quite small, it is often impossible to determine the inheritance pattern of a particular trait by performing a pedigree analysis on a single family. Other complications arise when analyzing human pedigrees. Among these are: anticipation; de novo mutations, improper identification of members of the pedigree; mosaicism; penetrance; variable expression; and recessive conditions appearing dominant, or pseudo-dominant.

Anticipation is the tendency of a trait to become more severely expressed in succeeding generations. This is called anticipation because the more severely affected child is discovered first, then other members of the pedigree are often “anticipated” as having to be affected with milder forms of that trait. While this anticipation was originally thought to be an error in backward identification of a trait in preceding generations caused by the identification of that trait in succeeding generations, it is now recognized as a true genetic characteristic. As an example, fragile X syndrome has been demonstrated to affect each succeeding generation more severely than the preceding generation within the same family.

De novo mutations, or mutations that were not inherited from either parent, can cloud the pedigree analysis within a family. The individual who is affected did not inherit these de novo mutations but he or she may pass them on to his or her children. In these cases, if the pedigree analysis does not span a significant number of generations after the de novo affected person, the true genetic inheritance pattern of this new trait may not be able to be identified. In such cases of a lack of succeeding generations, the cause can often be mislabeled as not of hereditary origin (sporadic).

Improper identification of members of the pedigree has to be avoided when performing a pedigree analysis. This occurs most often when the father of a particular child is misidentified.

Mosaicism often causes traits to appear to have a dominant inheritance pattern in some families while that same trait appears to be recessive in other families.

Penetrance is the term used to describe the probability that a person possessing a genetic mutation will express that mutation. A true dominant trait will have a penetrance of 100%. However, many traits that are termed dominant do not have complete penetrance. Therefore, some individuals with an otherwise dominant seeming trait may be asymptomatic for that trait. Penetrance is often also problematic in age-related traits. In these traits, a dominant inheritance pattern may be missed because members of the pedigree died of causes unrelated to the dominant trait prior to developing symptoms of the trait.

Variable expression is extremely common in dominant traits. In these cases, identical mutant alleles cause different characteristics of expression in different people. This may be a variance of symptoms from one affected family to another affected family or it may be a variance of symptoms from one individual to another within a single family.

Recessive traits may appear to be dominant, or pseudo-dominant, within a pedigree. If a particular trait has a high frequency in the population, it is likely that two or more people may have independently introduced this trait into a single pedigree. This is in contrast to the typical founder effect, in which a single “founder” individual introduces the trait into the pedigree. A “founder” may be a person who is affected with a de novo mutation

that enters the pedigree with them. Or, it may be a person who comes from a relatively separate gene pool, such as a European explorer entering the formerly isolated gene pool of a remote tribe or race of people.

Resources

BOOKS

Campbell, Neil A. Jane B. Reece, and Lawrence G. Mitchell. Biology. 5th edition. New York, New York: Benjamin Cummings, 1999, pp. 239-293.

PERIODICALS

Wilkie, A. O. “The molecular basis of genetic dominance.”

Journal of Medical Genetics 31, (1994): 89-98.

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 .

WEBSITES

“Complications to basic Mendelian inheritance.” http://www

.ich.ucl.ac.uk/cmgs/compmend.htm (February 28, 2001). “Mitochondrial inheritance and oxidative phosphorylation (oxphos) diseases.” http://www.emory.edu/WHSC/

GENETICSLAB/dna/mito.htm (February 28, 2001).

MITOMAP: A human mitochondrial genome database.

http://www.gen.emory.edu/mitomap.html (February 28, 2001)

OMIM—Online Mendelian Inheritance in Man. http://www

.ncbi.nlm.nih.gov/Omim/ (February 28, 2001). Patterns of inheritance. http://www.ich.ucl.ac.uk/cmgs/

modes.htm ( February 28, 2001).

Paul A. Johnson

Ivemark syndrome see Asplenia

Inheritance

I Jackson-Weiss syndrome

Definition

Jackson-Weiss syndrome (JWS) is a hereditary disease of varying severity affecting the skull, the face, and the feet. JWS is inherited in an autosomal dominant manner.

Description

Jackson-Weiss syndrome is characterized by a small midface, unusual skull shape, and foot abnormalities. The feet display very wide big toes and webbing of the skin between the second and third toes. Additionally, the toes are angled inward. Bony foot defects apparent on x ray include short, wide foot bones and fusion of some of the foot and ankle bones.

The hallmark skull differences associated with JWS are caused by the premature closure of skull sutures, or skull plates. Other features include a small jaw, flattening of the nasal bridge and the middle third of the face, and a beaked nose. The eyes may be crossed and are widely set and slanting downward with droopy eyelids. High arching of the roof of the mouth or cleft palate, an incomplete closure of the roof of the mouth, may also be present. Mental retardation has been reported in some individuals with JWS.

Genetic profile

Jackson-Weiss syndrome is inherited in an autosomal dominant manner. This means that possession of only one copy of the defective gene is enough to cause disease. When a parent has Jackson-Weiss syndrome each of his or her children have a 50% chance to inherit the disease-causing mutation. JWS is believed to have a high rate of penetrance. This means that almost all people who inherit the altered gene will manifest symptoms. JWS has also occurred spontaneously in babies with no family history of it or any similar disorder. This is known as a sporadic occurrence.

JWS has been associated with changes in two different fibroblast growth factor receptor genes, the FGFR1 and FGFR2 genes. The fibroblast growth factor receptor genes serve as a blueprint for proteins important in inhibiting growth during and after embryonic development. FGFR1 is located on human chromosome 8 in an area designated as 8p11.2-p11.1. FGFR2 is located on human chromosome 10 in an area designated as 10q26.

As of 2001, FGFR1 has been associated with JWS in only one reported patient who had an unusual presentation of the disorder. This patient displayed JWS’s characteristic toes, foot bone fusion, and short fingers, but only very mild skull and facial differences. The genetic change seen in this patient had been seen before in a patient with symptoms much like Pfeiffer syndrome, another inherited disorder that affects the skull, face, and hands.

Most commonly, JWS is associated with changes in FGFR2. Mutations in FGFR2 are also associated with the more common Crouzon syndrome, a similar inherited disease that affects the skull and face. As of 2001 it appears that the same mutations can be associated with different diseases. Some families, like the original Amish family diagnosed with Jackson-Weiss syndrome, have members who may appear to have Crouzon syndrome or Pfeiffer syndrome. The family as a whole, however, was diagnosed as having Jackson-Weiss syndrome. In 1996, two scientists proposed that the name Jackson-Weiss syndrome should strictly be used in families like the original JWS family where different family members display features of more than one of these similar disorders (Crouzon, Pfeiffer, and Apert syndromes). As of 2001, there is controversy regarding this suggestion.

Demographics

JWS has been described in different races and geographic regions. The original Jackson-Weiss family was a large Amish family with at least 138 affected members. JWS affects both sexes equally. The strongest risk factor

Jackson-Weiss syndrome

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.

Autosomal—Relating to any chromosome besides the X and Y sex chromosomes. Human cells contain 22 pairs of autosomes and one pair of sex chromosomes.

Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10-12 weeks gestation. Under ultrasound guidance a needle is inserted either through the mother’s vagina or abdominal wall and a sample of cells is collected from around the fetus. These cells are then tested for chromosome abnormalities or other genetic diseases.

Sporadic—Isolated or appearing occasionally with no apparent pattern.

for JWS is a family history of the disorder. As of 2001, no precise estimates on the frequency of JWS are available.

Signs and symptoms

Jackson-Weiss syndrome’s hallmarks are variable skull differences, flattened mid-face, and wide big toes that angle inward toward each other. The hands are usually not involved. Rarely, deafness or mental retardation can be seen in people with JWS.

Skull abnormalities vary between individuals. Abnormalities in skull shape happen when the sutures, or open seams between the bony plates that form the skull, fuse before they normally would. Premature closure of the skull sutures is known as craniosynostosis. Growth of the brain pushes outward on skull plates that have not yet fused. In JWS different sutures may be involved leading to different head shapes. The face may be lopsided due to skull deformity.

Facial differences also vary between individuals with Jackson-Weiss syndrome. Some individuals have no obvious facial differences. The hallmark face of JacksonWeiss syndrome has very prominent, bulging, down slanting, sometimes crossed eyes that are slightly further

apart than normal with droopy eyelids. The middle third of the face is underdeveloped and somewhat flattened with a beaked nose. The forehead is rounded prominently and the hairline may be slightly lower on the forehead than usual. The chin may be small and the lower jaw may come forward more than normal. Some people with JWS may have cleft palate or a steeply arched palate (roof of the mouth). These changes may cause unusually nasal sounding speech or more serious speech difficulties.

The feet display unusually wide big toes that curve inward toward each other. The large bones of the foot may be fused or abnormally shaped. Smaller bones of the feet and toes may be abnormally shaped or absent. These bony abnormalities may be obvious only on x ray. The fingers and toes may be abnormally short with webbing of the skin between the second and third toes. Extra toes may be present at birth.

Diagnosis

Characteristic facial features and unusual toes may be obvious to an untrained eye, but a thorough physical exam by a physician is necessary to check for less obvious differences. Bony differences may not be obvious, appearing only on x ray. Bony differences in the feet were found consistently, even in seemingly unaffected individuals, in the original Jackson-Weiss syndrome family. X ray is considered to be a very important element in diagnosing JWS. X rays are also important in determining what specific type of abnormal skull plate fusion is present.

DNA testing is available for Jackson-Weiss syndrome. This testing is performed on a blood sample in children and adults to confirm a diagnosis made on physical features. Prenatal genetic testing is also available. An unborn baby can be tested for JWS with DNA extracted from cells obtained via chorionic villus sampling or amniocentesis.

Treatment and management

There is no medication or cure for Jackson-Weiss syndrome. Treatment, if necessary, depends on an individual’s symptoms. Surgery is always offered to correct the most severe physical complications, like cleft palate. Foot and facial abnormalities can also be treated with surgery if they are bothersome to an affected individual. Cosmetic surgery on the face can yield excellent results. In many cases facial differences are so mild that surgical intervention is not recommended. Counseling and support groups may be helpful to patients experiencing emotional difficulty due to physical differences.

Genetic counseling is offered to persons who have this inheritable disorder. Parents with this disease have a

50% chance of passing it to each of their children. Prenatal diagnosis for JWS is available. This prenatal genetic testing cannot, however, predict the severity or scope of an individual’s symptoms. In the future, parents with genetic diseases like Jackson-Weiss syndrome may be able to opt for disease diagnosis from a cell of an embryo before the embryo is introduced to the mother’s womb. This testing is called preimplantation genetic diagnosis and is already available in some centers in the United States.

Prognosis

The lifespan of individuals with JWS is normal. Intelligence is often normal, though borderline intelligence and mental retardation have been described in some patients with JWS.

Resources

PERIODICALS

Roscioli, T., et al. “Clinical Findings in a Patient with FGFR1 P252R Mutation and Comparison with the Literature.”

American Journal of Medical Genetics 93 (2000): 22-28. Tartaglia, Marco, et al. “Jackson-Weiss syndrome: identification of two novel FGFR2 missense mutations shared with Crouzon and Pfeiffer craniosynostotic disorders.” Human

Genetics 101 (1997): 47-50.

ORGANIZATIONS

Children’s Craniofacial Association. PO Box 280297, Dallas, TX 75243-4522. (972) 994-9902 or (800) 535-3643. contactcca@ccakids.com. http://www.ccakids.com .

FACES. The National Craniofacial Assocation. PO Box 11082, Chattanooga, TN 37401. (423) 266-1632 or (800) 3322373. faces@faces-cranio.org. http://www.faces-cranio

.org/ .

WEBSITES

Online Mendelian Inheritance in Man.

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

Robin, Nathaniel, MD. [October 12, 1998]. “Craniosynostosis Syndromes (FGFR-Related).” Gene Clinics: Clinical Genetic Information Resource. University of Washington, Seattle. http://www.geneclinics.org/ profiles/craniosynostosis/index.html .

Judy C. Hawkins, MS

I Jacobsen syndrome

Definition

Jacobsen syndrome is a rare chromosome disorder that affects multiple aspects of physical and mental development.

Description

Jacobsen syndrome is characterized by a distinctive facial appearance, some degree of mental impairment, and certain types of birth defects, especially of the heart. Other common medical complications include recurrent infections, decreased platelet count, failure to thrive, and slow growth. The syndrome derives its name from a Danish physician, Dr. Petra Jacobsen, who first described an affected child in 1973. It is also known as 11q deletion syndrome or partial 11q monosomy syndrome because a specific region of one copy of chromosome 11 is missing and thus an affected person has one out of a possible two copies of the genes in that region. It is the loss of these genes that leads to the multiple problems found in Jacobsen syndrome.

Genetic profile

The loss of genetic material from a specific segment of chromosome 11q, which at least includes the critical region at band 11q24.1, leads to the manifestations of Jacobsen syndrome. There are several ways in which this portion of chromosome 11 can be deleted. In at least twothirds of Jacobsen syndrome cases there is a partial chromosome 11q deletion (a terminal deletion) that begins at band q23 and extends through the end of the chromosome. The remainder of cases are attributed to the loss of this chromosome 11q genetic material due a deletion within, but not including, the end of the chromosome (an interstitial deletion), or due to a chromosome rearrangement such as an unbalanced chromosome translocation or a ring chromosome.

Most deletions and chromosome rearrangements responsible for Jacobsen syndrome are not familial; they are the result of a new or de novo genetic change that occurred only in the gamete (the egg or sperm) contributed by the mother or father of that individual. Less often, the origin of chromosome deletion or rearrangement is familial. In a minority of cases a parent of an affected child has a folate-sensitive fragile site at chromosome band 11q23.3 that can cause chromosomal breakage and subsequent deletion of chromosome 11q when inherited. Also, there are children who have inherited an unbalanced chromosome translocation from a parent who is a balanced translocation carrier.

Demographics

Although it is not known how many people have Jacobsen syndrome, estimates are that one person in every 100,000 is affected by the disorder. More females than males have the disorder with 70–75% of cases being females.

syndrome Jacobsen

Signs and symptoms

Symptoms of Jacobsen syndrome are variable and the prognosis for an affected child depends on the presence of life-threatening birth defects or medical problems. Individuals with Jacobsen syndrome have a distinctive physical appearance. The face is characterized by wide-spaced eyes (hypertelorism), droopy eyelids (ptosis), redundant skin covering the inner eye (epicanthal folds), a broad or flat nasal bridge, a short nose with upturned nostrils, a small chin (micrognathia), low-set ears, and a thin upper lip. As many as 90–95% of affected individuals have a malformation of the skull, trigonocephaly, a defect that results from premature closure of one of the cranial sutures. A small head size (microcephaly) is found in over one-third of cases. Overall, individuals with Jacobsen syndrome are smaller than their peers or siblings. Prenatal growth retardation occurs about 75% of the time. A newborn with Jacobsen syndrome is usually small at birth and continues to have delayed growth and subsequent short stature. Feeding problems that can result in failure to thrive are also common.

Children with Jacobsen syndrome usually have some degree of developmental delay or mental retardation, ranging from mild to severe. Nearly all affected individuals also have decreased muscle tone (hypotonia) or increased muscle tone (hypertonia) as well as fine and gross motor delays. Occasionally, brain abnormalities are present.

Multiple types of physical abnormalities are known to occur in individuals with Jacobsen syndrome. Congenital heart disease is present in about half of affected children and, if severe, can pose a significant health problem. Other common internal abnormalities include pyloric stenosis, undescended testes, inguinal hernia, kidney defects, and urinary tract abnormalities. Craniofacial abnormalities such as strabismus, ptosis, colobomas, a high-arched palate, and external ear anomalies are frequent. Orthopedic problems, mainly joint contractures and abnormalities of the digits (the fingers and toes), have been described in some cases.

In addition to congenital defects, there are a variety of other health problems found in individuals with Jacobsen syndrome. Illnesses including recurrent respiratory infections, sinusitis, and otitis media occur more frequently in children with Jacobsen syndrome. Gastrointestinal problems such as gastroesophageal reflux and chronic constipation may occur. Blood disorders such as thrombocytopenia and pancytopenia are often seen in childhood and may improve with time.

Diagnosis

Most individuals with Jacobsen syndrome are diagnosed after birth. The diagnosis is usually made through a blood test called chromosome analysis in an infant or child who has mental retardation and a typical facial appearance. The karyotype will show a deletion or rearrangement of the longer segment, known as the q arm, of one copy of chromosome 11. Jacobsen syndrome can be diagnosed before birth. There have been reports of prenatal diagnosis through amniocentesis after an ultrasound demonstrated one or more fetal abnormalities. Another technique, known as FISH (fluorescent in-situ hybridization), may be used to further define the chromosome 11q deletion breakpoints; this laboratory test is being done on a research basis to identify the diseasecausing genes in the Jacobsen syndrome critical region.

Treatment and management

There is no cure for Jacobsen syndrome nor is there a therapy that can replace the missing genes from the deleted segment of chromosome 11. In addition to routine pediatric exams, there are management strategies and treatments that aim to prevent or minimize some of the serious health consequences associated with Jacobsen syndrome.

At the time of diagnosis a series of evaluations should be undertaken in order to appropriately guide medical management. Pediatric specialists in genetics, cardiology, orthopedics, ophthalmology, and neurology should be consulted, especially since some problems can be treated if caught early. Important tests may include a karyotype, a cardiac echocardiogram, a renal sonogram, a platelet count, a blood count, a brain imaging study, hearing and vision screenings, and a dental exam.

A neurodevelopmental evaluation should be initiated in infancy or at the time of diagnosis with implementation of age-appropriate early intervention services such as speech therapy, occupational therapy, and physical therapy. An ear, nose, and throat specialist (ENT) may be needed to treat problems such as otitis media. Craniofacial and neurosurgery consults may be indicated if trigonocephaly or other forms of craniosynostosis are present.

Some children may require a gastroenterology specialist to evaluate problems such as failure to thrive, chronic constipation, and/or severe gastroesophageal reflux, some or all of which may require surgical intervention. Boys with Jacobsen syndrome should be examined for undescended testes, a problem found in half of males and one that often requires surgery.

syndrome Jacobsen