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

Rubinstein-Taybi syndrome

I Rubinstein-Taybi syndrome

Definition

Rubinstein-Taybi syndrome is a rare genetic disorder involving mental retardation, short stature, broad thumbs and great toes, and characteristic facial features. First described in 1963 by the American physicians Dr. Jack Rubinstein and Dr. Hooshang Taybi, over 550 cases have since been reported.

Description

The clinical picture of Rubinstein-Taybi syndrome (RSTS) is highly variable. The most prominent features include mental retardation, thumb and great toe abnormalities, and distinct facial characteristics.

Rubinstein-Taybi syndrome may also be referred to as broad-thumb-hallux syndrome or Rubinstein syndrome. The abbreviation for Rubinstein-Taybi syndrome is denoted “RSTS” or “RTS,” although “RSTS” is preferred so as not to be confused with other syndromes such as Rett syndrome and Rothmund-Thompson syndrome.

Genetic profile

A change in a particular gene, known as the CREB binding protein (CBP) gene, causes RSTS. This gene is located on chromosome 16. Its position is denoted as 16p13.3 where p represents the short arm of the chromosome and 13.3 indicates the exact location on the arm.

CBP codes for a protein known as the human cyclic AMP regulated enhancer binding protein (CREBBP). CREBBP has many functions within a cell. Its general role is to regulate multiple pathways and the work of other genes. It is thought that this multifunctional aspect of CREBBP is what causes the diffuse abnormalities observed in RSTS.

RSTS is thought to be autosomal dominant. Only one copy of the CBP gene must be changed or mutated for a person to have RSTS. Most cases of RSTS are sporadic. That is, the majority of affected individuals do not have a parent with RSTS, rather RSTS arose due to a new mutation in the CBP gene. Sporadic mutations in genes occur by chance. They are rare and there is nothing a person can do during a pregnancy to cause or prevent them.

Demographics

The incidence of RSTS has been estimated at between one in 125,000 and one in 300,000 live births. Males and females are affected equally. Cases of RSTS have been observed throughout the world. Although

K E Y T E R M S

Great toe—The first and largest toe on the foot.

Hallux—The great toe.

Recurrence risk—The possibility that the same event will occur again.

Respiratory—Having to do with breathing.

RSTS is thought to be a rare disease, more cases are being diagnosed each year. In part, this is thought to be due to physicians’ increasing awareness of the signs and symptoms involved in RSTS.

Signs and symptoms

RSTS is a genetic disorder involving primarily physical malformations and mental retardation.

Babies with RSTS may be born small compared to other newborns. They often have trouble feeding and may need to be assisted in this area. In conjunction with feeding problems, there may be respiratory (breathing) difficulties.

As the child matures, growth remains delayed, with short stature persistent throughout life. An average height of 60 in (153 cm) in males and 58 in (147 cm) in females and an average weight of 106 lb (48 kg) in males and 120 lb (55 kg) in females has been reported.

Developmental milestones are usually delayed. Although most children with RSTS learn to walk and talk, they tend to develop these skills much later than their peers. For example, the average age at which children with RSTS learn to walk is 30 months, compared to 12 months in unaffected children.

There are several unique physical characteristics associated with RSTS. Typical facial features include down-slanting eyes, beaked nose, and the fleshy septum of the nose extending beyond the nostrils. By two to three years of age, most affected children grow into what is considered the classic physical picture of RSTS. Because of their similar facial appearances, they may resemble other children with RSTS as much as or more than they resemble family members.

The most well known features of patients with RSTS are the broad thumbs and great toes (halluces). This finding may be observed at birth although some patients with RSTS have only broad thumbs, only broad toes, or neither.

Other findings that occur on a less frequent basis include malignant (cancerous) and benign (non-cancer-

Patients with Rubinstein-Taybi syndrome have very distinct facial characteristics such as down-slanting eyes, beaked nose, and the fleshy septum of the nose extending beyond the nostrils. (Greenwood Genetic Center)

ous) tumors, chronic ear infections, early onset of breast development in females, kidney abnormalities, high arched palate (roof of the mouth), malformed teeth (named talon cusps after their shape), heart defects, small head, and short upper lip with a pouting bottom lip.

Mental retardation of varying degrees is a constant in RSTS. Affected individuals may present mild to severe mental retardation. They have particular difficulty in expression through speech. Although affected individuals are usually able to understand what is spoken to them, they have a difficult time responding with spoken words. In general, it has been observed that many patients with RSTS do not progress beyond a first-grade level.

It has been noted that affected individuals tend to have happy, outgoing, and energetic personalities. They have been described as people who “know no strangers.” People with RSTS tend to smile often, although, due to their physical differences, this smile is sometimes described as a grimace.

Not every person with RSTS will have all of the aforementioned medical, physical, and social characteristics. Although people with RSTS have much in common, it is important to remember that each person is unique with his or her own qualities and challenges.

Diagnosis

Diagnosis is usually based on clinical findings. Laboratory techniques for definitive diagnosis by DNA analysis are available, but at this time are only able to identify approximately 25% of affected individuals. This

is due to the considerable number of different changes within the same gene that all may lead to RSTS.

Prenatal diagnosis is available for RSTS; however, again, only approximately 25% of cases are picked up by current available techniques. Because the physical features associated with RSTS are difficult to distinguish prenatally, and the available DNA test does not identify most cases, the vast majority of individuals with RSTS are diagnosed after birth.

The age at which a person is diagnosed varies from patient to patient due to the range in severity of clinical findings. Those with a more mild presentation tend to be diagnosed later in life. Diagnosis may be more difficult in non-Caucasian persons due to the great majority of research and published data having been done on Caucasian patients.

Studies have been conducted in an effort to better identify individuals with RSTS. In 2000, the outcome of a study aimed at improving laboratory techniques for RSTS diagnosis was published. The data suggested that it soon may be possible to identify more affected individuals by DNA analysis both prenatally (before birth) and postnatally (after birth).

Misdiagnosis is sometimes made between RSTS and

Saethre-Chotzen syndrome because of their similar clinical findings.

A correct diagnosis is important when providing a family with genetic counseling. A family with a child with RSTS can have many questions. Genetic counseling may be helpful in providing the family with some answers, including information about the risk of having another child with RSTS.

In general, a recurrence risk of 0.1% is given to couples that have had one child with RSTS. For individuals

Broad thumbs is the most well known feature of RSTS.

(Greenwood Genetic Center)

syndrome Taybi-Rubinstein

Russell-Silver syndrome

with RSTS there is 50% chance of passing the condition on in each pregnancy.

Treatment and management

Treatment and management is aimed at encouraging and supporting cognitive development and alleviating medical symptoms. There is no cure for Rubinstein-Taybi syndrome.

Medical problems, such as ear and respiratory infections, are treated as they occur. Chronic ear infections may lead to hearing loss and it is therefore important to have this infection treated as quickly as possible.

Early intervention and occupational and physical therapy are encouraged along with behavioral management. It has been shown that children with mental retardation and developmental delay, due to any cause, benefit from these therapies. In particular, for children with RSTS, speech therapy and alternate forms of communication, such as sign language, have been found to be helpful. Alternative avenues of communication may help children with RSTS express their thoughts and feelings and reduce the frustration they may feel at not being understood verbally.

Prognosis

Prognosis is variable due to the wide range of presentations among affected individuals. Mental retardation and developmental delay may range from mild to severe, with a reported average IQ of 51 (the general population average IQ is 100). Medical problems also vary in number and severity.

Most individuals with RSTS will have a normal life span. As adults, affected individuals may live in group homes or supervised apartments. Many work in sheltered workshops or in supervised employment situations.

Individuals with RSTS are capable of having children of their own. In a study of 502 individuals with RSTS, two had reproduced. In total they had three children, one affected with RSTS and two unaffected. It has also been the case that a very mildly affected woman was not diagnosed with RSTS until her child was born with the same disorder.

Resources

PERIODICALS

Baxter, Garry, and John Beer. “Rubinstein-Taybi Syndrome.” Psychological Reports 70, no. 2 (April 1992): 451–56.

ORGANIZATIONS

Rubinstein-Taybi Parent Support Group. c/o Lorrie Baxter, PO Box 146, Smith Center, KS 66967. (888) 447-2989. lbaxter@ruraltelnet. http://www.specialfriends.org .

WEBSITES

Online Rubinstein-Taybi Pamphlet.http://www.rubinstein-taybi.org/html/pamplet.html .

Rubinstein-Taybi Website. http://www.rubinstein-taybi.org . The Arc—A National Organization on Mental Retardation.

http://www.thearc.org .

Java O. Solis, MS

I Russell-Silver syndrome

Definition

Russell-Silver syndrome (RSS) is one of the recognized forms of intrauterine growth retardation (IUGR) diseases. It was first independently described by H. K. Silver in 1953 and by A. Russell in 1954.

Description

Russell-Silver syndrome is one of more than 300 recognized forms of genetic disorders that lead to short stature. It is characterized by:

•the presence of a triangular shaped face

•an incurving fifth finger (clinodactyly)

•low birth weight and length (intrauterine growth retardation, or IUGR)

•a poor appetite in the first few years of life

This disorder is alternately known as Russell syndrome, Silver syndrome, or Silver-Russell syndrome. Some clinicians use the term Russell syndrome to indicate this disorder when the size of the sides of the body and the limbs are equal, and the term Silver syndrome to indicate this disorder when the size of the sides of the body or the length of the limbs is different (body asymmetry).

Genetic profile

The exact genetic cause, or causes, of RSS have not been fully identified in early 2001. It is currently believed that almost all cases of RSS are the result of mutations on a gene, or possibly more than one gene, on chromosome 7.

Demographics

RSS occurs in approximately one in every 200,000 live births. Almost all cases of RSS are sporadic, that is, they appear for the first time in individuals with no fam-

ily history of RSS. However, case studies indicating all three modes of inheritance—autosomal recessive, autosomal dominant, and X-linked—have been reported.

RSS does not appear to affect any particular race or ethnic group in a greater frequency than others. It is also observed equally in males and females.

Signs and symptoms

There are six characteristics that define RussellSilver syndrome: a triangular shaped face; down turned corners of the mouth; inwardly curved little fingers (clinodactyly); a combination of low birth weight (intrauterine growth retardation) and short birth length after a full term gestation; a long, narrow head (scaphocephaly); and a poor appetite that causes slow growth after birth. These characteristics are commonly observed in people affected with RSS.

Several other characteristics are found in most, but not all, RSS affected individuals. These include:

•low blood sugar (hypoglycemia) in infancy and early childhood

•unequal body and limb size from one side of the body to the other (body asymmetry)

•late closure of the soft spot in the front of the skull

•a broad forehead

•a small chin and jaw

•crowding of the teeth or abnormally small teeth caused by a smaller than normal jaw

•an abnormally thin upper lip

•low-set, small, and prominent ears

•fusion or webbing of the toes (syndactyly)

•poor muscle tone (hypotonia)

•a condition in which the bones are not as mature as the bones of a typical person of the same age (delayed bone age)

•developmental delays

In males affected with RSS, undescended testicles and a misplacement of the urethral opening (hypospadias) on the bottom of the penis rather than on the tip of the glans is often seen.

People affected with RSS may show other symptoms on a less uniform basis. These include:

•water on the brain

•a bluish coloration of the whites of the eyes

•a highly-arched palate

•an absence of certain teeth

K E Y T E R M S

Body asymmetry—Abnormal development of the body in which the trunk and/or the limbs are not of equal size from one side of the body to the other.

Clinodactyly—An abnormal inward curving of the fingers or toes.

Delayed bone age—An abnormal condition in which the apparent age of the bones, as seen in x rays, is less than the chronological age of the patient.

Hypoglycemia—An abnormally low glucose (blood sugar) concentration in the blood.

Intrauterine growth retardation—A form of growth retardation occuring in the womb that is not caused by premature birth or a shortened gestation time. Individuals affected with this condition are of lower than normal birth weight and lower than normal length after a complete gestation period.

Precocious puberty—An abnormal condition in which a person undergoes puberty at a very young age. This condition causes the growth spurt associated with puberty to occur before the systems of the body are ready, which causes these individuals to not attain normal adult heights.

Russell syndrome—An alternative term for Russell-Silver syndrome. Many doctors use this term to mean a Russell-Silver syndrome affected individual who does not have body asymmetry.

Scaphocephaly—An abnormally long and narrow skull.

Silver syndrome—An alternative term for RussellSilver syndrome. Many doctors use this term to mean an individual with Russell-Silver syndrome who also has body asymmetry.

•frequent ear infections caused by fluid in the ear, which can lead to temporary hearing loss

•migraine headaches

•a curvature of the spine (scoliosis) or other problems with the spine, often caused by body asymmetry

•abnormalities of the kidneys

•an abnormally early onset of puberty (precocious puberty)

•irregularly colored spots on the skin (café-au-lait spots)

syndrome Silver-Russell

Russell-Silver syndrome

•high energy levels

•attention deficit disorder (ADD)

•fainting spells

Diagnosis

Diagnosis of RSS is generally accomplished by performing a genetic test on cells grown from a skin sample. This test must be performed prior to the fifth year of life and it is not always accurate.

A diagnosis of RSS is supported by examination of the affected individual’s growth curve and daily food intakes. In a child affected with RSS, these will fall well short of the mean for children of the same age.

Body measurements for asymmetry and x rays to determine the bone age versus the actual age of the patient are also useful. Additionally, a blood test indicating hypoglycemia may indicate RSS. When RSS is suspected in males, an examination of the genitals may reveal undescended testicles or a misplacement of the urethral opening.

Treatment and management

Treatment of RSS varies on a case-by-case basis depending on the symptoms of the affected individual.

Dietary changes to increase food intake are required by all people with RSS. Many patients with RSS also require a diet high in sugars to treat hypoglycemia. When the necessary food intake can not be accomplished by dietary changes, it may be necessary to treat patients with the antihistamine periactin, which also serves as an appetite stimulant. Some patients may also benefit from a feeding pump or gastrostomy. Gastrostomy is a surgical procedure in which a permanent opening is made directly in the stomach for the introduction of food.

In cases of severe growth retardation, certain people will require the administration of an artificial form of growth hormone (recombinant growth hormone) to stimulate growth, increase the rate of growth, and to increase their final adult height.

Ear tubes may be required to improve fluid drainage from the ears of some patients affected with RSS.

In cases of body asymmetry, limb lengthening surgeries may be recommended. Alternatively, shoe lifts may be all that is necessary for the attainment of a normal gait.

Depending on the severity of physical, emotional, and psychological symptoms, some affected individuals may benefit from physical and/or occupational therapy. If ADD or other developmental problems exist, individuals

with RSS may require educational assistance, such as remedial reading. In cases where the jaw is extremely small, talking may be difficult. These patients may require speech therapy.

Precocious puberty is the entrance of a child into puberty prior to the age of eight or nine. This early onset of puberty is generally accompanied by a growth spurt prior to puberty. While entering puberty before one is emotionally ready is certainly a serious problem, it is the growth spurt prior to puberty that is of major medical significance and concern.

If this growth spurt occurs prior to puberty, it is generally not as robust as if it had occurred during puberty, which causes the individual undergoing this growth spurt to grow less than a person who undergoes this process during puberty. The result is that a person who undergoes precocious puberty will generally end up much shorter in adulthood than his or her peers.

There are three hormonal therapies available in the United States to treat precocious puberty. Histrelin (trade name: Supprelin) is administered by daily injection. Leuprolide acetate (trade name: Lupron) is available as a depot formulation every four weeks. A depot formulation places medication in a tiny pump that is attached to the patient’s body and releases the medication over time. Nafarelin acetate (trade name: Synarel) is administered as a nasal spray three times daily. Because of the age of people being treated, Lupron is most often the medication of choice because it is only administered once a month.

Some doctors have noticed that persons affected with RSS may have a slightly elevated chance of developing Wilm’s tumor, the most common form of kidney cancer. Most cases of this type of cancer occur before the age of eight, and this condition is extremely rare in adults. It is important that children with RSS be screened with ultrasound every three months until the age of eight to make sure they have not developed Wilm’s tumor. Wilm’s tumor is quite treatable via surgery, chemotherapy, and/or radiation.

Prognosis

With proper medical treatment to address their individual symptoms, people affected with RSS do not, in general, have a reduced quality of life relative to the remainder of the population. As these people age, the symptoms of RSS tend to become less noticeable: the triangular shape of the face tends to lessen, muscle tone and coordination improve, appetite improves, speech improves, and learning occurs. An affected adult is generally not less happy and/or healthy than any other person.

syndrome Silver-Russell

I Saethre-Chotzen syndrome

Definition

Saethre-Chotzen syndrome is an inherited disorder that affects one in every 50,000 individuals. The syndrome is characterized by early and uneven fusion of the bones that make the skull (cranium). This affects the shape of the head and face, which may cause the two sides to appear unequal. The eyelids are droopy; the eyes widely spaced. The disorder is also associated with minor birth defects of the hands and feet. In addition, some individuals have mild mental retardation. Some individuals with Saethre-Chotzen syndrome may require some medical or surgical intervention.

Description

Saethre-Chotzen (say-thre chote-zen) syndrome belongs to a group of rare genetic disorders with craniosynostosis. Craniosynostosis means there is premature closure of the sutures (seams) between certain bones of the cranium. This causes the shape of the head to be tall, asymmetric, or otherwise altered in shape (acrocephaly). There is also webbing (syndactyly) of certain fingers and toes. Another name for Saethre-Chotzen syndrome is acrocephalosyndactyly type III. It is one of the more mild craniosynostosis syndromes.

The story of Saethre-Chotzen syndrome goes back to the early 1930s. It was then that a Norwegian psychiatrist, Haakon Saethre wrote about a mother and two daughters in the medical literature. Each had a low frontal hairline; long and uneven facial features; short fingers; and webbing of the second and third fingers, and second, third, and fourth toes. A year later in 1931, F. Chotzen, a German psychiatrist, reported a family with similar features. However, these individuals were also quite short and had additional features of mild mental retardation and hearing loss.

Genetic profile

Saethre-Chotzen is usually found in several generations of a family. It is an autosomal dominant disorder and can be inherited, and passed on, by men as well as women. Almost all genes come in pairs. One copy of each pair of genes is inherited from the father and the other copy of each pair of genes is inherited from the mother. Therefore, if a parent carries a gene mutation for Saethre-Chotzen, each of his or her children has a 50% chance of inheriting the gene mutation. Each child also has a 50% chance of inheriting the working copy of the gene, in which case they would not have Saethre-Chotzen syndrome.

The search for the gene for Saethre-Chotzen syndrome is an interesting story. The first clue as to the cause of the disorder came in 1986, with the identification of patients who had a chromosome deletion of the short arm of chromosome 7. Linkage studies in the early 1990s narrowed the region for this gene to a specific site, at 7p21. Then, in 1996, scientists at Johns Hopkins Children’s Center began to study a gene called TWIST as the candidate gene for Saethre-Chotzen syndrome. The TWIST gene was suspected because of earlier studies that showed how this gene works in the mouse.

The mouse TWIST gene normally works in forming the skeleton and muscle of the head, face, hands, and feet. Mice lacking both copies of the gene die before birth. Many have severe birth defects, including failure of the neural tube to close. They have an abnormal head and limb defects. However, mice with just one non-working copy of the TWIST gene did not die. Closer examination of these mice showed that they had only minor hand, foot and skull defects. The features were similar to those seen in Saethre-Chotzen syndrome.

It was also known that the mouse TWIST gene was located on chromosome 12 in mice, a location that corresponds to the short arm of chromosome 7 in humans. With this evidence, the researchers went on to map and isolate the human TWIST gene on human chromosome 7. They showed that this gene was in the same location

Saethre-Chotzen syndrome

K E Y T E R M S

Acrocephaly—An abnormal cone shape of the head.

Chromosome deletion—A missing sequence of DNA or part of a chromosome.

Craniosynostosis—Premature, delayed, or otherwise abnormal closure of the sutures of the skull.

Cranium—The skeleton of the head, which include all of the bones of the head except the mandible.

Exon—The expressed portion of a gene. The exons of genes are those portions that actually chemically code for the protein or polypeptide that the gene is responsible for producing.

Linkage—The association between separate DNA sequences (genes) located on the same chromosome.

Syndactyly—Webbing or fusion between the fingers or toes.

Transcription—The process by which genetic information on a strand of DNA is used to synthesize a strand of complementary RNA.

Transcription factor—A protein that works to activate the transcription of other genes.

that was missing in some individuals with SaethreChotzen. The TWIST gene is a small gene, containing only two exons (coding regions). Upon searching for alterations (mutations) in the TWIST gene, they found five different types of mutations in affected individuals. Since none of these mutations were found in unaffected individuals, this was proof positive that the TWIST gene was the cause of Saethre-Chotzen syndrome.

Scientists have also used animal models and the fruit fly Drosophila, to study the function of the TWIST gene. They have found that it takes two TWIST protein molecules to combine together, in order to function as a transcription factor for DNA. The normal function of the TWIST protein is to bind to the DNA helix at specific places. By doing so, it works to regulate which genes are activated or “turned on”. Most of the mutations identified in the TWIST gene so far seem to interfere with how the protein product binds to DNA. In effect, other genes that would normally be activated during development of the embryo may in fact not be turned on.

More recent studies suggest that the TWIST protein may induce the activation of genes in the fibroblast

growth factor receptor (FGFR) pathway. Mutations in the FGFR family of genes cause other conditions with craniosynostosis such as Crouzon syndrome. Crouzon syndrome, like Saethre-Chotzen syndrome, is a mild craniosynostosis disorder. There is much overlap in the features of the face and hands in each condition. In fact, some patients initially thought to have SaethreChotzen were given a new diagnosis of Crouzon syndrome after studying both the TWIST and the FGFR genes for mutations.

In all, it is thought that the TWIST protein most likely acts to turn on the FGFR genes. These genes, in turn, instruct various cells of the head, face, and limb structures to grow and differentiate. If the TWIST gene or other genes of the FGFR pathway are altered, an individual will have one of the craniosynostosis syndromes.

Demographics

Saetre-Chotzen syndrome affects both males and females equally. It most likely occurs in every racial and ethnic group. Approximately one or two in every 50,000 individuals has Saetre-Chotzen syndrome, making it the most common of the craniosynostosis syndromes.

Signs and symptoms

The cranium is made up of three main sections. The three sections are the face, the base of the cranium, and the top and sides of the head. Most of the cranium assumes its permanent shape before birth. However, the bones that make up the top and side of the head are not fixed in place, and the seams between the bones (cranial sutures) remain open. This allows the top of the head to adjust in shape, as the unborn baby passes through the narrow birth canal during labor. After birth, the cranial sutures will close, most often within the first few years of life. The shape of the cranium is then complete.

In Saethre-Chotzen, the shape of the cranium is abnormally formed. The reason is that the coronal suture closes too early, sometimes even before birth. The coronal suture separates the two frontal bones (forehead) from the parietal bones (top of the head). If the early closure is unilateral or asymmetric, then the forehead and face will form unevenly, from one side to the other. This also forces the top of the head to become more pointed, almost tower-like. The forehead looks high and wide. The face will appear uneven on each side, especially in the area of the eyes and cheeks.

There is also less space for the normal features of the face to develop. For instance, the eye sockets are more

shallow and the cheekbones are flat. This makes the eyes more prominent, and spaced further apart than normal. Adding to the unevenness of the face is drooping of the upper eyelids, and a slight down slant to the eyes. The nose may look beaked or bent slightly downward at the tip. In some individuals, the ears look small and low-set on the face.

The other main feature of the syndrome is minor abnormalities of the hands and feet. Webbing (syndactyly) commonly occurs between the second and third fingers and toes. The thumbs are short and flat. The fifth finger may be permanently curved or bent at the tip.

Each individual with Saetre-Chotzen is affected somewhat differently. The features are usually quite variable even within the same family. Most individuals are mildly affected. Their facial features may be somewhat flat and uneven, but not strikingly so. However, if more than one cranial suture closes too early (and this can happen in some individuals), there is more severe disfigurement to their face.

In addition to the physical characteristics, individuals with Saetre-Chotzen may have growth delays, leading to less than average adult height. Most individuals are of normal intelligence, although some may have mild to moderate mental retardation (IQ from 50-70). For the growth and mental delays, it becomes necessary to provide special assistance and anticipatory guidance.

Diagnosis

For many years, there was widespread discussion among physicians (geneticists) over whether a given patient would have either Saethre-Chotzen or Crouzon syndrome. There may even be confusion with other craniosynostosis syndromes or with isolated craniosynostosis. However, the availability of direct gene testing now allows for a more definitive diagnosis for these patients. Simply using a blood sample, a direct gene test for mutations in the TWIST gene can be done. If an individual also has mental retardation or other significant birth defects, it is suggested that they be screened more fully for deletions of the TWIST gene.

Treatment and management

Very often, the physical characteristics of SaethreChotzen are so mild that no surgical treatment is necessary. The facial appearance tends to improve as the child grows. However, sometimes surgery is needed to correct the early fusion of the cranial bones. A specialized craniofacial medical team, experienced with these types of patients, should do this surgery. Surgery may also be done to release the webbing of the fingers and toes.

Some of the more severely affected individuals with Saethre-Chotzen may experience problems with their vision. There may be less space in the eye socket due to the bone abnormalities of the face. This can lead to damage of the nerves of the eye and may require corrective surgery. The tear ducts of the eye can also be missing or abnormal. Re-constructive surgery is sometimes performed to correct the drooping of the eyelids or narrowing of the nasal passage.

Prognosis

Most individuals with Saethre-Chotzen syndrome appear to have a normal life span.

Resources

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

.org .

Forward Face, Inc. 317 East 34th Street, Room 901, New York, NY 10016. (212) 684-5860, (800) 393-3223.

MUMS. National Parent to Parent Organization. 150 Custer Court, Green Bay, WI 54301-1243. (920)336-5333.http://www.netnet.net/mums .

WEBSITES

“Entry 101400: Seathre-Chotzen Syndrome.” OMIM—Online Mendelian Inheritance in Man. http://www. ncbi.nlm

.nih.gov/entrez/dispomim.cgi?id=101400 .

Kevin M. Sweet, MS, CGC

Sanfilippo syndrome (MPS III) see

Mucopolysaccharidosis (MPS)

Sarcoma-breast-leukemia-adrenal gland (SBLA) syndrome see Li-Fraumeni syndrome

SC syndrome see Roberts SC phocomelia

Scheie syndrome (MPS I) see

Mucopolysaccharidosis (MPS)

Schilder disease see Adrenoleukodystrophy

(ALD)

Schinzel acrocallosal syndrome see

Acrocallosal syndrome

syndrome Chotzen-Saethre

Schinzel-Giedion syndrome

I Schinzel-Giedion syndrome

Definition

Schinzel-Giedion syndrome, or Schinzel-Giedion Midface-Retraction syndrome is a rare malformation syndrome characterized by skeletal anomalies, a coarse face, urogenital defects, and severe mental retardation.

Description

In affected individuals, the ureter, or tube that carries urine from the kidney into the bladder, is obstructed causing the pelvis and kidney duct to become swollen with excess urine. This is called hydronephrosis. Other features of the syndrome include hypertrichosis or the excessive growth of hair, a flat midface, abnormal brain activity, skeletal abnormalities, and severe mental retardation.

Patients show abnormal bone maturation including broad and dense ribs and short arms and legs. Severely delayed mental and motor development is accompanied by seizures and spasticity.

Genetic profile

Some scientists have suggested that the syndrome is inherited as an autosomal recessive trait because they observed that the syndrome appeared in two sibs of different sex, which suggested autosomal-recessive inheritance. However, other researchers have hypothesized that Schinzel-Giedion syndrome may be a dominant disorder with gonadal mosaicism in one parent. Gonadal mosaicism can occur when either the testes or ovaries contain some cells with an extra chromosome. Scientists have also postulated that the syndrome may be caused by an unbalanced structural chromosome abnormality.

Demographics

Schinzel-Giedion syndrome is extremely rare and remains incompletely defined. About 25 to 30 well-doc- umented cases have been reported beginning in 1978. The syndrome was originally observed in a brother, who lived less than 24 hours and a sister who survived for 16 months. Both displayed multiple skull abnormalities and profound midface retraction. They each had congenital heart defects, hydronephrosis, clubfoot, and hypertrichosis. Eight other cases, all sporadic, including two offspring of consanguineous parents were subsequently identified that year. Less than 30 cases are described in the medical literature detailing major and minor features of the syndrome. Only one case has been described in Japan. The other described cases have occurred in Western countries.

K E Y T E R M S

Hydronephrosis—Obstruction of the tube that carries urine from the kidney into the bladder causing the pelvis and kidney duct to become swollen with excess urine.

Signs and symptoms

Clinical signs include a flat midface, low set ears, a prominent forehead, skull abnormalities including large fontanels or openings, a short broad neck, genital malformations, congenital heart defects including atrial septal defect, clubfoot, and growth retardation.

Diagnosis

The detection of renal defects using prenatal ultrasound is one of the primary means of diagnosis. Clinical observation of coarse facial features, skeletal anomalies, and MRI studies aid diagnosis after birth. Serial cranial MRI studies that show a progressive neurodegenerative process affecting both gray and white matter typify Schinzel-Giedion syndrome. Clinical signs of abnormal cortical gray matter include seizures, dementia, and blindness in some cases. Abnormalities in the white matter can produce spasticity and hypereflexia.

Treatment and management

MRI studies indicate the syndrome is a progressive neurodegenerative process and patients have a limited life span. Nursing care and supportive measures are required to keep the patient comfortable.

Prognosis

Death prior to the second year of life represents the most common outcome.

Resources

BOOKS

Menkes, John H., and Harvey B. Sarnat. Child Neurology. 6th ed. Lippincott Williams and Wilkins, 2000.

Volpe, Joseph J. Neurology of the Newborn. 4th ed. Philadelphia: W.B. Saunders Company, 2001.

PERIODICALS

McPherson, E., et al. “Sacral Tumors in Schinzel-Giedion Syndrome.” (Letter) American Journal of Medical Genetics 79 (1998): 62-63.

Schinzel, A., and A. Giedion. “A Syndrome of Severe Midface Retraction, Multiple Skull Anomalies, Clubfeet, and