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Trichorhinophalangeal syndrome type II (TRPS2), also known as Langer-Giedion syndrome, is an extremely rare inherited multisystem disorder. TRPS2 is characterized by fine, thin hair; unusual facial features; progressive growth retardation resulting in short stature (dwarfism); abnormally short fingers and toes (brachydactyly); "cone-shaped" formation of the "growing ends" of certain bones (epiphyseal coning); and/or development of multiple bony growths (exostoses) projecting outward from the surfaces of various bones of the body. In addition, affected individuals may exhibit unusually flexible (hyperextensible) joints, diminished muscle tone (hypotonia), excess folds of skin (redundant skin), and/or discolored elevated spots on the skin (maculopapular nevi). Affected individuals may also exhibit mild to severe mental retardation, hearing loss (sensorineural deafness), and/or delayed speech development. The range and severity of symptoms varies greatly from case to case. TRPS2 is due to the absence of genetic material (chromosomal deletions) on chromosome 8. The size of the deletion varies from case to case.
The range and severity of symptoms varies among individuals with trichorhinophalangeal syndrome type II. Affected individuals will not have all of the symptoms listed below. The most common symptoms include fine, thin hair; unusual facial features; short stature; abnormalities of the hands and feet; and/or development of multiple bony growths (exostoses) projecting outward from the surfaces of various bones of the body. Additional characteristic abnormalities may include mental retardation, diminished muscle tone (hypotonia), and/or skin abnormalities.
Affected infants may exhibit markedly thin, sparse hair at birth (congenital); the hair may also be abnormally brittle and/or may grow slowly. Affected individuals may lose most or all of their scalp hair (alopecia) at a young age, in some cases, by the second decade of life.
Infants with TRPS2 may also have abnormalities of the head and facial (craniofacial) area including a condition known as microcephaly, which indicates that the head circumference is smaller than would be expected for age and sex. Additional features may include an abnormally large, rounded (bulbous) nose with a broad nasal bridge and thick wide nostrils (tented alae); large, protruding ears; and/or an abnormally small jaw (micrognathia) that may be displaced father back than normal (retrognathia). Affected infants may also exhibit a prominent, elongated groove in the upper lip (philtrum); a thin upper lip that may droop; deep-set eyes; widely spaced eyes (ocular hyperterlorism); and/or deviation of one eye away from the other (exotropia). In some cases, children with TRPS2 may also have dental abnormalities such as extra teeth (supernumerary central incisors) and/or absence of certain teeth.
During infancy, growth delays (retardation) may also be present. Growth retardation is typically progressive, resulting in short stature (dwarfism). In most cases, individuals with TRPS2 may also have abnormally short fingers and toes (brachydactyly), resulting, in part, from "cone-shaped" development of the "growing ends" of certain bones in the hands and feet (epiphyseal coning). In addition, the nails may be thin and brittle and, in some cases, the fifth fingers may be abnormally bent (clinodactyly). As affected individuals age, they may develop numerous bony growths (exostoses) that may project outward from the surface of various bones (e.g., pelvis, long bones, shoulder blade) in the body. In some cases, the development of multiple exostoses may result in compression of the spinal cord, certain nerves, and/or blood vessels; unequal (asymmetric) growth of the limbs; and/or limitations in movements. In addition, some affected individuals may be abnormally prone to bone fractures. Additional skeletal abnormalities may also be present including thin, narrow ribs; unusual "wing-like" shoulder blades (winged scapula); webbing (syndactyly) of certain fingers and toes; and/or abnormalities of the spinal column including sideways curvature of the spine (scoliosis).
Some individuals with TRPS2 may develop hip problems similar to those experienced by people with Legg-Calve-Perthes disease including progressive degeneration of the end portion (head) of the thighbone (capital femoral epiphyseal osteonecrosis). (For more information on Legg-Calve-Perthes disease, see the Related Disorders section of this report.)
In many affected infants, mild to severe mental retardation is present at birth. In other cases, mental retardation may not become obvious until late infancy or childhood. However, in approximately 25 percent of affected individuals, intelligence may be normal.
Affected newborns may also exhibit additional physical abnormalities including excess (redundant) skin, numerous discolored elevated spots on the skin (maculopapular nevi), diminished muscle tone (hypotonia), and/or abnormally flexible (hyperextensible) joints. As affected children age, excess skin may appear tighter and muscle tone may improve; however, skin lesions may become more numerous. Affected infants may also exhibit hearing loss (sensorineural deafness) and delays in the development of speech. In some cases, individuals affected with TRPS2 may be susceptible to frequent respiratory infections. In some cases, affected individuals may have additional abnormalities affecting the genito-urinary tract (e.g., accumulation of fluid in the uterus (hydrometrocolpos) and blood in the uterus (hematometra) in females, ureteral reflux, etc.).
With few exceptions, most cases of trichorhinophalangeal syndrome type II are the result of the absence of genetic material (chromosome deletions). Rarely, those with the syndrome have children. Two documented cases show that the deletion is inherited in an autosomal dominant manner.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
TRPS2 results from deletions (mutations) and loss of function in several adjacent genes (contiguous gene syndrome) located on the long arm (q) of chromosome 8 (8q24.11-q24.13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 8q24.11-q24.13" refers to bands 24.11-24.13 on the long arm of chromosome 8. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Researchers have located two of the genes (i.e., TRPS1 and EXT1 genes) responsible for TRPS2. These genes are located on chromosome 8 between bands q24.11-q24.13.
Trichorhinophalangeal syndrome type II is an extremely rare disorder that appears to affect males approximately three times as frequently as females. More than 60 cases have been reported in the medical literature.
Many symptoms associated with the disorder (e.g., excess skin, abnormal facial features) may be apparent at birth. Changes affecting the "growing ends" (epiphyses) of certain bones may not be apparent on x-rays until approximately three years of age. The development of bony growths that project outward from the surfaces of certain bones (multiple exostoses) are usually apparent by the age of three or five years; however, in some cases, they may be present as early as the first year of life.
Symptoms of the following disorders can be similar to those of Trichorhinophalangeal Syndrome Type II. Comparisons may be useful for a differential diagnosis:
Trichorhinophalangeal Syndrome Type I (TRPS1) is an extremely rare inherited multisystem disorder characterized by fine, thin hair; unusual facial features; abnormalities of the fingers and/or toes; and multiple abnormalities of the "growing ends" (epiphyses) of the bones, especially in the hands and feet. Characteristic facial features may include a rounded (bulbous) "pear-shaped" nose, an abnormally small jaw (micrognathia), dental anomalies, and/or unusually large (prominent) ears. In most cases, the fingers and/or toes may be abnormally short (brachydactyly) and curved. In addition, affected individuals may exhibit short stature (dwarfism). Individuals with TRPS1 do not exhibit multiple bony growths (exostoses), excess skin, or mental retardation, symptoms that are common in TRPS2. Trichorhinophalangeal Syndrome Type I has autosomal dominant inheritance. (For more information on this disorder, choose "Trichorhinophalangeal Syndrome Type I" as your search term in the Rare Disease Database.)
Trichorhinophalangeal Syndrome Type III (TRPS3), also known as Sugio-Kajii Syndrome, is an extremely rare inherited disorder that is similar to TRPS1 and TRPS2. Affected individuals typically have thin, sparse hair; unusual facial features; and abnormally short fingers and toes (brachydactyly). Characteristic facial features may include a rounded (bulbous) or "beaked" nose, a high forehead, dental anomalies, underdeveloped (hypoplastic) jaws, and/or a pointed chin. Abnormal shortness of the fingers and toes is much more pronounced in children with TRPS3 than in those with TRPS1. Children with TRPS3 do not exhibit bony growths projecting outward from the surface of various bones of the body (multiple exostoses), excess skin, or mental retardation, symptoms that are common in TRPS2. Trichorhinophalangeal Syndrome Type III is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose "Trichorhinophalangeal Syndrome Type III" as your search term in the Rare Disease Database.)
Multiple Exostoses is a rare disorder characterized by multiple bony growths (multiple exostoses) on the surface of various bones of the body. These bony growths continue to form until shortly after puberty and may cause deformities, particularly of the ankle, knee, and wrist. In some cases, affected individuals may also have abnormally short bones in the fingers (metacarpals). Multiple Exostoses may result in short stature and/or compression of the spinal cord and/or various nerves. Multiple Exostoses has autosomal dominant inheritance. (For more information on this disorder, choose "Multiple Exostoses" as your search term in the Rare Disease Database.)
Fibrodysplasia Ossificans Progressiva (FOP) is a very rare inherited connective tissue disorder characterized by the abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification), such as the ligaments, tendons, and muscles. Major symptoms may include skeletal malformations and/or abnormally short and malformed toes and fingers. The abnormal development of bone leads to stiffness in affected areas and may also limit movements in affected joints (e.g., knees, wrists, shoulders, spine, neck, etc.). Fibrodysplasia Ossificans Progressiva usually begins during early childhood and progresses throughout life. Most cases of FOP occur randomly (sporadically). In the few cases where affected individuals have had children, inheritance has been in an autosomal dominant manner. (For more information on this disorder, choose "Fibrodysplasia Ossificans Progressiva" as your search term in the Rare Disease Database.)
The following disorder may be associated with Trichorhinophalangeal Syndrome as a secondary characteristic. It is not necessary for a differential diagnosis:
Legg-Calve-Perthes Disease is a rare disorder characterized by degeneration of the end portions of the thigh bones (capital femoral epiphyseal osteonecrosis). Onset may be between the ages of six and 12 years and typically begins as mild aching in the hips followed by impaired ability to move the affected leg(s). Pain in the hips may become more intense over time and muscle spasms may also develop. In most cases, the pain subsides without intervention (spontaneously). In some cases, the thigh bone may become shorter than normal, causing a noticeable limp. The exact cause of Legg-Calve-Perthes Disease is not known. (For more information on this disorder, choose "Legg-Calve-Perthes" as your search term in the Rare Disease Database.)
The diagnosis of trichorhinophalangeal syndrome type II may be suspected at birth in some cases by a thorough clinical evaluation and identification of characteristic features. Abnormalities that are usually present at birth include unusual facial features including a large, rounded (bulbous) nose, thin, sparse hair and/or excess skin. Molecular genetic testing can confirm a diagnosis of TRPS2 by identifying mutations of the TRPS1 or EXT1 genes.
As affected individuals age, specialized imaging techniques (e.g., various x-ray methods) may be used to identify "cone-shaped" development of the end portions of certain bones (epiphyseal coning) and/or the formation of numerous bony growths (exostoses) projecting outward from the surfaces of various bones in the body. Mental retardation, hearing loss, and/or speech delays may not be detectable until affected infants grow older.
The treatment of TRPS2 is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating skeletal abnormalities (orthopedists), orthopedic surgeons, speech pathologists, physicians who specialize in assessing and treating hearing problems (audiologists), and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.
In some cases, treatment may include surgical removal of multiple exostoses that cause pain, result in compression of nerves, hinder proper development of limbs, and/or cause impairment of certain movements. Physical therapy in combination with other supportive measures may also improve an affected individual's ability to perform certain movements more easily. Hearing aids may be used to help treat significant hearing loss. In addition, physicians may regularly monitor affected individuals and recommend preventative measures for those who may be prone to repeated respiratory infections.
Early intervention is important in ensuring that children with TRPS2 reach their potential. Special services that may be beneficial to affected children include special remedial education, speech therapy, and other medical, social, and/or vocational services.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., short stature, bone abnormalities, etc.]
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Champion RH, et al., eds. Textbook of Dermatology. 5th ed. Cambridge, MA: Blackwell Scientific Publications; 1992:335-36, 1700-1.
Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:806-11.
Buyce ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1699-1701.
Dunbar JD, et al., Hip pathology in the trichorhinophalangeal syndrome. J Pediatr Orthop. 1995;15:381-5.
Hou J, et al., A 4-megabase yac contig that spans the Langer-Giedion syndrome region on human chromosome 8q24.1: use in refining the location of the trichorhinophalangeal syndrome and multiple exostoses genes (TRPS1 and EXT1). Genomics. 1995;29:87-97.
Ludecke HJ, et al., Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome. Hum Mol Genet. 1995;4:31-6.
Bauermeister S, et al., The orthopaedic manifestations of the Langer-Giedion syndrome. Orthop Rev. 1992;21:31-5.
FROM THE INTERNET
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor; Johns Hopkins University, Last Edit Date 10/4/95. Entry Number 150230.
Report last updated: 2008/05/25 00:00:00 GMT+0