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NORD is very grateful to Eniko Karman Pivnick, MD, professor at the University of Tennessee Health Science Center, for assistance in the preparation of this report.
Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a very rare genetic disorder characterized by an aged appearance at birth (old man look) growth delays before and after birth (prenatal and postnatal growth retardation), and deficiency or absence of the layer of fat under the skin (subcutaneous lipoatrophy). It is anticipated that most individuals with WRS have decreased life expectancy. There are few individuals who have lived well in to the teens and afew still live in their 20s. WRS is inherited as an autosomal recessive trait, as several pairs of siblings have been reported in families with unaffected parents.
WRS is characterized by an aged appearance at birth and deficiency or absence of the layer of fat under the skin (subcutaneous lipoatrophy). Progressive neurological deterioration may occur. The specific symptoms may vary from case to case as affected individuals may not have all of the symptoms listed below.
In individuals with WRS, abnormal growth delays may occur before birth (intrauterine growth retardation), particularly during the last three months (third trimester) of fetal development. The growth delays will continue well after birth (postnatal). Patients with WRS also experience poor weight gain, and failure to thrive through their lifetime.In addition, in some cases, affected infants may experience swallowing (dysphagia) and feeding difficulties that may contribute to growth delays and failure to thrive.
Infants with WRS have an aged (progeroid) appearance at birth due to a deficiency or absence of the layer of fat under the skin (subcutaneous lipoatrophy). As a result, the skin may appear unusually thin, fragile, wrinkled, and aged. Certain veins and muscles may be abnormally prominent, particularly those of the forehead. For unknown reasons, as affected infants age, abnormal deposits of fat may accumulate under the skin (subcutaneous) in lower (caudal) areas of the body, particularly around the buttocks, the areas around the genitals and the anus (anogenital area), and the area between the ribs and the hips (flanks). In addition, in infants and children with the disorder, the abdomen may appear unusually large and prominent.
Infants and children with WRS also have distinctive abnormalities of the head and face (craniofacial) . In many cases, the soft spot in the front of the skull (anterior) may be abnormally large and wide, and its closure may be unusually delayed. The fibrous gaps between other bones in the skull (cranial sutures) may also be abnormally wide. In addition, in infants with the disorder, bones of the forehead (frontal bones) and the sides of the skull (parietal bones) are abnormally prominent (frontal and biparietal bossing), while the facial bones are unusually small and underdeveloped (hypoplastic).
Such abnormalities may cause the head to appear unusually large (pseudohydrocephalus). In affected infants and children, distinctive facial abnormalities may include an unusually small mouth (microstomia); a prominent chin, and low-set ears that are abnormally angled toward the back of the head (posteriorly angulated). Facial features typically appear unusually small when compared with the large forehead and sides of the skull. In addition, affected infants may have an unusually small, distinctively "beak-shaped" nose that becomes more pronounced with advancing age.
In most infants and children withWRS, additional craniofacial abnormalities are also present. Affected infants may have two to four front teeth (neonatal incisors) which fall out during the course of early infancy. Subsequent tooth development (dentition) is delayed and impaired. In addition, in infants and children with the disorder, the lower eyelids may droop or turn outward (ectropion), exposing the thin, delicate mucous membranes that line the eyelids as well as a portion of the eyeballs (conjunctivae). An interesting feature in a few cases is that the lower eyelids may cover more than the lower half of the eyeball as if the eyelids are situated higher than expected. Affected infants and children may also have unusually sparse scalp hair, eyebrows, and eyelashes. (hypotrichosis).
Infants and children with WRS may also have distinctive abnormalities affecting the hands, feet, arms, and legs (extremities). The arms and legs are abnormally thin, the hands and feet are disproportionately large; and the fingers and toes are long with unusually small, incompletely developed (atrophic) nails. Recent MRI (magnetic resonance imaging) studies have confirmed the presence of normal amounts of subcutaneous truncal fat, and marked loss of fat from the face and distal extremities. Bone thinning (osteopenia) may predispose to bony fractures. Bone progenitor cell transformation to bone (osteoblasts) and cartilage cells (chondrocytes) are also impaired. The lack of cellular differentiation capacity in WRS patients may be responsible for the clinical appearance and symptoms of this rare disorder.
Most infants and children with the disorder also have varying degrees of mental retardation, which may range from mild to severe. However, a few children have demonstrated near normal mental development. During infancy, affected individuals may begin to experience progressive neurological and neuromuscular abnormalities. In most cases, there are severe delays in the acquisition of skills requiring the coordination of physical and mental activities (psychomotor retardation). In addition, in many cases, infants and children with the disorder lack head control; exhibit diminished muscle tone (hypotonia), and have an impaired ability to coordinate voluntary movements of the chest and abdominal areas (truncal ataxia). For example, they may have difficulty controlling the range of movements during certain muscular actions and may experience rhythmic, involuntary tremors when performing certain movements (intention tremor). Infants and children with the disorder may also experience rapid, involuntary, horizontal movements of the eyes (horizontal nystagmus) and limited clearness (acuity) of vision. Older children may have an unusual high-pitched voice.
In addition, investigators have reported that neurological deterioration observed in a few individuals with WRS may be associated with loss of the myelin sheath from nerve fibers (demyelization) within the white substance of the brain (e.g., pure sudanophilic leukodystrophy). Myelin is a whitish fatty substance that forms a protective wrapping or "sheath" around certain nerve fibers (axons) and serves as an electrical insulator, enabling the effective transmission of nerve impulses. "White substance" within the brain and spinal cord (central nervous system) primarily consists of bundles of myelinated nerve fibers. The majority of cases with WRS did not have leukodystrophy at the age ascertained.
The lack of subcutaneous fat tissue has prompted researchers to compare WRS with generalized lipodystrophy (Berardinelli) syndrome. Laboratory studies, however in those cases examined, have shown no elevation of fasting glucose, lipids, or insulin as would be expected in Berardinelli syndrome. A few patients however, had elevated triglyceride levels.Individuals with WRS may also develop abnormal side-to-side curvature of the spine (scoliosis). In addition, infants and children with WRS are often prone to recurrent respiratory infections, which may result in life-threatening complications.
WRS is most likely inherited as an autosomal recessive genetic condition. Several siblings with WRS have been reported in unrelated families.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person is a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Some individuals with WRS have had parents who were related by blood (consanguineous).
All individuals carry several abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than non-consanguineous parents to carry the same abnormal gene, which increases the risk to have children with a rare recessive genetic disorder.
The specific underlying defect responsible for the disorder remains unknown. However, some researchers suggest that disturbances in bone maturation and hormonal and fatty (lipid) metabolism may play some role.
WRS is an extremely rare genetic disorder that appears to affect males and females relatively equally. WRS has been observed in various ethnic and racial groups. The disorder was initially described as a distinct entity in 1979 (Wiedemann HR) based upon observation of two unrelated individuals as well as previous reports of two affected sisters in 1977 (Rautenstrauch T). More than 30 cases have been reported in the medical literature to date.
Symptoms of the following disorders may be similar to those of Wiedemann-Rautenstrauch Syndrome. Comparisons may be useful for a differential diagnosis:
WRS shares some common clinical characteristics with Hutchinson-Gilford Progeria Syndrome (HGPS). It is a recent discovery, that a single gene called lamin A (LMNA), is responsible for HGPS. This particular gene makes a protein necessary to hold the center (nucleus) of a cell together. However, when the LMNA gene was analyzed in a few cases of WRS, there was no abnormality found. Similarly there was no telomere length shortening in skin fibroblast in a patient with WRS. This result differs from those observed in Hutchinson-Gilford Progeria. (For more information on this disorder, choose "progeria, Hutchinson-Gilford " as your search term in the Rare Disease Database.)
Hallerman-Streiff Syndrome, a rare genetic disorder, is characterized by distinctive craniofacial malformations including an abnormally small head (microcephaly) that is unusually wide (brachycephaly) with a prominent forehead (frontal bossing); an underdeveloped lower jaw (hypoplastic mandible), an unusually small mouth (microstomia); and/or a "beak-shaped" nose. The disorder is also characterized by proportionate short stature (dwarfism); abnormalities of the eyes; malformations of the teeth; and/or other abnormalities. Eye (ocular) abnormalities may include unusually small eyes (microphthalmia); clouding of the lenses of the eyes at birth (congenital cataracts), rapid, involuntary eye movements (nystagmus), crossing of the eyes (strabismus), decreased clarity of vision (visual acuity), and/or other ocular abnormalities. Dental defects may include the presence of certain teeth at birth (neonatal teeth), improper development of tooth enamel (enamel dysplasia); and/or absence (hypodontia or partial adontia), malformation, and/or improper alignment of certain teeth. Individuals with Hallerman-Streiff Syndrome typically have normal intelligence. In most cases, the disorder appears to occur randomly for unknown reasons (sporadically). In other cases, Hallermann-Streiff Syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Hallermann Streiff" as your search term in the Rare Disease Database.)
De Barsy Syndrome (also known as Progeroid Syndrome of De Barsy) is an extremely rare genetic disorder that is apparent at birth. The disorder is characterized by abnormal looseness of the skin (cutis laxa); an aged (progeroid) appearance, clouding of the lenses of the eyes (cataracts); continual, involuntary writhing movements, particularly of the arms and legs (athetosis); and/or short stature. Affected infants and children may also have abnormalities of the head and facial area including an unusually small head (microcephaly) with a prominent forehead (frontal bossing); large, misshapen (dysplastic) ears; thin lips, and/or sparse scalp hair. Additional characteristics often associated with the disorder may include diminished muscle tone (hypotonia), psychomotor retardation, and mental retardation. De Barsy Syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "De Barsy" as your search term in the Rare Disease Database.)
Hutchinson-Gilford Progeria Syndrome is a very rare progressive disorder of childhood characterized by premature aging (progeria), growth delays occurring in the first year of life resulting in short stature and low weight, deterioration of the layer of fat beneath the skin (subcutaneous adipose tissue), and characteristic craniofacial abnormalities including an abnormally small face, underdeveloped jaw (micrognathia), unusually prominent eyes, and/or a small, "beak-like" nose. In addition, during the first year or two of life, scalp hair, eyebrows, and eyelashes may become sparse, and veins of the scalp may become unusually prominent. Additional symptoms and physical findings may include joint stiffness, repeated nonhealing fractures, a progressive aged appearance of the skin, delays in tooth eruption (dentition), and/or malformation and crowding of the teeth. Individuals with the disorder typically have normal intelligence. In most cases, affected individuals experience premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), potentially resulting in life-threatening complications. Hutchinson-Gilford Progeria Syndrome is thought to be due to an autosomal dominant genetic change (mutation) that occurs for unknown reasons (sporadic). (For more information on this disorder, choose "Hutchinson Gilford" as your search term in the Rare Disease Database.)
Cockayne Syndrome is a very rare genetic disorder characterized by growth retardation, abnormal sensitivity to sunlight (photosensitivity), a prematurely aged (progeroid) appearance, and/or other abnormalities. In the classical form of Cockayne Syndrome (Type I), the symptoms are progressive and typically become apparent within the first year of life. In Early Onset Cockayne Syndrome (Type II), associated symptoms and physical findings are apparent at birth (congenital). Affected individuals have distinctive craniofacial abnormalities including an unusually small head (microcephaly), loss of fat underneath the skin, sunken eyes, malformed ears, and a thin, beaked nose. Such abnormalities contribute to a prematurely aged appearance. Individuals with the disorder also exhibit short stature, progressive loss of vision due to degeneration of the nerve-rich membrane lining the eyes (retina); extreme sensitivity to sunlight (photosensitivity), and/or neurological degeneration including progressive mental retardation, movement disturbances, deafness, and loss of intellectual abilities (dementia). In some cases, affected individuals may exhibit premature thickening and loss of elasticity of artery walls (arteriosclerosis), potentially resulting in life-threatening complications. Cockayne Syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Cockayne" as your search term in the Rare Disease Database.)
There are additional congenital disorders that may be characterized by growth delays, progeroid appearance, craniofacial malformations, mental retardation, progressive neurological and neuromuscular symptoms, and/or other abnormalities similar to those occurring in association with Wiedemann-Rautenstrauch Syndrome. Such disorders usually have other symptoms or physical findings that may differentiate them from Wiedemann-Rautenstrauch Syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
In some cases, growth retardation, macrocephaly, and/or other characteristic findings suggestive of Wiedemann-Rautenstrauch Syndrome may be detected before birth (prenatally) by ultrasound.
In most cases, Wiedemann-Rautenstrauch Syndrome is diagnosed shortly after birth, based upon a thorough clinical evaluation and identification of characteristic physical findings (e.g., small stature, characteristic craniofacial and skeletal malformations, absence or deficiency of subcutaneous fat, etc.). In some cases, specialized tests may also be conducted to detect certain abnormalities potentially associated with the disorder. For example, X-ray studies may reveal and/or confirm wide cranial sutures and/or other abnormalities of cranial bones. In addition, it is possible that computer-assisted tomography (CAT), magnetic resonance imaging (MRI), and/or other specialized tests may reveal widespread loss of the fatty coverings (myelin sheath) on nerve fibers (demyelination) within the white matter of the brain (pure sudanophilic leukodystrophy).
The treatment of Wiedemann-Rautenstrauch Syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat disorders of the nervous system (neurologists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.
Specific therapies for Wiedemann-Rautenstrauch Syndrome are symptomatic and supportive. In some cases, if affected infants and children experience swallowing and feeding difficulties and cannot feed appropriately by mouth, a tube may be surgically inserted into the stomach or a portion of the small intestine (tube feeding) to help provide appropriate nourishment. In addition, affected infants and children should be carefully monitored to help guard against respiratory infections. Genetic counseling will be of benefit for affected individuals and their families.
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 [progeroid appearance, neurological abnormalities, mental retardation, etc.].)
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Home page: http://www.progeriaresearch.org
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Report last updated: 2010/08/31 00:00:00 GMT+0