NORD gratefully acknowledges Robert Power, NORD Editorial Intern from the University of Notre Dame, and Maian Roifman, MD, Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, for assistance in the preparation of this report.
Autosomal recessive Robinow syndrome is characterized by short stature, characteristic facial features, skeletal abnormalities, and/or genital abnormalities. The range and severity of symptoms vary from person to person.
Most children with Robinow syndrome experience growth delays after birth, resulting in slight to moderate short stature. Most children have normal intelligence but approximately 20 percent of those affected may have intellectual disability, delays in reaching developmental milestones, and/or delays in developing language skills.
Facial features resemble those of a developing fetus, a finding often termed “fetal facies” in the medical literature. Characteristic abnormalities of the head and facial area may include a large head (macrocephaly) with a bulging forehead (frontal bossing) and underdevelopment of the middle portion of the face (midface hypoplasia). Affected infants may also have widely spaced eyes (ocular hypertelorism) that are prominent (exophthalmos); unusually wide, downwardly slanting eyelid folds (palpebral fissures); a small, upturned nose with nostrils that are flared forward (anteverted); a sunken (depressed) nasal bridge; and/or abnormally positioned (i.e. low-set, posteriorly rotated) ears. Some affected infants may have a broad, triangularly-shaped downwardly turned mouth with a long groove (philtrum) in the center of the upper lip; a small chin; a small jaw (micrognathia); and/or overgrown gums (gingival hyperplasia).
Dental abnormalities may also be present including misaligned teeth, crowding of the back (posterior) teeth, and/or delayed eruption of the secondary (permanent) teeth. The soft-tissue structure at the back of the throat (uvula) may be underdeveloped or abnormally divided (bifid). Affected infants may also have incomplete closure of the roof of the mouth (cleft palate), an abnormal vertical groove or opening in the upper lip (cleft lip), and/or restricted movements of the tongue (ankyloglossia). Aankyloglossia may contribute to delays in language skill development. In most children, the facial abnormalities associated with Robinow syndrome become less pronounced as children age.
Skeletal abnormalities may include forearm bones (radius and ulna) that are abnormally short and underdeveloped (forearm brachymelia); abnormal deviation of the thumb side of the forearm (radius) due to shortening of the radius (Madelung deformity of the wrist); unusually short fingers (brachydactyly); permanent fixation of the fifth fingers in a bent position (clinodactyly); and/or abnormally small hands with broad thumbs. The end bones (terminal phalanges) of the thumbs and great toes may be abnormally divided (bifid) and/or the bones (phalanges) of the fingers and toes may be underdeveloped (hypoplastic). Additional abnormalities may include dislocation of the hips, limited extension of the elbows, abnormal fusion or absence of certain ribs, abnormal side-to-side curvature of the spine (scoliosis), underdevelopment of one side of the bones (vertebrae) in the middle (thoracic) portion of the spinal column (hemivertebrae), and/or fusion of certain vertebrae. Affected infants may exhibit abnormal depression of the bone forming the center of the chest (“funnel chest” or pectus excavatum).Infants may also have malformed (dysplastic) nails and/or abnormalities of the skin ridge patterns (dermatoglyphics) on the fingers and palms.
Most infants with Robinow syndrome also have abnormalities of the genitals and some may have external genitals that are not distinctly male or female (ambiguous genitalia). Gender can usually be properly determined during early infancy. In females, the clitoris and the outer, elongated folds of skin on either side of the vaginal opening (labia majora) may be underdeveloped (hypoplastic). In males, the penis may be abnormally small (micropenis) and may be hidden under the surrounding skin; in addition, one or both of the testes may fail to descend into the scrotum (cryptorchidism).Rarely, affected males may have abnormally low levels of testicular function (partial primary hypogonadism, but experience normal development of secondary sexual characteristics (e.g., deepening of the voice, characteristic hair growth patterns, sudden increase in growth and development of the testes and scrotum, etc.) with the exception of the persistence of micropenis. Affected females exhibit normal function of the ovaries (normal gonadal function) and normal fertility.
Individuals with Robinow syndrome may have additional physical abnormalities such as duplication of the kidneys, unusual accumulation of urine in the kidney (hydronephrosis), protrusion of portions of the large intestine through an abnormal opening in the muscular lining of the abdominal cavity (inguinal hernia), and/or protrusion of portions of the large intestine through the abdominal wall near the navel (umbilical hernia). In addition, approximately 13 percent of infants with Robinow syndrome have heart (cardiac) defects that are present at birth (congenital heart defects). In such cases, the most common heart defect has been “right ventricular outlet obstruction,” in which the flow of blood from the lower chamber of the heart (ventricle) was obstructed due to abnormal narrowing (stenosis) or closure (atresia) of the vessel that arises from the ventricle (pulmonary trunk) and divides into the left and right pulmonary arteries. Symptoms associated with this heart defect vary greatly depending upon the size and location of the obstruction. In some infants with Robinow syndrome, other cardiac abnormalities may be present including complex congenital heart defects that may lead to life-threatening complications. Rarely, infants and children with Robinow syndrome may be prone to repeated infections of the lungs (pneumonia). In rare, severe cases, without appropriate treatment, pneumonia may result in life-threatening complications.
The dominant and recessive forms of Robinow syndrome share many of the same symptoms and physical findings (e.g., craniofacial abnormalities, short stature, skeletal malformations, and genital hypoplasia). However, the symptoms and physical findings associated with the recessive form tend to be more severe. Infants with the recessive form of Robinow syndrome exhibit more numerous rib abnormalities (e.g., abnormal displacement, fusion, and/or absence of certain ribs) and defects affecting bones of the spinal column (vertebrae) than those infants with the dominant form of the disorder. In addition, short stature, underdevelopment of the forearm bones (radioulnar hypoplasia), and abnormalities of the fingers are more severe. Affected children may exhibit dislocation of the head of one of the forearm bones (radial head dislocation), an abnormality rarely seen in individuals with the dominant form of Robinow syndrome. Individuals with the recessive form may also tend to have a more triangularly-shaped mouth.
A variant form of autosomal dominant Robinow syndrome, the osteosclerotic form, is characterized by increased bone mineral density, particularly in the skull; normal height; large head; and hearing loss, in addition to the typical signs and symptoms.
The autosomal recessive and autosomal dominant forms of Robinow syndrome are caused by changes (mutations) in different genes.
Autosomal recessive Robinow syndrome occurs due to mutations in the ROR2 gene resulting in a lack of ROR2 protein. Without this protein, development is disrupted, particularly the formation of the skeleton, heart and genitals.
Autosomal dominant Robinow syndrome occurs due to mutations in the WNT5A gene or DVL1 gene, resulting in a lack of specific proteins necessary for normal development. The osteosclerotic form is caused by DVL1 gene mutations.
Some people with Robinow syndrome do not have mutations in any of these genes and the cause of the condition is unknown.
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. 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 inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and 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.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular 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 an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
Autosomal recessive Robinow syndrome has been reported in fewer than 200 people in families from various ethnic backgrounds.
Autosomal dominant Robinow syndrome has been reported in fewer than 50 families.
Diagnosis of Robinow syndrome is usually made shortly after birth based on physical findings including short stature, limb and genital abnormalities and characteristic facial features. Molecular genetic testing for mutations in the ROR2 gene is available to confirm the diagnosis of autosomal recessive Robinow syndrome. Molecular genetic testing for mutations in the WNT5A gene and DVL1 gene is available to confirm the diagnosis of autosomal dominant Robinow syndrome.
The treatment of Robinow 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 treat skeletal abnormalities (orthopedists), surgeons, specialists who diagnose and treat heart problems (cardiologists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
In affected infants who have ambiguous genitalia, gender may be properly determined by clinical examination during the newborn period. In some children, surgery may be performed and/or other measures may be taken to correct cryptorchidism and/or other genital abnormalities. Additionally, hormone supplements such as human chorionic gonadotropin and/or testosterone are sometimes administered in order to treat micropenis by improving penile length and testicular volume. Growth hormone deficiency in some patients has been found to respond positively to growth hormone therapy. These forms of hormone therapy however, must be closely monitored by a pediatric endocrinologist.
Braces, casts, special exercises, and/or surgery may be beneficial in treating certain vertebral abnormalities. Surgery may also be performed to correct inguinal hernias, certain craniofacial abnormalities, severe curvature of the spine (scoliosis) secondary to hemivertebrae and rib abnormalities, wholly or partly united fingers/toes (syndactyly), cleft lip/palate, and/or other malformations. Use of braces, dental surgery, and/or other supportive techniques may be used to help correct misalignment of the teeth and/or other dental abnormalities.
Infants and children with Robinow syndrome should receive thorough medical evaluations to ensure prompt detection and immediate appropriate treatment of heart (cardiac) abnormalities that may be potentially associated with the disorder. Affected infants and children should also be carefully monitored to help prevent and/or immediately detect infections of the lungs (pneumonia) and to ensure prompt, appropriate treatment.
Early intervention is important to ensure that children with Robinow syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education, special social support, physical therapy, and/or other medical, social, and/or vocational services.
Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder 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
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For information about clinical trials sponsored by private sources, contact: www.centerwatch.com.
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., short stature, intellectual disability, etc.].)
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