NORD gratefully acknowledges Bianca Fox, NORD Editorial Intern from the University of Notre Dame, and Samantha A. Vergano, MD, FAAP, Attending Physician, Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, Norfolk, VA, for assistance in the preparation of this report.
Una traducción en español de este reporte está disponible aquí.
CSS is characterized by distinctive abnormalities of the head and facial (craniofacial) region with affected individuals often described as having coarse facial features that become more prominent with age. Affected individuals may have an unusually small head (microcephaly); a wide mouth with full, prominent lips; a broad nasal tip; a low nasal bridge; and an abnormally long vertical groove between the nose and the upper lip (philtrum). Additional features may include thick eyebrows, long eyelashes, and generalized excessive hair growth (hypertrichosis) with the exception of the scalp hair, which tends to be relatively sparse (scalp hypotrichosis). Reports suggest that sparse scalp hair improves with age.
Individuals with CSS also have characteristic skeletal abnormalities. For example, certain fingers and toes (digits), particularly the fifth fingers (“pinkies”) and toes, may be unusually short due to absence or underdevelopment (hypoplasia) of the end bones (terminal phalanges) within these digits. The fingernails and toenails may also be underdeveloped or absent. Additional abnormalities may include dislocation of the inner forearm bone (radius) at the elbow, deformity of the hip (coxa valga), or unusually small or absent knee caps (patellae).
Early in life, infants with CSS typically experience feeding difficulties, vomiting, slow growth and weight gain (failure to thrive) which may have begun while the infant was still in the womb (intrauterine growth retardation), and frequent respiratory infections. In addition, affected infants and children may have hypotonia, abnormally loose joints, delayed bone age (2 to 3 years behind the chronological age), and mild to severe intellectual disability. Affected infants and children may also have mild to severe speech delays, where expressive language is affected more severely than receptive language, as well as moderate to severe delays in motor skills such as sitting and walking. Reports suggest that on average, affected children learn to sit up at 12 months (typically occurs at 6 to 8 months), walk at 30 months (typically occurs at 9 to 18 months), and speak at 24 months (typically begins around 12 months).
Affected individuals may also have eye (opthamologic) abnormalities. This can include drooping of the upper eyelid (ptosis), clouding of the lens of the eye (cataracts), and misalignment of the eyes (strabismus, commonly known as “lazy eye”).
CSS has been reported to manifest kidney (renal) or genitourinary abnormalities in some affected individuals. There have been reports of affected individuals with fused kidneys at the lower end (horseshoe kidney) and the urethra – the tube through which urine drains from the bladder to exit the body – opening on the underside of the penis instead of at the tip (hypospadias).
Individuals with CSS may also have gastric abnormalities which may include one portion of the bowel sliding into the next like a telescope (intussusception) or an opening in the diaphragm allowing abdominal organs to push up into the chest cavity (diaphragmatic hernia).
Less commonly, affected individuals may have additional physical abnormalities, such as choanal atresia, a malformation in which a bony or thin layer of tissue blocks the passageway between the nose and throat, leading to breathing difficulties. Some individuals with CSS may also have heart abnormalities at birth. In addition, a brain abnormality known as Dandy-Walker malformation has been reported in some cases. This condition is characterized by cystic malformation and expansion of one of the cavities in the brain (fourth ventricle). Dandy-Walker malformation is usually associated with an abnormal accumulation of cerebrospinal fluid (CSF) in the skull (hydrocephalus), resulting in increased fluid pressure, a rapid increase in head size, abnormal prominence of the back region of the head (occiput), and/or other associated findings. Some individuals with CSS may also have partial or complete absence of the band of nerve fibers that joins the two hemispheres of the brain (agenesis of the corpus callosum) and fewer folds in their brain (gyral simplification). Some affected individuals may also experience hearing loss, seizures and tics. There have been reports of liver cancer (hepatoblastoma) in affected individuals, but the link between CSS and tumor risk needs to be further investigated.
CSS is thus far known to be caused by mutations in one of the following five genes: ARID1A, ARID1B, SMARCA4, SMARCB1, or SMARCE1. Genes provide instructions for creating proteins that play a critical role in many functions of the body. The genes linked to CSS provide the instructions to make several different protein complexes that are known as switch/sucrose nonfermentable (SWI/SNF) complexes. These protein complexes regulate gene activity by altering how tightly regions of DNA are packaged, which can affect gene expression. Subsequently, SWI/SNF complexes are involved in a variety of processes including cell growth, division, and differentiation and the replication and repairing of DNA. It is still unclear how the mutations affect SWI/SNF complexes, but researchers believe the mutations alter DNA packaging, which can disrupt gene activity and cellular processes and lead to the symptoms of CSS.
CSS appears to be inherited as an autosomal dominant condition. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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 affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. With CSS, most mutations appear to be the result of a new (de novo) mutation that occurs during early development in the embryo rather than inherited.
In some dominant disorders, including CSS, disease expression may be variable. If individuals inherit a mutated gene for the disease, the characteristics that are expressed may vary greatly and range in severity from case to case.
Other researchers indicate that CSS may be inherited as an autosomal recessive trait. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one abnormal gene, 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 defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier is 50% with each pregnancy. The chance for a child to receive a normal gene from each parent for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are related by blood (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. Parents of some individuals with CSS have been closely related by blood.
Not all affected individuals have mutations in the ARID1A, ARID1B, SMARCA4, SMARCB1, or SMARCE1 genes. It is likely that there are additional genes that may cause CSS. Some researchers also suggest that isolated (sporadic) and familial cases of CSS may be due to unknown chromosomal abnormalities. Further research is required to fully determine the disorder’s underlying cause and potential mode of transmission.
Mutations in the genes that cause CSS have also been linked to other disorders (allelic disorders). Mutations in the ARID1B gene have been reported in several individuals with intellectual disability. Mutations in the SMARCA4 and SMARCB1 genes have been reported to carry a potential increased risk toward the growth of rhabdoid tumors (tumors of muscle tissue) and atypical teratoid and rhabdoid tumors (tumors typically located in the brain and other areas of the central nervous system). Overall, the risk of tumor growth is very low; further research is required to better assess the cancer risk in individuals with these mutations.
CSS occurs worldwide with no ethnic predisposition. The disorder may affect females about four times more frequently than males. Since the disorder was originally described in 1970 (G.S. Coffin), at least 80 cases have been reported.
CSS should be suspected in newborns with underdeveloped nails and short fifth fingers and distinctive facial features. The facial features may become more apparent as the child grows. A diagnosis is based upon a thorough clinical evaluation and characteristic physical findings. Specialized testing may be conducted to detect certain findings that may be associated with the disorder. Diagnostic criteria were proposed in 2012 noting that most affected individuals have short fifth fingers with absent or underdeveloped nails, developmental and/or cognitive delays, and facial features such as a wide mouth and broad nose. Given the recent discovery of the genetic mutations causing CSS, diagnostic criteria will likely evolve to include clinical evaluations and molecular testing.
It is possible that a diagnosis of CSS may be suggested before birth (prenatally) based upon specialized tests such as ultrasound. During fetal ultrasonography, reflected sound waves are used to generate an image of the developing fetus. Ultrasound studies may reveal characteristic findings, such as cardiac or kidney malformations and intrauterine growth retardation, which may be associated with the disorder.
If a disease causing mutation has been identified in an affected family member, molecular testing can be done on the fetus. This involves the removal of fetal cells through chorionic villus sampling (performed at 10 to 12 weeks gestation with cells removed from the placenta) or amniocentesis (performed at 15 to 18 weeks gestation with cells removed from the amniotic fluid). DNA extracted from the fetal cells is then examined to see if the mutation is present in the fetus. Molecular genetic testing is available as a diagnostic service at specialized laboratories.
Clinical Testing and Workup
If indicated, further examinations and specialized imaging techniques are recommended to establish the extent of the disorder. For example, an MRI (magnetic resonance imaging) may be used to detect structural abnormalities, such as in the brain. During an MRI, radio waves and a magnetic field are used to generate an image. X-rays of the hands can be performed to confirm the underdevelopment or absence of the end bones in the fifth fingers. Echocardiograms, which are a type of ultrasound, can be used to generate images of the heart to detect any cardiac abnormalities that may be present. Other examinations can include developmental examinations, dietary evaluations, and eye and hearing examinations.
Once diagnosed, individuals with CSS should have yearly follow-up exams. This includes evaluation by a pediatrician to assess developmental progress and to determine the need for any educational or therapeutic interventions and follow-ups with other specialists to track any feeding, gastrointestinal, vision, or hearing abnormalities.
The treatment of CSS is directed toward the specific features of each individual. Such treatment may require the coordinated efforts of a team of medical professionals who may need to systematically and comprehensively plan an affected child’s treatment. These professionals may include pediatricians; physicians who specialize in disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who diagnose and treat heart abnormalities (cardiologists); physicians who specialize in digestive abnormalities; physical therapists; geneticists and/or other health care professionals.
In some affected individuals, treatment may include surgical repair of certain craniofacial, skeletal, cardiac, or other abnormalities potentially associated with the disorder. The surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms, and other factors.
In addition, in those with choanal atresia, surgery or other appropriate methods may be required to decrease the airway obstruction or correct the malformation. If affected individuals have Dandy-Walker malformation, treatment may include surgical implantation of a specialized device (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. During infancy, treatment may also require measures to help prevent or aggressively treat respiratory infections.
Early intervention may be important in ensuring that affected children reach their potential. Special services that may be benefit developmental outcomes include special education, physical, speech, or occupational therapy, or other social, and/or vocational services. Additional treatments to assist affected children can include eyeglasses, hearing aids, and nutritional supplements. If needed, the placement of a gastrostomy tube (a tube inserted through the abdomen to deliver nutrition directly to the stomach) can help with feeding difficulties.
Genetic counseling will also be of benefit for individuals with CSS and their families. Other treatment is symptomatic and supportive.
Dr. Samantha Vergano at the Children’s Hospital of The King’s Daughters in Norfolk, Virginia has an IRB-approved clinical registry for Coffin-Siris syndrome and related disorders. Physicians and family members can obtain more information about enrollment by contacting Dr. Vergano by phone at (757) 668-9723 or at Samantha.Vergano@chkd.org.
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