Coffin Siris Syndrome

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Coffin Siris Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Fifth Digit Syndrome
  • CSS

Disorder Subdivisions

  • None

General Discussion

Coffin-Siris syndrome (CSS) is a rare genetic disorder that may be evident at birth (congenital). The disorder may be characterized by abnormalities of the head and facial (craniofacial) area, resulting in a coarse facial appearance. Craniofacial malformations may include an abnormally small head (microcephaly); a wide nose with a low nasal bridge; a wide mouth with thick, prominent lips; thick eyebrows and eyelashes (hypertrichosis); and sparse scalp hair. In addition, affected infants and children typically have short fifth fingers ("pinkies") and toes with underdeveloped (hypoplastic) or absent nails; other malformations of the fingers and toes; and eye abnormalities. Feeding difficulties and frequent respiratory infections during infancy, diminished muscle tone (hypotonia), abnormal looseness (laxity) of the joints, delayed bone age, developmental delays, hearing loss, and intellectual disability may also be present. The specific symptoms and severity can vary among affected individuals. Treatment is directed towards the symptoms that are present in an individual with CSS. Mutations in five different genes, ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1, have been found to cause CSS. Researchers believe the disease can be transmitted genetically as an autosomal dominant trait but most cases appear to be the result of a new mutation.

Symptoms

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.

Causes

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.

Affected Populations

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.

Standard Therapies

Diagnosis

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.



Treatment

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.

Investigational Therapies

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

Email: prpl@cc.nih.gov



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/

References

TEXTBOOKS

Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:582-583.



Adams RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill Company; 1997:1003



Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:1684.



Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990:831-832.



Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:355, 423-424.



JOURNAL ARTICLES

Tsurusaki Y, Okamoto N, Ohashi H, et al. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet. 2012;44(4):376-378. doi: 10.1038/ng.2219



Schrier SA, Bodurtha JN, Burton B, et al. The Coffin-Siris Syndrome: a proposed diagnostic approach and assessment of 15 overlapping cases. Am J Med Genet A. 2012; 158(A):1865-1876. doi: 10.1002/ajmg.a.35415



Braun-Quentin C, et al. Variant of Coffin-Siris syndrome or previously undescribed syndrome? Am J Med Genet. 1996;64:568-572.



Swillen A, et al. The Coffin-Siris syndrome: data on mental development, language, behavior and social skills in children. Clin Genet. 1995;48:177-182.



Bonioli E, et al. Autosomal recessive mode of inheritance of a Coffin-Siris like syndrome. Genet Counsel. 1995;6:309-312.



deJong G, et al. Choanal atresia in two unrelated patients with the Coffin-Siris syndrome. Clin Genet. 1992;42:320-322.



Levy P, et al. Coffin-Siris syndrome. J Med Genet. 1991;28:338-341.



Richieri-Costa A, et al. Coffin-Siris syndrome in a Brazilian child with consanguineous parents. Rev Brasil Genet. 1986;IX:169-177.



Franceschini P, et al. The Coffin-Siris syndrome in two siblings. Pediat Radiol. 1986;16:330-333.



Haspeslagh M, et al. The Coffin-Siris syndrome: report of a family and further delineation. Clin Genet. 1984;26:374-378.



Coffin GS, et al. Mental retardation with absent fifth fingernail and terminal phalanx. Am J Dis Child. 1970;119:433-439.



INTERNET

Schrier Vergano S, Santen G, Wieczorek D, et al. Coffin-Siris Syndrome. 2013 Apr 4 [Updated 2013 Jul 11]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK131811/ Accessed Jan 8, 2014.



U.S. National Library of Medicine. Coffin-Siris syndrome. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/coffin-siris-syndrome. May 2013. Accessed Jan 8, 2014.



Genetic and Rare Diseases Information Center. Coffin-Siris syndrome.

http://rarediseases.info.nih.gov/gard/6124/coffin-siris-syndrome/more-about-this-disease. Last updated: 10/7/2013. Accessed Jan 8, 2014.



Online Mendelian Inheritance in Man, OMIM. John Hopkins University, Baltimore, MD. Entry Number 135900; Available at: http://omim.org/entry/135900 Last Updated: 05/04/2012. Accessed Jan 8, 2014.

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