About coffin syndrome

What is coffin syndrome?

Coffin-Lowry syndrome is a rare genetic disorder characterized by mental retardation; abnormalities of the head and facial (craniofacial) area; large, soft hands with short, thin (tapered) fingers; short stature; and/or various skeletal abnormalities. Characteristic facial features may include an underdeveloped upper jawbone (maxillary hypoplasia), an abnormally prominent brow, downslanting eyelid folds (palpebral fissures), widely spaced eyes (hypertelorism), large ears, and/or unusually thick eyebrows. Skeletal abnormalities may include abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and unusual prominence of the breastbone (sternum) (pectus carinatum). Coffin-Lowry syndrome is caused by mutations in the RSK2 gene and is inherited as an X-linked dominant genetic trait. Males are usually more severely affected than females.



What are the symptoms for coffin syndrome?

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 or Large head (micro- or macrocephaly); 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). However, there are individuals with CSS who do not have the classic fifth digit findings.

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 (ophthamologic) 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.



What are the causes for coffin syndrome?

CSS is thus far known to be caused by mutations in one of the following seven genes: ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1 and SOX11. Genes provide instructions for creating proteins that play a critical role in many functions of the body. The ARID– and SMARC– genes linked to CSS provide the instructions to make several different protein complexes that are known as BRG-1 associated factor (BAF) complex in humans. SOX11 is involved with transcriptional regulation of the BAF complex. These protein complexes regulate gene activity by altering how tightly regions of DNA are packaged, which can affect gene expression. Subsequently, the BAF complex is 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 the BAF complex, 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, SMARCE1, or SOX11 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 isolated intellectual disability and absence of other physical features of CSS. 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.



What are the treatments for coffin syndrome?

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.



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