Kuskokwim Syndrome - Clinical Features, Cause, Diagnosis, and Management

Introduction:

Kuskokwim Syndrome is a genetic disorder that is commonly seen in the Southwest Alaska population called Yup'ik Eskimos. Individuals affected by this syndrome present with congenital contractures in which the joints are stiff and swollen and have decreased range of movements due to the shortening of muscles around them, which is present by birth. Other joints, such as knees, elbows, and ankles, can also be affected. This condition is diagnosed with the help of clinical features such as contractures and genetic testing. Management includes mainly treating joint deformities with the help of orthopedic treatment.

What Is Kuskokwim Syndrome?

Kuskokwim Syndrome is a rare genetic disorder that occurs due to a mutation in the FKBP10 (FKBP prolyl isomerase 10) gene which disrupts the collagen cross-linkage and causes deformity in joints.

What are the Other Names for Kuskokwim Syndrome?

The other names of Kuskokwim Syndrome are:

• Bruck syndrome 1.

• Arthrogryposis-like syndrome.

What Are the Clinical Features of Kuskokwim Syndrome?

The clinical features may vary among individuals, and some may develop at birth or in childhood. The skeletal features of Kuskokwim Syndrome are:

• Joint contractures (stiffness of the joints due to shortening of tissues, muscles, and tendons around them) affect mostly ankles, elbows, and knees and can result in loss of range of movements and pain. These features are present by birth and can increase in severity as the child ages.

• Lordosis (a deep spine curve that makes stomach and hip areas stick out).

• Scoliosis (sideward curve of the spinal cord).

• Wedge-shaped bone deformity of the spine.

• Abnormal clavicles (collarbone).

• Hypoplasia of the patella (kneecap).

• Hypoplasia of the radius (bone in the forearm).

• Clubfoot (foot turns inward).

• Reduced tendon reflexes.

• Clubbing (bulbous enlargement) of toes and fingers.

Other features include:

• Abnormal gait.

• Macrocephaly (large head).

• Short stature.

• Skeletal muscle atrophy (decreased muscle mass).

What Is the Cause of Kuskokwim Syndrome?

Kuskokwim Syndrome occurs due to a mutation in the FKBP10 gene. This gene mutation has an autosomal recessive pattern of inheritance, in which the mutated gene is present in both the parents and is passed down to the child with two copies of the mutated gene. The parents are not affected by the condition and are called carriers. The features of this gene include:

• The FKBP10 gene is located on chromosome 17.

• The FKBP10 gene provides information in the production of a protein called FKBP10 protein.

• The FKBP10 protein is found in the endoplasmic reticulum and helps in the production, processing, and movement of proteins.

• The FKBP10 protein is important in the processing of elastin (a type of protein that helps in stretching the skin and also provides strength to it), collagen (a protein that provides strength, shape, and structure to the skin), and the molecules present in the extracellular spaces of cells. These collagen proteins are cross-linked, resulting in strong long fibrils in the extracellular matrix. This FKBP10 protein helps in cross-linking of these collagen molecules through a reaction called hydroxylation (an oxidation reaction).

• The FKBP10 protein helps in the production and formation of elastin by folding multiple tropoelastins.

• These elastin and collagen support the body’s organs, joints, and bones.

A mutation in the FKBP10 gene can result in the formation of an unstable FKBP10 protein which can break down easily. Therefore causing problems in collagen crosslinking and results in features of Kuskokwim Syndrome. Another medical condition that occurs due to mutation in the FKBP10 gene is osteogenesis imperfecta (a genetic disorder of bone in which the mutations occur in the COL1A1 and COL1A2 genes in 90 % of cases, and in the remaining 10 %, the mutation occurs due to other genes, among which FKBP10 gene is one of them).

What Is the Diagnosis of Kuskokwim Syndrome?

• Diagnosis can be made with the help of a complete physical examination of clinical features such as joint deformities of the knee, collarbone, spine, elbow, and forearm, along with a positive family history.

• Prenatal molecular genetic testing and preimplantation genetic testing, which is done during pregnancy, reveal a mutation in the FKBP10 gene.

• Molecular genetic testing in the affected individual shows a mutation in the FKBP10 gene. Molecular genetic testing can be single-gene testing or by a multigene panel.

  1. Single-gene testing is done to identify changes in one gene, such as small deletions, insertions, or duplications.

  2. Multigene panel testing is done to identify changes in several genes.

• Radiological features include an abnormal wedge-shaped spinal bone, an abnormal kneecap, and a radius.

What Are the Complications of Kuskokwim Syndrome?

The complications of Kuskokwim Syndrome are:

• Severe back pain due to lordosis.

• Crowding of lungs and heart due to severe scoliosis.

• Increased risk for fractures.

• Severe movement disorder.

• Decreased range of movements.

What Is the Treatment of Kuskokwim Syndrome?

The treatment of Kuskokwim Syndrome is supportive and involves pediatricians and an orthopedist to treat the joint deformities. Management includes:

• Physical therapy to improve muscle movements.

• Occupational therapy to improve daily activities.

• Alignment of the lower limb.

• Use of assisted devices to help in walking.

• Use of medications such as botulinum toxin to decrease the inflammation in the joints.

• Use of ankle-foot orthotics to help stabilize joints and improve walking.

• Use of braces, splints, and casts for correcting limb contractures.

• Use of surgical treatments to lengthen the muscles or tendons.

• Genetic counseling should be given to the affected individuals and families as they have a risk of passing down the syndrome to the next generation.

Conclusion:

Kuskokwim Syndrome is a rare disorder that affects mainly joints, and the prognosis depends on the severity of the symptoms. Management is supportive and includes treating joint deformities with the help of splints, braces, surgical treatment, physical therapy, and occupational therapy. Individuals with Kuskokwim Syndrome and family members should receive genetic counseling since it is inherited in an autosomal recessive pattern. The couple who are carriers have a 25 percent risk of transmitting the syndrome to the child, and a 50 percent risk of being carriers by their children. The other 25 percent of children may have normal genes and are not affected by this condition.