Amelia (birth defect)

For other uses, see Amelia (disambiguation).

Nick Vujicic, a motivational speaker born with tetra-amelia syndrome affecting all four limbs

Introduction

Tetra-amelia syndrome (TETAMS), also known as Tetra-amelia autosomal recessive, or Tetraamelia multiple malformations X-linked is an extremely rare congenital disorder characterized by the absence of all four limbs. The condition is often accompanied by severe malformations affecting other parts of the body, including the face, lungs, heart, nervous system, skeleton, and reproductive organs. Tetra-amelia syndrome is most commonly inherited in an autosomal recessive pattern and has been linked to mutations in the WNT3 gene, which plays an important role in early embryonic development. Because of the severity of associated abnormalities, many affected infants are stillborn or die shortly after birth, although rare long-term survivors have been reported.

The term may be modified to indicate the number of arms or legs missing at birth, such as tetra-amelia, which refers to the absence of all four limbs. The word is derived from Ancient Greek: a- meaning “lack of,” melos meaning “limb,” and tetra meaning “four.”

Description

Tetra-amelia syndrome has been described in two main clinical forms, type 1 and type 2, which differ in the severity and pattern of associated malformations. Type 1 is generally associated with severe abnormalities of the digestive and urinary systems. These may include defects in the abdominal wall that allow internal organs to protrude, malformations of the diaphragm, absence of an anal opening (imperforate anus), and underdevelopment or absence of one or both kidneys.

Type 2 is typically more severe and is characterized by major defects affecting the respiratory, cardiac, and craniofacial systems. This can include absence of both lungs, structural heart defects such as abnormalities in the walls between heart chambers or missing heart valves, and facial anomalies such as fused eyelids, abnormal attachment of the tongue to the mouth floor, and a significantly undersized lower jaw (micrognathia).

Diagram of the Wnt signaling pathway, which regulates cell growth and plays a key role in embryonic development and limb formation.

Tetra-amelia syndrome is caused by genetic variants that disrupt normal limb and embryonic development. Mutations in two genes have been identified: WNT3, which is associated with type 1, and RSPO2, which is associated with type 2. Both genes are involved in the Wnt signaling pathway, a key biological system that regulates cell growth, differentiation, and development before birth.

The WNT3 gene produces a protein that plays an important role in early development, particularly in limb formation and nervous system development. The RSPO2 gene encodes the R-spondin-2 protein, which enhances Wnt signaling by inhibiting proteins that normally suppress this pathway. When either gene is altered, the resulting loss of functional protein can interfere with Wnt signaling, disrupting normal embryonic patterning and leading to severe limb and organ abnormalities characteristic of the syndrome.

In some cases, the exact genetic cause has not been identified. Researchers suggest that additional, as yet undiscovered genes involved in limb development may also contribute to the condition.

Although tetra-amelia is primarily genetic, some studies note that amelia in general may also be influenced by environmental factors such as maternal diabetes, intrauterine infections (including TORCH infections), and exposure to teratogens. However, these factors are not clearly established causes of tetra-amelia specifically.

Symptoms

Tetra-amelia syndrome can often be identified before birth through routine prenatal ultrasound, which may reveal the absence of all four limbs and other major structural abnormalities. Diagnosis can be supported through molecular genetic testing, particularly by identifying mutations in the WNT3 gene.

Because relatively few families have been studied, the overall mutation detection rate is not well established. In many cases, affected pregnancies result in stillbirth, and infants who are born alive typically survive only a short time due to severe associated malformations.

Causes

Limb development occurs early in embryogenesis, typically between 24 and 36 days after fertilization. This may eventually lead to complete or partial absence of one or more limbs. Tetra-amelia syndrome appears to have an autosomal recessive pattern of inheritance – that is, the parents of an individual with tetra-amelia syndrome each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

In some cases, tetra-amelia may be attributed to health complications during the early stages of pregnancy, including infection, or the use of teratogenic drugs, such as thalidomide.

Management

Tetra-amelia syndrome is considered exceptionally rare, with only a small number of cases reported worldwide. Estimates have suggested an incidence of approximately 2.4 per 10 million births, which is equal to about 0.000024 percent of live births.

Management of tetra-amelia syndrome is primarily supportive and focuses on improving quality of life and addressing associated medical complications. Because the condition often involves multiple organ systems, care typically requires a multidisciplinary approach. In individuals who survive, prosthetic devices may be used to assist with mobility and daily functioning, although outcomes depend on the severity of associated abnormalities. Supportive medical care is also directed toward respiratory, cardiac, and gastrointestinal complications, which are common in affected individuals.

See also

• Amniotic band constriction
• Dysmelia
• Hemimelia
• Phocomelia
• Thalidomide