Lethal congenital contracture syndrome

Overview

Lethal congenital contracture syndrome (LCCS) is a group of rare, inherited neuromuscular disorders characterized by severe fetal akinesia (lack of movement), joint contractures, and multiple congenital abnormalities. These syndromes typically present during pregnancy and result in death before birth or shortly thereafter. LCCS is part of a broader group of disorders known as arthrogryposis multiplex congenita, but it is distinguished by its early onset and uniformly fatal outcome. Multiple subtypes (LCCS1 through LCCS11) have been described, each associated with different gene mutations.

Causes

LCCS is caused by mutations in genes involved in motor neuron development and function, muscle contraction, or cellular metabolism. These mutations lead to the degeneration of anterior horn motor neurons or disruption in neuromuscular function. The most commonly affected genes include:

• GLE1 – associated with LCCS type 1

• ERBB3, GLE1, PIP5K1C, ADCY6, and others – associated with various LCCS subtypes

LCCS follows an autosomal recessive inheritance pattern, meaning both parents must carry one defective copy of the gene to pass it on to their child. It is more prevalent in populations with higher rates of consanguinity (closely related parents).

Symptoms

The hallmark of LCCS is a lack of fetal movement, typically noticed on prenatal ultrasound. Symptoms and physical features include:

• Fetal akinesia or hypokinesia – minimal or absent fetal movements in utero

• Multiple joint contractures – stiff, immobile joints (arthrogryposis), often affecting all four limbs

• Hydrops fetalis – abnormal fluid accumulation in fetal tissues

• Pulmonary hypoplasia – underdeveloped lungs, leading to respiratory failure

• Facial abnormalities – including micrognathia (small jaw) and low-set ears

• Muscle atrophy – underdeveloped muscles due to lack of movement

• Spinal and skeletal deformities – including scoliosis and abnormal limb positioning

In most cases, affected fetuses are stillborn or die shortly after birth due to respiratory insufficiency.

Diagnosis

Diagnosis of LCCS can be made prenatally or postnatally based on clinical and genetic findings. Diagnostic methods include:

• Prenatal ultrasound – detects reduced fetal movement, joint contractures, and other anomalies

• Fetal MRI – may provide additional detail on central nervous system development and joint abnormalities

• Genetic testing – targeted gene panels or whole exome sequencing to identify specific mutations associated with LCCS subtypes

• Amniocentesis or chorionic villus sampling (CVS) – for prenatal genetic analysis in at-risk pregnancies

Family history and consanguinity can also be important clues in the diagnostic process.

Treatment

There is no cure or effective treatment for LCCS. Management is limited to supportive care and counseling. In most cases, the condition is lethal in the perinatal period. Management strategies include:

• Prenatal counseling – for families at risk based on genetic findings or family history

• Supportive care after birth – if the infant survives delivery, palliative care may be provided

• Termination of pregnancy – may be considered in confirmed severe cases depending on local laws and family preferences

• Genetic counseling – for future family planning and risk assessment in subsequent pregnancies

Prognosis

The prognosis for Lethal congenital contracture syndrome is extremely poor. Most affected fetuses are either stillborn or die within hours to days after birth due to respiratory failure from underdeveloped lungs. Because of its genetic basis, recurrence risk in future pregnancies is 25% if both parents are carriers. Early diagnosis through prenatal screening and genetic counseling is essential for at-risk families.