Hydrolethalus syndrome

Overview

Hydrolethalus syndrome (HLS) is a rare and typically lethal congenital disorder characterized by severe developmental abnormalities of the brain and other organs. The name “hydrolethalus” refers to the hallmark findings of hydrocephalus (excess fluid in the brain) and the condition's often lethal outcome in utero or shortly after birth. It is part of a group of disorders known as ciliopathies, which result from defects in the function of cilia-microscopic, hair-like structures involved in cellular signaling and development.

Causes

Hydrolethalus syndrome is most commonly caused by mutations in the HYLS1 gene, located on chromosome 11. This gene plays a role in ciliogenesis, the formation and function of cilia during embryonic development. Affected individuals inherit the disorder in an autosomal recessive manner, meaning both parents must carry one copy of the mutated gene for a child to be affected. The condition has a higher prevalence in certain populations, such as in Finland, due to a founder effect.

Symptoms

The symptoms of Hydrolethalus syndrome are severe and typically detectable during prenatal development. Common features include:

• Severe hydrocephalus (accumulation of cerebrospinal fluid in the brain)

• Polydactyly (extra fingers or toes)

• Midline facial clefts (cleft lip and/or palate)

• Small jaw (micrognathia)

• Malformed brain structures, especially the absence or underdevelopment of the midline structures such as the corpus callosum

• Cardiac and genitourinary abnormalities

• Lung hypoplasia (underdeveloped lungs)

These malformations are usually incompatible with life, and most affected fetuses do not survive to term or die shortly after birth.

Diagnosis

Diagnosis of Hydrolethalus syndrome is often made prenatally through advanced imaging and genetic testing. Diagnostic steps may include:

• Ultrasound: May detect hydrocephalus, facial clefts, polydactyly, and other anomalies during the second trimester

• Fetal MRI: Provides more detailed visualization of brain malformations

• Genetic testing: Confirms the diagnosis by identifying mutations in the HYLS1 gene or other related genes

• Family history: Especially important in populations with known carrier status or consanguinity

Early diagnosis is critical for parental counseling and pregnancy management.

Treatment

There is no curative treatment for Hydrolethalus syndrome due to the severity of the malformations and the typically lethal outcome. Management is limited to supportive care and palliative options. In many cases, prenatal diagnosis leads to discussions about pregnancy continuation, palliative planning, or termination based on parental wishes and local regulations.

Prognosis

The prognosis for Hydrolethalus syndrome is extremely poor. The majority of affected fetuses are either stillborn or die shortly after birth due to severe brain malformations and respiratory failure caused by lung underdevelopment. There are no known long-term survivors with confirmed HLS. Genetic counseling is highly recommended for families with a history of the condition, especially when both parents are confirmed carriers.