Hydrolethalus syndrome (HLS) is a rare genetic disorder that causes improper fetal development, resulting in birth defects and, most commonly, stillbirth.HLS is associated with HYLS1 mutations. The gene encoding HYLS1 is responsible for proper cilial development within the human body. Cilia are microscopic projections that allow sensory input and signalling output within cells, as well as cell motility. Dysfunction results in a range of abnormalities that are often the result of improper cell signalling. A variant form, HLS2, with additional mutations to the KIF7 gene, is less common. KIF7 also ensures correct cilia formation and function, specifically cilia stability and length.Hydrolethalus syndrome (HLS) was first mistakenly identified in Finland, during a study on Meckel syndrome. Like HLS, Meckel syndrome presents with severe physiological abnormalities, namely disruptions to the central nervous system and the presence of extra fingers or toes (polydactyly). HLS can be distinguished from Meckel syndrome by analysing kidney function, which is dysfunctional in Meckel syndrome as a result of cyst formation. Signs and symptoms
HLS presents itself as various, lethal developmental abnormalities, which often result in either premature stillbirth or death shortly after birth. Rare cases of children born with HLS surviving for several months have been noted. A characteristic abnormality of HLS is an absence of brain tissue and midline structures, with the presence of excess brain fluid (hydrocephalus) as a result of abnormal development of the central nervous system. Other common defects include incomplete lung development, heart defects, a cleft lip or palate, polydactyly, and an abnormally small jaw.
Variations and related pathologies
Mutations in KIF7 have also been noted in patients that present a similar phenotype to HLS and the characteristic HYLS1 A to G transformation; homozygous deletion of the KIF7 gene causes a variant form of HLS, HLS2. KIF7 encodes a structural factor vital to cilial transport, and is also implicated in other developmental disorders, such as Joubert syndrome (JS). Additionally, mutations in HYLS1 are no longer explicitly connected to HLS in humans. Homozygous mutations removing the stop codon in exon 4 of HYLS1 result in a different genomic sequence disruption to the missense mutation of HLS, and phenotypically present as JS. The ‘molar tooth sign’ of the brain, an anomaly in which cerebellar volume is reduced but cerebellar shape is retained, resembles the molar tooth and is used to identify JS. JS presents with mutations in more than 30 genes, whilst the HYLS1 mutation is the sole cause of HLS, but is also present in the HLS2 variant form with the mutated KIF7 gene. Diagnosis
HLS can be readily diagnosed during pregnancy through the use of ultrasound, which will often reveal hydrocephaly and an abnormal structure of the brain. Precise examination via ultrasound or at birth is necessary to rule out Meckel syndrome, Trisomy 13, or Smith–Lemli–Opitz syndrome, which present with similar physiological defects. HLS can be detected at the end of the first trimester, approximately 13 weeks gestation. Treatment
No cure or treatment option for individuals with HLS currently exist.