Hydrolethalus (ORPHA:2189)
Hydrolethalus (HLS) is a severe fetal malformation syndrome characterized by craniofacial dysmorphic features, central nervous system, cardiac, respiratory tract and limb abnormalities.
Epidemiology
HLS is mostly present in families of Finnish descent, and annual incidence has been estimated at 1/20,000 in Finland. The mutation carrier frequency in the Western parts of Finland is 1.1% and 2.5% in Central and Eastern parts. The disease is much rarer in other geographical areas. The prevalence is not known.
Clinical description
Micrognathia and retrognathia, cleft lip/palate, a poorly formed nose, posteriorly rotated ears and deep-set eyes are the main craniofacial dysmorphic features observed in HLS. A midline defect in the occipital bone dorsal to the foramen magnum is present, resulting in a keyhole-shaped defect. Brain abnormalities include hydrocephaly and agenesis of midline structures such as corpus callosum, cerebellar vermis and septum pellucidum, leading to a wide opened fluid-filled space between lateral ventricles. HLS is also characterized by postaxial and preaxial polydactyly, respectively in the hands and feet, the latter being clubbed. About half of the patients have large septal cardiac defect. Abnormal lobulation of the lungs, stenosis of the airways (larynx, trachea or bronchus), and abnormal genitalia (including uterus duplex in females and ectopic testis in males) are also found.
Etiology
HLS is caused by mutations in HYLS1 (11q24.2) and KIF7 (15q26.1). All Finnish cases are homozygous for an A to G mutation in exon 6 of i>HYLS1 resulting in D211G substitution. The KIF7 mutation has been characterized in only one HLS family to date. Both genes code for ciliary or centriolar proteins that seem to be involved in early embryonic development of the midline.
Diagnostic methods
Ultrasound scan during pregnancy often reveals hydrocephaly and an abnormal structure of the brain. Cleft lip/palate, polydactyly, especially double big-toe with club-feet, and the heart defect may also be visible. Diagnosis of a newborn is based on physical examination, brain imaging autopsy, and/or genetic tests. Genetic testing of the affected child to verify the mutation helps prenatal diagnosis in future pregnancies.
Differential diagnosis
Differential diagnosis of HLS includes, in the absence of an index case, other midline multiple malformation syndromes like Pallister-Hall, pseudo-trisomy 13, oro-facio-digital type IV or VI, Joubert syndromes, as well as the severe form of Smith-Lemli-Opitz syndrome (see these terms).
Antenatal diagnosis
Antenatal diagnosis by ultrasonography and/or genetic testing is feasible at the end of the first trimester when a previous pregnancy was affected. HLS is associated with hydramnios (often severe) and preterm delivery when pregnancy evolves spontaneously.
Genetic counseling
As an autosomal recessive syndrome, HLS has a 25% recurrence risk after an affected pregnancy. Genetic counseling should be offered to affected families.
Management and treatment
There is no treatment for HLS.
Prognosis
Stillbirth or neonatal death is the rule, although rare cases with several months survival have been reported.

                            Last update: 
                            December 2011


                            - Expert reviewer(s): 
                            Dr Riitta SALONEN-KAJANDER