Hydrolethalus Syndrome

Abstract

Hydrolethalus syndrome is a lethal malformation syndrome with a severe brain malformation, most often hydrocephaly and absent midline structures. Other frequent findings are micrognathia, polydactyly, and defective lobation of the lungs. Hydrolethalus syndrome is inherited in an autosomal recessive manner and is caused by a missense mutation in the HYLS1 gene. Here, we report the neuropathologic features of 21 genetically confirmed cases. Typically, 2 separated cerebral hemispheres could be identified, but they lacked midline and olfactory structures and were situated basally with a massive accumulation of cerebrospinal fluid. Temporal and occipital lobes were hypoplastic, and normally developed hippocampi were not found. Primitive thalami and basal ganglia were fused in the midline. A hypothalamic hamartoma was a frequent finding, and brainstem and cerebellum were hypoplastic. Three cases were hydranencephalic, and 1 was anencephalic. A midline "keyhole" defect in the skull base was a constant finding. Histologically, the cortex was dysplastic. This pattern of brain pathology, clearly belonging to the midline patterning defects, seems to be unique for the hydrolethalus syndrome and combines features of disturbed neurulation, prosencephalization, and migration. Despite variation in the clinicopathologic phenotype, all cases in the series carried the same homozygous missense mutation in HYLS1.

The ciliopathy gene ftm/rpgrip1l controls mouse forebrain patterning via region-specific modulation of hedgehog/gli signaling

“…However, a precise analysis of the forebrain is rarely possible in fetuses with severe ciliopathies such as Meckel syndrome. Microphthalmia and benign tumors called diencephalic or hypothalamic hamartomas have been observed in Meckel syndrome and other ciliopathies (Ahdab-Barmada and Claassen, 1990; Roume et al, 1998; Paetau et al, 2008; Poretti et al, 2011, 2017; Del Giudice et al, 2014). Interestingly, diencephalic hamartomas have been linked to mutations in GLI3 and other SHH pathway genes (Shin et al, 1999; Hildebrand et al, 2016), suggesting that those observed in ciliopathies could also be caused by defects in SHH signaling.…”

Finnish neuroscience from past to present

“…Aspartylglycosaminuria (AGU) Palo and Mattsson (1970) and Haltia et al (1975) Infantile neuronal ceroid lipofuscinosis (CLN1) , Haltia, Rapola, Santavuori and Keranen (1973) and Santavuori et al (1973) Late infantile neuronal ceroid lipofuscinosis (CLN5) See Mole and Haltia (2015) Progressive epilepsy with mental retardation (CLN8) See Mole and Haltia (2015) Congenital neuronal ceroid lipofuscinosis (CLN10) See Mole and Haltia (2015) Progressive myoclonus epilepsy (EPN1) Haltia, Kristensson, and Sourander (1969) and Koskiniemi, Donner, Majuri, Haltia, and Norio (1974) Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO) Haltia and Somer (1993) and Salonen, Somer, Haltia, Lorentz, and Norio (1991) Muscle-eye-brain disease (MEB) Haltia et al (1997) and Santavuori et al (1998) Hydrolethalus syndrome Paetau et al (2008) Infantile onset spinocerebellar ataxia (IOSCA) Koskinen et al (1994) and Lonnqvist, Paetau, Nikali, Boguslawski, and Pihko (1998) Foetal motoneuron disease Nousiainen et al (2008) T A B L E 1 Early-onset neurological disorders discovered and/or characterized by Finnish investigators (Kalimo et al, 1988) and tibial muscular dystrophy (Udd et al, 1998). The latter condition is caused by mutations in the gene encoding the giant skeletal-muscle protein, titin (Hackman et al, 2002).…”

Syndromes associated with holoprosencephaly

“…However, no cases of hydrolethalus syndrome with a molecular diagnosis have been associated with HPE. A review of 21 cases with molecularly confirmed variants in the gene HYLS1 found that all cases had a complete interhemispheric fissure, and in a few cases, a hypothalamic hamartoma was found (Paetau et al, 2008). Holoprosencephaly is not a common finding in hydrolethalus syndrome.…”