This lethal syndrome was discovered in Finland in the course of studying the Meckel syndrome (see 249000), which is frequent there (Salonen et al., 1981). Like the Meckel syndrome, this disorder is characterized by polydactyly and central nervous ... This lethal syndrome was discovered in Finland in the course of studying the Meckel syndrome (see 249000), which is frequent there (Salonen et al., 1981). Like the Meckel syndrome, this disorder is characterized by polydactyly and central nervous system malformation, but unlike that syndrome, it does not show cystic kidney and liver and the CNS derangement is hydrocephalus not encephalocele. The pregnancy is characterized by hydramnios, which is often massive, and by preterm delivery. The ventricles are open to the subarachnoid space so that the hydrocephalus is external. The foramen magnum is keyhole-shaped. The polydactyly is postaxial in the hands and preaxial in the feet. A highly characteristic hallux duplex is seen in almost no other situation. The feet are clubbed. The mandible is always small and the nose poorly formed; the eyes are hypoplastic. About half the affected have a large atrioventricular communis defect of the heart. Stenosis of the airway and abnormal lobation of the lungs are also found. Prenatal diagnosis by ultrasonography is possible. The grandparents of affected persons come from a thinly populated area of eastern Finland. Salonen et al. (1981) described the syndrome in 28 newborns in 18 Finnish families. Polyhydramnios and stillbirth or neonatal death were the rule. Anyane-Yeboa et al. (1987) described 2 infant brothers with this syndrome. Both showed severe CNS abnormalities, cleft lip/palate, polydactyly, and lung hypoplasia. The parents were related as double first cousins once removed. Aughton and Cassidy (1987) presented a case still living at more than 5 months of age; previously, the longest survival reported had been 2 days. Comparisons with 50 previously reported cases were presented. Macrocephaly with frontal and occipital protuberances, postaxial hexadactyly, and duplicated hallux were illustrated. Bachman et al. (1990) described 2 fetuses with features of holoprosencephaly, hydrocephalus, and postaxial polydactyly, who were born to a consanguineous Mexican-American couple. The features were considered consistent with the hydrolethalus syndrome, although holoprosencephaly had not previously been seen in that condition. Bachman et al. (1990) suggested that cases of 'pseudotrisomy 13,' i.e., trisomy 13 phenotype with normal chromosomes, may be instances of the hydrolethalus syndrome; see 264480. Pryde et al. (1993) described the hydrolethalus syndrome in 2 successive pregnancies in a nonconsanguineous black couple, and discussed the problems in prenatal differential diagnosis. The second fetus showed what they referred to as crossed polydactyly: upper postaxial and lower preaxial (bifid hallux) polydactyly. The fetus had bilateral cleft lip and palate, as well as short, distorted lower limbs and omphalocele. Morava et al. (1996) described a Hungarian infant with macrocephaly, Dandy-Walker malformation (including absence of cerebellar vermis), keyhole foramen magnum with occipitoschisis, and postaxial polydactyly of the left hand and both feet. No visceral abnormalities were found. The authors considered this case to be a variant of hydrolethalus syndrome, although absence of hydrocephaly and preaxial polydactyly of the feet may suggest other diagnoses, e.g., Joubert syndrome (213300). De Ravel et al. (1999) reported a non-Finnish (Portuguese/German/South African) family with hydrolethalus syndrome. The first affected child presented with a milder form of the disorder and survived to 7 months; there were 2 subsequent pregnancies with typical features detected early by ultrasound evaluation. De Ravel et al. (1999) proposed that the 'milder' cases are indeed true cases of the hydrolethalus syndrome and that allelic variability may be responsible for these 'non-typically Finnish' findings. They also demonstrated that, especially in families where there has been a previously affected fetus, echographic diagnosis can be made in the first trimester, as early as the eleventh week of gestation. Shotelersuk et al. (2001) described the first Asian case of hydrolethalus syndrome. The patient lived to 44 days of age, making her the fourth reported case to survive the neonatal period.
Mee et al. (2005) identified the gene carrying the mutation responsible for hydrolethalus syndrome in the Finnish population, HYLS1 (610693). They determined that a D211G mutation (610693.0001) is the common mutation carried in the Finnish population.
Salonen and Herva (1990) referred to a total of about 56 cases of the hydrolethalus syndrome in Finland, giving an incidence of at least 1 in 20,000. They found 5 reports of cases from other parts of the ... Salonen and Herva (1990) referred to a total of about 56 cases of the hydrolethalus syndrome in Finland, giving an incidence of at least 1 in 20,000. They found 5 reports of cases from other parts of the world. After identifying the mutation responsible for hydrolethalus syndrome in the Finnish population, Mee et al. (2005) genotyped 908 Finnish control chromosomes and 98 chromosomes of mixed European descent to determine the population frequency of this variant. They found that among chromosomes originating from the late settlement central and eastern Finland, 2.5% (14/556) carried this change, whereas 1.1% (4/352) chromosomes collected from early settlement western Finland carried the change. No carriers were identified in the European sample.