ORPHA: 2189; DO: 0111355;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q24.2 | Hydrolethalus syndrome | 236680 | Autosomal recessive | 3 | HYLS1 | 610693 |
A number sign (#) is used with this entry because the form of hydrolethalus syndrome belonging to the Finnish disease heritage, hydrolethalus-1 (HLS1), is caused by homozygous mutation in the HYLS1 gene (610693) on chromosome 11q24.
Hydrolethalus-1 (HLS1) is an autosomal recessive lethal malformation syndrome characterized by hydrocephaly with absent upper midline structures of the brain, micrognathia, and polydactyly. Various other features such as cleft lip or palate, club feet, anomalies of the ears, eyes, and nose, keyhole-shaped defect in the occipital bone, abnormal genitalia, and congenital heart and respiratory organ defects have also been observed in affected individuals. Affected individuals are stillborn or die shortly after birth (summary by Mee et al., 2005).
Genetic Heterogeneity of Hydrolethalus Syndrome
See also HLS2 (614120), caused by mutation in the KIF7 gene (611254) on chromosome 15q26.
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.
The transmission pattern of HLS1 in the families reported by Mee et al. (2005) was consistent with autosomal recessive inheritance.
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.
Visapaa et al. (1999) assigned the hydrolethalus syndrome locus to 11q23-q25 in Finnish families. The initial genome scan was performed using DNA samples from only 15 affected individuals. In the next step, the locus was assigned to an 8.5-cM interval between markers D11S4144 and D11S1351 by linkage analysis in 8 families. Finally, the critical locus could be restricted by linkage disequilibrium and haplotype analyses to a 0.5- to 1-cM region between markers D11S933 and D11S934. Genealogic studies performed in 40 families affected by hydrolethalus revealed no regional clustering, suggesting a relatively early introduction of the disease mutation into the Finnish population and the spreading of the mutation with the inhabitation of the late-settlement area.
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.
Anyane-Yeboa, K., Collins, M., Kupsky, W., Maidman, J., Malin, J., Yeh, M. Hydrolethalus (Salonen-Herva-Norio) syndrome: further clinicopathological delineation. Am. J. Med. Genet. 26: 899-907, 1987. [PubMed: 3296755] [Full Text: https://doi.org/10.1002/ajmg.1320260418]
Aughton, D. J., Cassidy, S. B. Hydrolethalus syndrome: report of an apparent mild case, literature review, and differential diagnosis. Am. J. Med. Genet. 27: 935-942, 1987. [PubMed: 3321994] [Full Text: https://doi.org/10.1002/ajmg.1320270421]
Bachman, H., Clark, R. D., Salahi, W. Holoprosencephaly and polydactyly: a possible expression of the hydrolethalus syndrome. J. Med. Genet. 27: 50-52, 1990. [PubMed: 2407847] [Full Text: https://doi.org/10.1136/jmg.27.1.50]
de Ravel, T. J. L., van der Griendt, M. C., Evan, P., Wright, C. A. Hydrolethalus syndrome in a non-Finnish family: confirmation of the entity and early prenatal diagnosis. Prenatal Diag. 19: 279-281, 1999. [PubMed: 10210131] [Full Text: https://doi.org/10.1002/(sici)1097-0223(199903)19:3<279::aid-pd518>3.0.co;2-l]
Mee, L., Honkala, H., Kopra, O., Vesa, J., Finnila, S., Visapaa, I., Sang, T.-K., Jackson, G. R., Salonen, R., Kestila, M., Peltonen, L. Hydrolethalus syndrome is caused by a missense mutation in a novel gene HYLS1. Hum. Molec. Genet. 14: 1475-1488, 2005. [PubMed: 15843405] [Full Text: https://doi.org/10.1093/hmg/ddi157]
Morava, E., Adamovich, K., Czeizel, A. E. Dandy-Walker malformation and polydactyly: a possible expression of hydrolethalus syndrome. Clin. Genet. 49: 211-215, 1996. [PubMed: 8828988] [Full Text: https://doi.org/10.1111/j.1399-0004.1996.tb03289.x]
Pryde, P. G., Qureshi, F., Hallak, M., Kupsky, W., Johnson, M. P., Evans, M. I. Two consecutive hydrolethalus syndrome-affected pregnancies in a nonconsanguineous black couple: discussion of problems in prenatal differential diagnosis of midline malformation syndromes. Am. J. Med. Genet. 46: 537-541, 1993. [PubMed: 8322817] [Full Text: https://doi.org/10.1002/ajmg.1320460516]
Salonen, R., Herva, R., Norio, R. The hydrolethalus syndrome: delineation of a 'new' lethal malformation syndrome, based on 28 patients. Clin. Genet. 19: 321-330, 1981. [PubMed: 7028327] [Full Text: https://doi.org/10.1111/j.1399-0004.1981.tb00718.x]
Salonen, R., Herva, R. Hydrolethalus syndrome. J. Med. Genet. 27: 756-759, 1990. [PubMed: 2074561] [Full Text: https://doi.org/10.1136/jmg.27.12.756]
Shotelersuk, V., Punyavoravud, V., Phudhichareonrat, S., Kukulprasong, A. An Asian girl with a 'milder' form of the hydrolethalus syndrome. Clin. Dysmorph. 10: 51-55, 2001. [PubMed: 11152149] [Full Text: https://doi.org/10.1097/00019605-200101000-00011]
Toriello, H. V., Bauserman, S. C. Bilateral pulmonary agenesis: association with the hydrolethalus syndrome and review of the literature from a developmental field perspective. Am. J. Med. Genet. 21: 93-103, 1985. [PubMed: 4003452] [Full Text: https://doi.org/10.1002/ajmg.1320210114]
Visapaa, I., Salonen, R., Varilo, T., Paavola, P., Peltonen, L. Assignment of the locus for hydrolethalus syndrome to a highly restricted region on 11q23-25. Am. J. Hum. Genet. 65: 1086-1095, 1999. [PubMed: 10486328] [Full Text: https://doi.org/10.1086/302603]