Hydrolethalus Syndrome

Hydrolethalus syndrome was coined by Salonen et al.

in 1981 in patients with severe CNS malformations,

hydrocephalus, micrognathia, cleft lip/palate, lung

hypoplasia club foot, and polydactyly, distinguishable

from the Meckel syndrome by the absence of polycys-

tic kidneys (Salonen et al. 1981). The majority of cases

were reported from Finland.

Genetics/Basic Defects

1. Inheritance: autosomal recessive

2. Hydrolethalus syndrome locus: assigned to 11q23-

q25 in Finnish families

3. HYLS1 gene mutation

a. Responsible for hydrolethalus syndrome in the

Finnish population, HYLS1

b. c.632A > G (D211G) mutation: the common

mutation carried in the Finnish population

Clinical Features

1. A lethal condition: stillborn or died within a few

hours of birth in majority of cases

2. Hydramnios

3. Severe midline CNS malformations

a. A midline cerebral cleft: more common

b. Absence of the corpus callosum

c. Absence of septum pellucidum

d. Hydrocephalus secondary to aqueductal

stenosis

e. Dorsal midline defect of the foramen magnum,

forming a keyhole-shaped opening

(occipitoschisis)

f. Cerebellar heterotopias

g. Brain stem malformations

h. Cerebral gyral abnormalities

i. Absent olfactory lobes

j. Hypothalamic hamartomas

k. Dandy-Walker malformation

4. Craniofacial features

a. Microphthalmia

b. Nasal anomalies

c. Small mandible

d. Cleft lip/palate

e. Small tongue

f. Low-set, malformed ears

5. Pulmonary anomalies

a. Abnormal larynx, trachea, and bronchi

b. Pulmonary hypoplasia/agenesis

c. Defective lung lobulation

6. Congenital heart defects

a. Ventricular septal defect

b. Open foramen ovale

c. Common atrioventricular canal

7. Renal anomalies

8. Duplex/bicornis uterus

9. A typical “keyhole” occipital bone defect

10. Polydactyly

a. Hands: always postaxial

b. Feet: almost always preaxial

11. Differential diagnosis

a. Acrocallosal syndrome

i. Macrocephaly

ii. Craniofacial anomalies

iii. Hallux duplication

iv. Postaxial polydactyly

v. Absence of corpus callosum

vi. Mental retardation

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_122,# Springer Science+Business Media, LLC 2012

1081

b. Smith-Lemli-Opitz syndrome (severe form)

i. Hydrocephalus

ii. Cerebellar hypoplasia

iii. Cardiac anomalies

iv. Genital anomalies

v. Polydactyly

c. Orofacialdigital syndrome, type VI

i. Cerebellar anomalies

ii. Hypertelorism

iii. Micrognathia

iv. Midline cleft lip

v. Cleft palate

vi. A small tongue with lingual nodules and

multiple frenula

vii. Laryngeal anomalies

viii. Cardiac anomalies

ix. Preaxial polysyndactyly of hands and feet

x. Postaxial polysyndactyly of the feet

d. Pallister-Hall syndrome

i. Hypertelorism

ii. Micrognathia

iii. Midline cleft lip

iv. Cleft palate

v. A small tongue with lingual nodules and

multiple frenula

vi. Laryngeal anomalies

vii. Lung segmental anomalies

viii. Cardiac anomalies

ix. Postaxial polysyndactyly of the feet

e. Walker-Warburg syndrome

i. Overlapping features

a) Encephalocele

b) Agenesis of midline brain structures

c) Hydrocephalus

ii. Features usually not seen

a) Eye abnormalities

b) Polydactyly

Diagnostic Investigations

1. Radiologic studies

a. Skull

i. Microcephaly

ii. Occipital bone defect continuous with fora-

men magnum

iii. A keyhole shaped defect at the base of skull

b. Digital anomalies

i. Postaxial polydactyly of the hands

ii. Preaxial polydactyly or hallux duplication of

the feet

2. Ultrasound or MRI of the brain for delineation of

brain anomalies

3. Echocardiogram for delineation of congenital heart

defects

4. Molecular genetic study: target mutation analysis of

HYLS1 gene (c.632A > G)

Genetic Counseling

1. Recurrence risk

a. Patient’s sib

i. Recurrence risk: 25%

ii. Unaffected sibs of a proband: two thirds

chance of being heterozygotes

b. Patient’s offspring: a lethal entity not surviving

to reproduction

2. Prenatal diagnosis

a. Possible by prenatal ultrasonography in at-risk

families

b. Possible for pregnancies at risk when the dis-

ease-causing mutation in the family is known

3. Management

a. Supporting care

b. No treatment available for the underlying lethal

disorder

References

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diagnosis of hydrolethalus syndrome in a Chinese family.

Prenatal Diagnosis, 24, 587–590.Christensen, B., Blaas, H. G., Isaksen, C. V., et al. (2000). Sibs

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Hydrolethalus Syndrome 1083

c

ad

e

b

Fig. 1 (a–e) A neonate with hydrolethalus syndrome showing

malformed skull, microcephaly, ocular hypertelorism, anoma-

lous nose, micrognathia, left cleft lip and palate, a small tongue,

low-set and malformed ears, short neck, postaxial polydactyly of

the hands, and preaxial polydactyly of the feet

1084 Hydrolethalus Syndrome