X-linked microhydranencephaly is a male-lethal disorder characterized by intrauterine growth retardation, extreme microcephaly, and lack of fetal movement on prenatal ultrasound, with death in utero or stillbirth. Autopsy shows limb contractures with talipes equinovarus and hypoplastic lungs and kidneys. Brain findings are consistent with severe holoprosencephaly or near-anencephaly. Obligate carrier females may show a milder phenotype of short stature and microcephaly (Hockey et al., 1988; Carroll et al., 2017).

An autosomal recessive form of microhydranencephaly (MHAC; 605013) is caused by mutation in the NDE1 gene (609449).

Morse et al. (1987) reported the prenatal diagnosis of a characteristic abnormality in 2 fetuses with congenital contractures, markedly decreased fetal movement, and microcephaly due to severe holoprosencephaly. The knees were in extension. Both were male; the parents were normal and not related. The disorder resembled the Neu-Laxova syndrome (256520) in intrauterine growth retardation, multiple joint contractures, severe microcephaly, and recurrence in families. However, the lack of hyperkeratosis or ichthyosis and the resulting characteristic facial appearance, the lack of distal extremity swelling, and the presence of holoprosencephaly distinguished the disorder from the Neu-Laxova syndrome.

Hockey et al. (1988) reported 2 stillborn males whose mothers were sisters. Prenatal ultrasound in both showed growth retardation, microcephaly, and lack of fetal movements. Postmortem in affected male III-1 showed contractures of the limbs with talipes equinovarus, narrow thorax with hypoplastic atelectatic lungs, and kidneys with growth arrest at an earlier stage of fetal maturation. The brain showed a paper-thin ribbon-like cortex surrounding a single ventricle, with absence of olfactory bulbs and tracts, consistent with holoprosencephaly. Affected male III-2, who had absent falx and fetal edema on prenatal ultrasound, showed gross edema, bilateral hydrothorax with hypoplastic lungs, and penile chordee on postmortem. Neuropathologic findings included absent medullary pyramids, deeply clefted large fourth ventricle, and immature thalamus with no evidence of neuronal differentiation. There was absence of the anterior part of the telencephalon, prosencephalon, and diencephalon, with only derivatives of the rhombencephalon present. The authors characterized this as holoprosencephaly and hydranencephaly, verging on anencephaly. Family history revealed that the sisters' mother had experienced a pregnancy resulting in fetal death in utero of a male at 6 months' gestation, described as abnormal in appearance, but no postmortem was done. The authors stated that these cases corresponded in almost every detail to the male sibs described by Morse et al. (1987), with holoprosencephaly, extreme microcephaly, hypokinesia and contractures, and lethality, and noted that they provided evidence of probable X-linked recessive inheritance.

Carroll et al. (2017) restudied the family originally reported by Hockey et al. (1988) and described 2 additional affected males. The first patient (III-7) showed marked microcephaly and possible holoprosencephaly on prenatal ultrasound at 18 weeks. The pregnancy was terminated at 21 weeks, and autopsy showed microcephaly, sloping forehead, small eyes, and rocker-bottom feet with profound lateral deviation. Microscopy of the brain revealed cortical gyral development around 15 weeks' gestation. The optic nerves and optic chiasm could not be visualized. The second patient (IV-1) showed microcephaly and ventriculomegaly as well as growth restriction on ultrasound at 15 weeks' gestation. By 18 weeks ventriculomegaly had increased and amniotic fluid was increased. Delivery occurred at 18.5 weeks' gestation and autopsy showed small but normally formed lungs and kidneys. The eyes were small and orbital contents consisted of predominantly loose connective tissue with a small amount of very immature retinal-type epithelium. Examination of the central nervous system showed 2 separate cerebral hemispheres, no obvious corpus callosum, and an apparent doubling of the cortex laterally, suggesting a neuronal migration defect. Carroll et al. (2017) noted that 2 of the obligate carrier mothers (II-2 and II-8) exhibited short stature with microcephalic head circumferences (2nd centile), whereas another (III-2) was of average height with a small head (2nd to 10th centile), indicating a possible mild phenotype in heterozygous females.

The transmission pattern of MHACX in the families reported by Morse et al. (1987) and Hockey et al. (1988) was consistent with X-linked recessive inheritance.

For discussion of a possible association between X-linked microhydranencephaly and variation in the GPKOW gene, see 301003.0001.