Gomez-Lopez-Hernandez Syndrome

Description

Gomez-Lopez-Hernandez syndrome, also known as cerebellotrigeminal dermal dysplasia, is a rare neurocutaneous syndrome classically characterized by the triad of rhombencephalosynapsis, trigeminal anesthesia, often giving rise to corneal opacities, and bilateral parietal or parietooccipital alopecia, However, trigeminal anesthesia is an inconsistent finding (summary by Sukhudyan et al., 2010).

Clinical Features

Four unrelated patients with a constellation of features, consisting of craniosynostosis, ataxia, trigeminal anesthesia, scalp alopecia, cerebellar anomaly, midface hypoplasia, corneal opacities, low-set ears, mental retardation, and short stature were reported by Gomez (1979), Lopez-Hernandez (1982), and Pascual-Castroviejo (1983). These patients belonged to different families, and only 2 were from the same country (Gomez, 1987).

Munoz et al. (1997) presented 3 new cases of this disorder from 3 different Brazilian families and reported their clinical signs, symptoms and course, and neuroradiologic studies, including magnetic resonance imaging (MRI). The disorder appeared to be sporadic. The corneal opacities are apparently secondary to the trigeminal anesthesia. All 3 patients had cerebellar and brainstem hypoplasia on MRI.

Brocks et al. (2000) stated that 7 patients with this condition had been documented since 1979. They reported a male with the syndrome who, at the age of 19 years, was the oldest patient identified. Since he had been followed from birth, it was possible to report on the progression of his physical findings and psychiatric problems, including hyperactivity, depression, self-injurious behavior, and bipolar disorder. In addition, he was of short stature and had growth hormone deficiency.

Tan et al. (2005) stated that rhombencephalosynapsis, defined as fusion of the cerebellar hemispheres, agenesis or hypogenesis of the vermis, and fusion of the dentate nuclei and the superior cerebellar peduncles, is the most consistent cerebellar malformation reported in GLH syndrome.

Bowdin et al. (2007) reported a 24-month-old boy who presented at age 9 months with marked developmental delay, failure to thrive, and ventriculomegaly. Hydrocephalus had been noted at 20 weeks' gestation. MRI showed rhombencephalosynapsis and primary absence of the septum pellucidum. Other features included temporoparietal balding, marked central hypotonia, brisk reflexes, and clenched fists. The boy had 3 normal sibs, and there was no family history of neurologic disorder.

Gomy et al. (2008) reported 2 unrelated Brazilian males with Gomez-Lopez-Hernandez syndrome. The first patient was 29 years old at the time of the report, born of consanguineous parents, and had 10 unaffected sibs. He had severely delayed psychomotor development with moderate mental retardation, inability to walk due to spastic paraplegia, and seizures. He had striking turribrachycephaly, relative macrocephaly with a broad forehead, small nose, thin lips, high-arched palate, midface hypoplasia, and low-set ears. Brain MRI scan showed absence of the septum pellucidum, ventricular enlargement with a thin cortex, and fused cerebellar hemispheres and absence of the cerebellar vermis. The second patient was a 12-year-old boy with delayed development who had to be institutionalized due to lack of family resources. He had brachycephaly, hypertelorism, low-set ears, small nose, and thin lips. MRI scan showed rhombencephalosynapsis. The older patient had evidence of partial growth hormone deficiency. Psychiatric evaluation was suggestive of early-onset bipolar disorder in the second patient. Psychiatric evaluation of 2 patients reported by Munoz et al. (1997) revealed that 1 patient had irritability, agitation, verbal aggression and self-aggression. Genetic analysis excluded pathogenic mutations in the ACP2 gene (171650).

Sukhudyan et al. (2010) reported 6 male patients, ranging in age from 1.5 to 20 years, with Gomez-Lopez-Hernandez syndrome. Four were of Armenian origin, and 2 were of European origin; none were born of consanguineous parents. Two presented in the neonatal period with feeding problems and hydrocephalus, whereas the other 4 presented in infancy with global or motor developmental delay, marked hypotonia, and ventriculomegaly. All patients had bilateral alopecia from birth, and brain MRI of all patients showed typical rhombencephalosynapsis. None had trigeminal analgesia. Two older patients had normal IQ at ages 12 and 20 years, respectively, and 2 younger patients had normal development at ages 2 and 1.5 years, respectively. The other 2 patients had low IQ (59 and 78, respectively). Four patients had hypotonia, and 4 had head nodding, but only 1 had ataxia. Dysmorphic craniofacial features were variable and included midface hypoplasia in 4, low-set, posteriorly rotated ears in 4, brachycephaly in 3, strabismus in 3, and mild ptosis in 2.

Rush et al. (2013) reported 4 unrelated children with Gome-Lopez-Hernandez syndrome. All had rhombencephalosynapsis, alopecia, and delayed motor milestones. All also had low-set ears and brachy- or turricephaly. Only 1 of the 4 had trigeminal anesthesia with absent corneal reflexes and corneal clouding. Three had intellectual disability with head shaking or stereotypic behavior. More variable features included hydrocephalus, midface retrusion, strabismus, widely spaced eyes, hypotonia, and short stature. A review of features of 30 previously published cases confirmed the inconsistent finding of trigeminal anesthesia, and emphasized craniofacial abnormalities.

Diagnosis

In a literature review of the diagnostic criteria for Gomez-Lopez-Hernandez syndrome, Sukhudyan et al. (2010) noted that rhombencephalosynapsis and alopecia are consistent findings, but that trigeminal anesthesia was absent in 4 of 21 cases in the literature, as well as in their 6 patients, and suggested that trigeminal anesthesia may not always be present. Inconsistent additional features include craniofacial dysmorphic signs, such as a brachyturricephaly, midface hypoplasia, and low-set, posteriorly rotated ears, ataxia, muscular hypotonia, short stature, and corneal opacities secondary to trigeminal anesthesia. Cognitive functions are usually impaired, but patients may also have normal intellectual development. Sukhudyan et al. (2010) suggested that the syndrome may be underdiagnosed.

Rush et al. (2013) proposed that the diagnostic criteria for Gomez-Lopez-Hernandez must include rhombencephalosynapsis and alopecia, although the presence of these 2 features is not sufficient for diagnosis. The additional finding of trigeminal anesthesia would confirm the diagnosis. Other features that should be considered as part of the phenotype include the major criteria of brachycephaly/turricephaly and midface retrusion, as well as the minor criteria of strabismus, widely spaced eyes, plagiocephaly, and lambdoid craniosynostosis. Neurologic features that should be considered include motor delay, ataxia, hypotonia, intellectual disability, and stereotypic movements.

Prenatal Diagnosis

Tan et al. (2005) reported the prenatal diagnosis of Gomez-Lopez-Hernandez syndrome in an Australian fetus at 21 weeks' gestation by detection of rhombencephalosynapsis on fetal MRI imaging after an ultrasound showed an abnormally shaped small cerebellum. At birth, the infant showed turribrachycephaly with a wide anterior fontanel and overlapping sutures, low-set and posteriorly rotated ears, hypertelorism, small anteverted nose, and a smooth philtrum with thin upper lip. By age 6 weeks, there was striking parietooccipital alopecia.

Animal Model

Tan et al. (2005) noted that the naked ataxic mouse 'nax,' which has a spontaneous recessive mutation in the Acp2 gene (Mannan et al., 2004), shows some similar features to Gomez-Lopez-Hernandez syndrome.