Gomez–López–Hernández syndrome: A case report with clinical and molecular evaluation and literature review

Abstract

Gomez–López–Hernández syndrome (GLHS) is characterized by rhombencephalosynapsis (RES), alopecia, trigeminal anesthesia and a distinctive phenotype, including brachyturricephaly. It has been suggested that GLHS should be considered as part of the spectrum of RES-associated conditions that include alopecia, trigeminal anesthesia, and craniofacial anomalies, rather than a distinct entity. To the best of our knowledge, 57 patients with GLHS have been described. Despite its first description in 1979, the etiology of this syndrome remains unknown. Here, we describe, to our knowledge, the first case of a patient with GLHS who was molecularly evaluated and had been prenatally exposed to misoprostol. We also reviewed the clinical and morphological features of the patients described to date to better delineate the phenotype and focus on any evidence for adverse pregnancy outcomes or exposure, including teratogens.

1 |. INTRODUCTION

Gomez–López–Hernández syndrome (GLHS) was first described by Manuel Gomez in 1979 in a female child with trigeminal anesthesia, focal congenital alopecia, brachycephaly, hypertelorism, convergent strabismus, and cerebellar ataxia (Gomez, 1979). It is a rare neurocutaneous disorder that is characterized by a triad of findings as follows: partial alopecia of the scalp, rhombencephalosynapsis (RES), and trigeminal anesthesia. Sukhudyan et al. (2010) evaluated 27 patients with GLHS and concluded that RES and alopecia are the required diagnostic criteria, while trigeminal anesthesia, dysmorphic features, and ataxia are inconsistent findings (Sukhudyan et al., 2010). Some authors have proposed that GLHS is part of the spectrum of RES-associated conditions that include alopecia, trigeminal anesthesia, and craniofacial differences, rather than a distinct entity (Tully et al., 2012).

To date, approximately 57 patients with GLHS have been reported worldwide. Although the first case have been described more than 30 years ago, the etiology remains unknown.

Here, we reported the case of a female child with GLHS whose mother had gestational exposure to misoprostol, which may have played a role of a disruption event in the pathogenesis of GLHS. We also reviewed the clinical and morphological features of the patients described to date to better delineate the phenotype. We focus on any evidence for adverse pregnancy outcomes or exposure, including teratogens.

2 |. CASE REPORT

The patient was the only child of a nonconsanguineous marriage. Prenatal ultrasound at the 27th gestational week showed posterior ventriculomegaly, third ventricle enlargement, and vermis cerebellar hypoplasia. The child was born via cesarean delivery and the body measurements were as follows: weight 2,850 g (10th–25th percentile), height 47.5 cm (3rd–10th percentile), and occipital frontal circumference (OFC) 36.5 cm (90th–97th percentile). Morphological examination showed brachyturricephaly, flat midface, bilateral parietal alopecia, and convergent strabismus. Magnetic resonance imaging confirmed prenatal ultrasound findings and showed vermis cerebellar agenesis and partial fusion of the cerebellar hemispheres with continuity of the cerebellar folia (RES; Figure 1). The results of abdominal ultrasound, echocardiography, and ophthalmologic evaluation were normal. Owing to RES, alopecia, and the characteristic phenotype, the newborn was diagnosed with GLHS.

FIGURE 1.

(a) T2-weighted sagittal view: Severe hydrocephalus caused by aqueductal stenosis, fusion of cerebellar hemispheres, and thinning of corpus callosum. (b) T1-weighted axial view: Severe hydrocephalus, fusion of cerebellar hemispheres. Fusion of dentate nuclei, with abnormally shaped fourth ventricle (diamond shape). (c) Coronal T2: fusion of cerebellar hemispheres and horizontal orientation with continuity of the cerebellar folia across the midline

Following discharge, the patient was lost to follow-up until the age of 6 years, when hypotonia, late independence in walking (21 months), and head stereotypies (head up and down/yes–yes movements) were raised as concerns by the family. At this time, the information that the mother had taken misoprostol (two pills) during the first trimester of pregnancy was also disclosed. The medicine had been taken orally and vaginally as soon as she had discovered the pregnancy (approximately 3 weeks after conception). The only consequence of this exposure was moderate bleeding.

The results of morphological examination at the age of 6 years showed brachyturricephaly, flat midface and bilateral parietal alopecia, downslanted palpebral fissures, low-set ears, and convergent strabismus (Figure 2). Anthropometric measurements were as follows: Weight 19.8 kg (25th–50th percentile), height 1.22 m (50th–75th percentile), and OFC 51.5 cm (50th–75th percentile).

FIGURE 2.

(a) Lateral and (b) frontal views showing alopecia, flat midface, and brachyturricephaly [Color figure can be viewed at wileyonlinelibrary.com]

Her neurological examination revealed cerebellar ataxia, expressed by unsteady and wide-based gait and dynamic balance abnormalities. Trigeminal nerve function was intact, including corneal reflexes, facial sensation, chewing, and swallowing.

She underwent a neuropsychological assessment focusing on intellectual performance (Brazilian version of the Wechsler Intelligence Scale for Children [WISC-IV]; Wechsler, 2013). The WISC-IV scores indicated an average intelligence quotient (IQ 98), with no discrepancies between the verbal comprehension (93) and perceptual organization (93) indices.

3 |. MATERIALS AND METHODS

3.1 |. Editorial policies and ethical considerations

Informed consent for publication of the manuscript and photographs was obtained from the patient and her mother. The procedures were performed in accordance with the ethical standards as laid out in the Declaration of Helsinki.

3.2 |. DNA extraction

Genomic DNA was purified from fresh whole blood using the Gentra Puregene kit (Qiagen Sciences, Germantown, MD), in accordance with the manufacturer’s instructions.

3.3 |. Single-nucleotide polymorphism genotyping

Whole-genome single-nucleotide polymorphism (SNP) genotyping was performed using the HumanExome-12v1–1_A, Illumina HumanCoreExome-24v1–3, in accordance with the manufacturer’s instructions.

3.4 |. Target capture and exome sequencing

To capture the target regions, we used the Agilent SureSelect Human All Exon 50 Mb Kit (Agilent Technologies, Santa Clara, CA), following the protocol provided by the manufacturer. We performed whole-exome sequencing (paired-end 100 bp reads) on the proband and her mother using the Illumina HiSeq2500 platform (Illumina, Inc., San Diego, CA). We aligned each read to the reference genome (NCBI human genome assembly build 36; Ensembl core database release 50_361; Hubbard et al., 2009) using the Burrows–Wheeler Alignment tool and identified single-nucleotide variants (SNVs) and small insertions/deletions (indels) using SAM tools (Li et al., 2009). PCR duplicates were removed using Picard software. We also performed local realignment and base call quality recalibration using GATK (McKenna et al., 2010).

3.5 |. Identification of potentially causal variants

We identified variants of interest using standard filtering criteria. We evaluated compound heterozygous variants, homozygous variants, and de novo heterozygous variants, as we had no hypothesis about the pattern of inheritance. We prioritized functional variants (missense, nonsense, splice site variants, and indels). We excluded variants found in the Exome Variant Server and the 1000 Genomes Project with minor allele frequency >1%. We also excluded any variant (SNVs or indels) with a frequency >1% found in in-house controls. Next, we analyzed the remaining variants for known associations with Mendelian diseases (OMIM).

3.6 |. Literature review

We performed a literature review using the PubMed and Web of Science databases. We used the following keywords: “Gomez López Hernández syndrome” or “GLH syndrome” or “cerebellotrigeminal dysplasia” or “parietal alopecia” or “congenital alopecia” or “trigeminal anesthesia” or “rhombencephalosynapsis.” In our review, we included case reports that had at least two of the following features: RES, trigeminal anesthesia, and alopecia. We did not exclude non-English language papers, with papers written in Spanish and German being translated.

4 |. RESULTS

4.1 |. Molecular evaluation

SNP array testing did not reveal pathogenic copy number variants. Moreover, we used whole-exome sequencing to rule out pathogenic variants associated with known conditions and did not find pathogenic variants in disease-related genes (which have already been linked to any phenotype in the OMIM database).

4.2 |. Literature review

After using the keywords, we were able to find 320 papers in the Web of Science database and 268 papers in the PubMed database. In the first stage, we excluded papers that were not linked to the Gomez–López–Hernández spectrum, as determined by just reading the title. In the second step, we read the remaining abstracts, excluding those that were not associated with case reports. For the remaining papers, in the third step, we read them comprehensively to check whether the described patients met the inclusion criteria for this study.

After this filtering process, we obtained 30 papers from the Web of Science database and 34 from the PubMed database. There were 28 papers which were found in Web of Science and PubMed simultaneously, while 2 and 6 papers were exclusively found in Web of Science and PubMed, respectively. One paper was found by a manual search by an author (Zaldívar-Páscua et al., 2011). Therefore, we obtained a total of 37 papers, describing 57 patients who met our inclusion criteria, as listed in Table S1.

4.3 |. Discussion

Our patient fulfilled the clinical criteria for definitive GLHS as she had RES, alopecia, and the characteristic phenotype (Rush et al., 2013). SNP array and whole-exome analysis did not reveal pathogenic variants associated with known phenotypes.

To date, approximately 57 cases have been described, and the etiology of this syndrome remains unknown. Clinical and morphological features of patients with GLHS were reviewed, and the data are summarized in Table S1. No familial recurrence was identified, so all the cases appeared to have arisen de novo. The proportion of affected males to females is approximately 1.6:1; 4 out of 57 patients had consanguineous parents.

Trigeminal anesthesia was described in 29 out of 44 patients for whom information was available (65.9%). The patient in the present case did not have trigeminal anesthesia, which reinforces the claim that trigeminal anesthesia is not an obligatory finding in these patients.

Our patient revealed no intellectual disability (ID). Indeed, our review showed that merely 12 out of 43 patients for whom information was available (27.9%) did not have an ID or neurodevelopmental delay (ND). Among these 12 patients, 9 had undergone a formal neuropsychological test, while 3 were classified as having normal neurodevelopment on the basis of only clinical/history evaluation. Therefore, our case and review support the assertion that ID/ND is not a universal finding in these patients, although it is a prevalent feature.

We also identified the report of a patient without RES, but with alopecia and trigeminal anesthesia (Pastor-Idoate, Carreño, Téson, & Herreras, 2012), which supports the assertion that GLHS is part of a spectrum of RES-associated conditions that include alopecia, trigeminal anesthesia, and craniofacial abnormalities (Tully et al., 2012). To the best of our knowledge, the case described by Pastor-Idoate et al. is the first without RES.

All patients for whom data were available had alopecia, which could be associated with ascertainment bias. This also raises the question of whether it is better to understand the spectrum as RES-associated anomalies or as focal alopecia-associated anomalies. Tully et al. (2012) evaluated clinical features in groups of patients with RES and showed that patients with alopecia had higher composite morphology scores than those without it.

Rush et al. (2013) evaluated four patients with GLHS using comparative genomic hybridization and found no copy number variations that could explain the syndrome. Moreover, recently, Aldinger et al. (2018) used exome sequencing for 59 probands with RES, but did not find a candidate gene. They also found a monozygotic (MZ) twin pair discordant for the RES phenotype. It is known that a discordant phenotype in MZ twins could be explained by somatic mosaicism or imprinting disorders; moreover, MZ twins have an increased risk for structural defects associated with presumed prenatal vascular perfusion deficiency (Aldinger et al. 2018).

Few studies of environmental factors that could contribute to the phenotype have been performed. Aldinger et al. (2018) interviewed mothers of children with RES in their cohort, but did not identify any obvious pregnancy exposures (medications, high fever, illicit drug or alcohol use, severe illness, trauma), although diabetes and the use of assisted reproduction were reported by some mothers. Rush et al. (2013) also reported a patient who was born after an in vitro fertilization procedure.

Although Aldinger et al. (2018) did not identify any obvious pregnancy exposures, Choudhri, Patel, Wilroy, Pivnick, and Whitehead (2015) reported a patient whose mother had a history of multiple substance abuse. Tan, McGilivray, Goergen, and White (2005) also described a proband whose mother had a history of cannabis exposure.

Since its first description in 1979, Gomez suggested that developmental arrest of the ectoderm, which gives rise to the alar plate of the rhombencephalon, the overlying epidermis, and the trigeminal nerve, could be the cause of this syndrome (Gomez, 1979).

The cerebellum arises from the hindbrain (rhombencephalon), which is divided into segments called rhombomeres. Rhombomere 2 contributes to trigeminal nerve development, while rhombomere 1 is the source of the cerebellum. According to Haldipur et al. (2018), the cerebellum is derived from anterior and dorsal segments of the hindbrain. Its development is initiated as soon as the boundary between midbrain and hindbrain (MHB) is established, at approximately 17–19 days of development, during the neural plate stage. The boundary between MHB is the first segmental division of the neural plate and occurs before neural tube closure (in the middle of the third week). The MHB functions as a local organizing center for the development of the MHB (Harada et al., 2016).

In the embryo, the trigeminal ganglia are first visible in week 4, initially developing from neural crest cells before neural fold fusion; after fusion, they receive contributions from the neural tube roof plate. The trigeminal placode also contributes to trigeminal development and is located in the superficial ectoderm, posteriorly to the optical placode in a region that could correspond to the temporal area. It is important to highlight that all of these structures come from the ectodermal layer, which appears during gastrulation in Week 3 (O’Rahilly & Muller, 2007). A genetic and/or environmental factor that interferes with ectodermal development in this period could provide us with insights regarding a possible etiology for GLHS.

Misoprostol is an orally active prostaglandin, which can be used for patients with upper gastrointestinal ulceration, but it is contraindicated to treat this condition in pregnant women, since it can cause miscarriage. Indeed, this drug can be used to terminate a pregnancy. A spectrum of malformations ranging from scalp anomalies to Moebius sequence and limb reduction defects has been associated with prenatal exposure to misoprostol. It has been proposed the mechanism behind its contribution to birth defects involves vascular disruption (Vargas et al., 2000).

Some cerebellar malformations have already been shown to be related to vascular/disruptive effects, such as cerebellar hypoplasia, cerebellar clefts, and Dandy–Walker malformation. Moreover, upon analysis of prenatal human cerebellar tissue, gene enrichment in neuronal and vascular cell types was identified (Aldinger et al., 2019). However, this rationale cannot be applied to RES, considering the evidence currently available.

Additional reports of cases with very well-documented prenatal history, as well as experimental data and epidemiological studies, could help us to better understand whether environmental factors contribute to the etiology of GLHS. Considering the rarity of GLHS, which represents a challenge for performing epidemiological and case–control studies, and that information regarding attempts to end early pregnancies may be under-reported by mothers due to ethical and legal issues, we believe that our case raises an important issue regarding the role of environmental factors in the etiopathogenesis of GLHS.