Holoprosencephaly (HPE) : case report and review of the literature

Abstract

Introduction

Holoprosencephaly (HPE) is a complex brain malformation resulting from a medial cleavage defect of the prosencephalon into right and left hemispheres, occurring during early embryonic development.

Case presentation

We report an alobar holoprosencephaly diagnosed on imaging (obstetrical ultrasound) and revealed by a polymalformative syndrome in an 8-month-old infant.

Discussion

Holoprosencephaly affects the forebrain and face, causing neurological manifestations and facial anomalies of varying severity. HPE is a cerebral midline anomaly.

Conclusion

Its fetal prognosis is extremely guarded, particularly for the alobar form.

Highlights

• •Holoprosencephaly (HPE) is a complex brain malformation resulting from a medial cleavage defect of the prosencephalon into right and left hemispheres, occurring during early embryonic development.
• •holoprosencephaly affects the forebrain and face, causing neurological manifestations and facial anomalies of varying severity. HPE is a cerebral midline anomaly.
• •Its fetal prognosis is extremely guarded, particularly for the alobar form.

1. Introduction

Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete division of the prosencephalon, occurring between days 18 and 28 of embryonic life and affecting both the brain and the face [1]. It is a rare fetal pathology with a great heterogeneity of aetiology. It affects one in 15,000 to 16,000 births [2]. Three degrees of increasing severity have been described: lobar, semi-lobar, and alobar holoprosencephaly [1]. Early antenatal diagnosis of this malformation is essential for adequate and early obstetrical management. The aim of our work is to analyze the etiopathogenic aspects and modalities of prenatal diagnosis of EH. We report in this clinical case, an alobar holoprosencephaly diagnosed on imaging (obstetrical ultrasound) and noted by a polymalformative syndrome in an 8-month-old newborn. All our work was reported in accordance with the SCARE criteria and guidelines [14].

2. Presentation of the case

Mrs. W.R, 27 years old, third gesture, with no notable pathological history, was referred to us for a threat of premature delivery due to hydramnios associated with a fetal brain malformation discovered at 8 months of pregnancy. The obstetrical examination showed a uterine height of 37 cm, fetal poles difficult to perceive and muffled fetal heart sounds, with a dilated cervix of 3 cm on vaginal touch, in the process of being erased, with an intact water sac. Obstetrical ultrasound showed clear hydramnios, microcrania with a single ventricular cavity and fusion of the thalami. As part of a pregnancy check-up, fasting and postprandial blood glucose levels were normal. Toxoplasmosis and rubella serology showed residual immunity. The evolution was marked by a premature delivery by vaginal route of a female fetus with a birth weight of 1100 g. The evolution was rapidly fatal. The outcome was rapidly fatal. The clinical examination revealed facial malformations with a proboscis, rudimentary and retracted eyelids and a microstomy. This was a rhinocephalic cyclops (Fig. 1).

Fig. 1.

Fetal face: presence of a proboscis above a single orbit with one eyeball.

3. Discussion

Holoprosencephaly is a potentially severe and complex malformation of the brain associated with suggestive and peculiar facial anomalies related to a defect in the formation and individualisation of the cerebral hemispheres [1,3]. It is the translation of a defect of ventral induction of the prosencephalon at the level of the mesodermal prechordal plate after, during, but also before, the closure of the neural tube. In particular, classical EH is a result of the defect in cleavage of the telencephalic vesicles in the fifth week of development [3]. As a result, a medial hemispheric mass is formed, replacing both cerebral hemispheres, with the absence of medial structures, notably the commissures. There is also an absence or abnormality in the differentiation of structures derived from the prosencephalic vesicles and the diencephalic vesicle [2,7]. A relatively rare condition, EH is the most common malformation of the brain and face with an incidence of 0.48–0.88 per 10,000 births (excluding abortions) [5,6]. Depending on the degree of individualisation of the cerebral hemispheres, three anatomical forms of EPH have been described by Demyer and Zeman: alobar, semi-lobar and lobar [3]. The first two forms have a very poor prognosis, thus justifying early medical termination of the pregnancy [2].

Alobar HPE is the most severe form, characterised by a single ventricular cavity forming the telencephalon. This cavity is closed in its posterior part by a thin wall with a pseu-dokystic appearance. Alobar HPE is characterised by the absence of olfactory lobes, a rudimentary appearance of the thalami which are fused on the midline and constant microcephaly. Like many congenital disorders, the aetiology of holoprosencephaly is complex and multifactorial, with genetic and environmental risk factors. In fact, it is thought that a “multiple hits” hypothesis may contribute to the expressiveness and penetrance of the disease in holoprosencephaly [9]. Identified environmental risk factors include gestational diabetes, low socioeconomic status and aspirin use, maternal diabetes is a risk factor for a large number of congenital malformations including HPE [10]. Several mechanisms have been proposed to explain the effects of maternal hyperglycaemia as a cause of congenital malformations, including increased oxidative stress, hypoxia, apoptosis and epigenetic changes [11]. Multivitamin supplements could mitigate the risk of some birth defects associated with diabetes; however, diabetes was a high risk factor for EHD, even in women who took folic acid supplements [12,13]. In our case of alobar HPE, obstetric ultrasound showed microcephaly and a single ventricular cavity with fusion of the thalami in the absence of an interhemispheric cleft. In contrast, lobar EPH, which is the minor form, is characterised on obstetric ultrasound and MRI by a median sulcus without an interhemispheric cleft and showing individualised frontal, temporal and occipital lobes. It thus always associates a single ventricular cavity without medial structure and without individualization of the corpus callosum. Hypoplastic olfactory lobes are sometimes present. Ultrasound shows a single ventricular cavity with a partial interhemispheric cleavage associated with fusion of the thalami [7]. Semi-lobar EH is characterised by the presence of a medial sulcus of variable length, which forms an outline of two occipital lobes at the posterior part of the holosphere. The olfactory lobes are absent while microcephaly is usually observed.

HPE is frequently associated with facial dysmorphia, most commonly with a median cleft, cyclopia and nasal anomalies. These malformations are in 80% of cases predictive of the nature of the brain anomalies. As a result, five groups have been described according to the association of cerebral and facial malformations: groups I, II and III correspond to severe cerebral anomalies associated with a manifest facial dysmorphia ranging from cyclopia and ethmorephaly to cebocephaly. These groups often correspond to an alobar form with a very poor prognosis and where surgical solutions are not possible. Group IV A combines hypothelorism with an alobar or semi-lobar form and is also characterised by a poor prognosis. Groups IV B, V A and V B have a better prognosis and correspond to a lobar form with even a normal morphological appearance of the brain [7]. In the case of HPE in our study, facial malformations were found and included microcephaly, cyclopia, proboscis and ear implantation anomalies.

EHPs are characterised by a high degree of etiological heterogeneity dominated by genetic factors and the effect of environmental agents. The genetic aetiopathogenesis of EH is widely accepted and is dominated by chromosome 13 abnormalities, the frequency of which varies between 24 and 45%. In addition, 18–25% of EHH is part of a single-gene polymalformative syndrome such as Meckel syndrome or of unknown cause. EH is usually associated with different types of visceral and/or skeletal malformations. Isolated, non-sporadic, familial HPE with normal karyotype has an autosomal dominant mode of inheritance, less frequently an autosomal recessive or X-linked mode. Currently four genes involved in the development of HPE have been identified: sonic hedgehog (Shh), SIX3, ZIC2 and TGIF. Some sporadic cases are characterised by a normal karyotype without genetic abnormalities with a 6% risk of occurrence.

In our study, gestational diabetes as well as recent toxoplasmosis and rubella infection were ruled out in the case studied.

The antenatal diagnosis of EH is based on conventional obstetrical ultrasound completed by fetal MRI showing cerebral anomalies such as a single ventricular cavity with absence or abnormal development of the medial structures, thalami fusion and microcephaly. These abnormalities are more or less constituted depending on the anatomical form of EH. Ultrasound diagnosis of EH can be made early in the first trimester of pregnancy, allowing early termination of the pregnancy, particularly for the alobar and semi-lobar forms [2].

4. Conclusion

Holoprosencephaly is a rare fatal pathology with a great heterogeneity of aetiology that can be revealed at birth by a cleft lip and palate in the context of a polymalformative syndrome. It results from an anomaly in the cleavage of the proencephalon into cerebral hemispheres, which occurs during the second month of gestation. The antenatal diagnosis of EH is made by fetal ultrasound. In the antenatal period, imaging (FET, CT and MRI) allows an exhaustive lesion assessment of this pathology with an extremely reserved prognosis (Fig. 2).

Fig. 2.

Obstetric ultrasound, in axial, showing fusion of the tha-lami and cerebral hemispheres with a single ventricular cavity.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ethical approval

I declare on my honor that the ethical approval has been exempted by my establishment.

Funding

None.

Author contribution

Faizi Issam: Corresponding author writing the paper

Gotni Aicha: writing the paper

Watik Fedoua: writing the paper

Maha Mostatir: writing the paper

Lamrissi Amine^b: correction of the paper

Bouhya Said^c: correction of the paper

Guarantor

DR FEDOUA WATIK.

Research registration number

researchregistry2464.

Declaration of competing interest

The authors declare having no conflicts of interest for this article.