Alobar holoprosencephaly and cebocephaly in neonate: a case report

INTRODUCTION

Holoprosencephaly (HPE) is a congenital brain malformation resulting from the incomplete division of the forebrain into two separate hemispheres. Abnormal development of the central nervous system is often accompanied by midline defects of the face and forebrain structures.¹ HPE presents a wide spectrum of neurological and craniofacial abnormalities, ranging from mild facial dysmorphism to severe cognitive and physical impairments. The most severe form, alobar HPE, is typically incompatible with life. Clinical manifestations include facial anomalies such as hypotelorism, microcephaly, and a blind-ended or single nostril.² Cebocephaly is a rare congenital craniofacial anomaly characterized by hypotelorism and a malformed nose, often small, flattened, or presenting as a single, imperforate nostril.³ Understanding the clinical spectrum of HPE and its associated anomalies is essential for healthcare professionals in improving antenatal diagnosis, counseling, and management strategies.⁴ Here, we present a case of alobar holoprosencephaly with cebocephaly, aiming to highlight the importance of early prenatal detection and multidisciplinary counseling.

CASE REPORT

We reported the case of an 860-gram male neonate born via spontaneous vaginal delivery at 28+5 weeks of gestation. The mother, a third gravida with two previous healthy children, presented to the emergency department in active labor approximately four hours prior to delivery. An antenatal ultrasound performed on the day of admission revealed findings suggestive of holoprosencephaly and polyhydramnios. No prior antenatal ultrasound or fetal MRI had been conducted during the pregnancy.

At birth, the neonate did not cry and required immediate resuscitation. APGAR scores at 1 and 5 minutes were both 2. Umbilical artery blood gas analysis indicated severe metabolic acidosis, with a pH of 6.9, PCO₂ of 30 mmHg, HCO₃⁻ of 10 mmol/l, base excess of –16, and lactate level of 7 mmol/l.

Physical examination revealed multiple craniofacial anomalies, including microcephaly, hypotelorism, anophthalmia, and a small, malformed nose with a single imperforate nostril (Figure 1, 2).

A cranial ultrasound performed in the delivery room revealed an alobar brain structure with a single fluid-filled ventricle and absence of the interhemispheric fissure or septum, confirming the diagnosis of alobar holoprosencephaly (Figure 3). Based on clinical and radiographic findings, the neonate was diagnosed with alobar holoprosencephaly associated with cebocephaly. The parents were counseled extensively regarding the multiple congenital anomalies, including severe hypoxic-ischemic encephalopathy, and the extremely poor prognosis for survival and quality of life.

Following a multidisciplinary discussion involving the medical team and family, a decision was made to initiate palliative care. Supportive measures included thermoregulation under a radiant warmer in servo mode, oxygen support via nasal prongs, minimal handling, and encouragement of parental involvement. The infant passed away at one hour of life. The parents declined consent for post-mortem examination and genetic testing, limiting further etiological evaluation. In this clinical context, differential diagnoses considered included septo-optic dysplasia, DiGeorge syndrome, hydranencephaly, porencephalic cyst, and arachnoid cyst. However, the combination of clinical features and imaging findings was most consistent with alobar holoprosencephaly.

DISCUSSION

Holoprosencephaly (HPE) is a severe congenital anomaly caused by the failure of the prosencephalon to divide properly between days 18 and 28 of embryonic development, leading to abnormalities in both brain and facial structures. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses.¹ The severity of the clinical phenotype is broad and usually mirrors the radiologic and associated facial features.⁵ 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.

Based on how distinctly the cerebral hemispheres develop, Demyer and Zeman classified HPE into three types: alobar, semi-lobar, and lobar. The first two forms have a very poor prognosis, thus justifying early medical termination of the pregnancy.⁶ HPE has a diverse range of causes, though it frequently arises sporadically. Chromosomal anomalies are detected in 25–50% of cases, predominantly trisomy 13 (75%), followed by triploidy (20%) and trisomy 18 (1–2%). Single-gene disorders have also been reported. HPE may result from teratogenic exposure, such as poorly controlled blood glucose levels in maternal diabetes.⁷

HPE probably results from a combination of genetic mutations and environmental influences during the initial weeks of pregnancy. While some individuals with HPE may not survive the neonatal period, others may live but often present with varying degrees of developmental delay.⁸ Severe craniofacial anomalies linked to HPE include conditions such as cyclopia, synophthalmic, cebocephaly, and the presence of a proboscis. Milder features can include a small head (microcephaly), closely spaced eyes (hypotelorism), a flat nasal bridge, a single central incisor, and midline facial clefts.⁷

Several characteristic midline facial malformations are associated with holoprosencephaly, including hypotelorism.⁹ Our case had microcephaly, anophthalmus, hypotelorism, and a single nostril. These complex malformations probably led to severe hypoxic ischemic encephalopathy and the baby died at one hour of life. Uttara et al reported a similar case of a 28-year-old primigravida who came for medical termination at 25 weeks of gestation and delivered a 600-gram dead female fetus with cyclopia, fetal proboscis, and neurocutaneous marker.

High-resolution prenatal imaging plays a critical role in diagnosing HPE and providing prenatal counseling, though milder brain abnormalities may be challenging to detect before birth.⁸ Poenaru et al. reported a similar case of a preterm male infant born at 32 weeks gestational age by a 26-year-old mother. The birth weight was 1800 grams. The infant died immediately after birth. The pregnancy, which was partially investigated, had an uncomplicated course. The mother had a previous cesarean section in 2002, and her first child had normal neurologic development until now. At 29 weeks of gestation, alobar holoprosencephaly was diagnosed by a brain scan.

The sonography showed: fused cerebral hemispheres in their anterior and middle regions, major dilatation of the cerebral ventricles, proboscis, microcephaly, bilateral microphthalmia, and hypotelorism; the orbits were situated between the mouth and the proboscis. At birth, the infant presented with: cyclopia, proboscis, and macroglossia.

The autopsy showed, besides the facial malformations, fused cerebral hemispheres, a single ventricle, and fused thalamic nuclei in their caudal portion and suprarenal glands agenesis.¹¹ Our case involved an unbooked pregnancy with only a single antenatal visit during the first trimester. At this visit, a nuchal translucency (NT) measurement of 2.7 mm was recorded. However, no follow-up anomaly scan or additional diagnostic tests were performed. The mother did not take folic acid supplementation during the first trimester. At 28 weeks and 5 days of gestation, the mother presented to the labor room in active preterm labor.

A late antenatal ultrasound revealed severe brain malformations consistent with alobar holoprosencephaly. Molecular diagnosis can be made by gene sequencing and allele quantification. Clinically, prenatal detection of HPE primarily relies on ultrasound and MRI, as molecular testing is not commonly employed during routine screening. Treatment is symptomatic and supportive and requires multidisciplinary management. Child outcome depends on the HPE severity and the medical and neurological complications associated. Severely affected children have a very poor prognosis. Mildly affected children may exhibit few symptoms and may live a normal life.¹

CONCLUSION

Alobar holoprosencephaly and cebocephaly presents significant challenges in prenatal care, neonatal resuscitation, and ethical decision-making. As the condition is incompatible with life, early detection via ultrasonography and fetal MRI is vital for appropriate management and counselling of the parents. The case emphasizes the need for comprehensive antenatal screening, including early diagnostic testing and anomaly scans. Palliative care plays important role in such cases where survival with quality of life is unlikely.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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