Holoprosencephaly.NA Thomas, A Cherian, S Sridhar
Neonatology Department, Christian Medical College, Vellore - 632 004, India. , India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 12867699
Source of Support: None, Conflict of Interest: None
A baby boy, product of a non-consanguinous union was born normally to a second gravida mother at 40 weeks of gestation. A routine antenatal scan done at 32 weeks had shown dilated lateral ventricles suggestive of hydrocephalus. The mother was not a diabetic nor had she taken any drugs during her pregnancy. The Apgar score was 7 at 1 and 5 minutes after birth.
The birth weight, length and head circumference were 3030 gms, 44 cm and 34 cm, respectively. Examination revealed a term baby with a midline cleft lip and palate, hypotelorism, flattened nose with a single nostril, micropenis and unilateral cryptorchidism [Figure - 1]. There were no clinical features suggestive of trisomy 13 or trisomy 18.
With a clinical diagnosis of holoprosencephaly (HPE), a CT scan was done, which showed absence of midline structures, a single ventricle with thinned out cortex, suggestive of alobar holoprosencephaly [Figure - 2]. The baby was given oro-gastric feeds. He developed multi-focal seizures on the second day of life, which were controlled with phenobarbitone. The parents were unwilling for further investigations or treatment and he was discharged against medical advice.
Holoprosencephaly is a disorder caused by absent or incomplete diverticulation and cleavage of the embryonic forebrain (prosencephalon) into the cerebral hemispheres and lateral ventricles, which leads to defects in the development of the face and in brain structure and function. HPE can be classified depending on the degree of abnormality as lobar, semi lobar and alobar.
In alobar HPE, the most severe of the three types, a single ventricular cavity is present, the thalami are fused and the corpus callosum, falx, inter-hemispheric fissure, optic tracts and olfactory bulbs are absent. The associated mid-facial defects include cyclopia, ethmocephaly, cebocephaly and cleft lip/palate associated with hypotelorism. In semi-lobar HPE, the occipital horns of the ventricles are partially formed and the posterior portions of the falx and inter-hemispheric fissures are seen. The thalami may only be partially fused. Anteriorly, the ventricles are fused and the corpus callosum, optic tracts and olfactory bulbs are absent. Facial defects are milder and cyclopia and ethmocephaly are not usually seen.
In the mildest form-lobar HPE, the fusion is partial with presence of anterior cleavage. The corpus callosum, inter-hemispheric fissure and falx are not fully developed and the roof of the anterior end of the frontal horn looks squared.
The incidence of HPE is 1:250 during embryogenesis and 1:16000 of live births. HPE is an etiologically heterogeneous disorder and about 30-40% of all affected individuals have an underlying chromosomal disorder. It is usually associated with an abnormality of chromosome 13 (trisomy 13, deletion or duplication of 13q or ring 13). Other associated chromosomal abnormalities include trisomy 18, deletion 2p, duplication 3p, deletion 7q, etc. HPE can also occur as a component of multiple malformation syndromes like Meckelís syndrome, Oral-facial-digital syndrome type VI, Pallister-Hall syndrome More Details and Smith-Lemli-Opitz syndrome. About 1-2% of infants born to diabetic mothers have HPE. Isolated cases with Mendelian inheritance are also seen. These are usually transmitted as autosomal dominant trait with variable penetrance and wide familial variance. Here, parents may have only mild cranio-facial abnormalities like single central maxillary incisor. Four genes have been so far identified for autosomal dominant non-syndromal HPE. These are the Sonic Hedgehog gene on 7q36, ZIC2 on 13q32, SIX3 on 2p21 and TGIF on 18p11.3.
With the advent of transvaginal ultrasound, alobar HPE can be diagnosed antenatally from as early as 9 weeks and semilobar and lobar HPE from 13 and 21 weeks respectively. The differential diagnosis would include hydranencephaly, severe hydrocephalus, large porencephalic cyst and callosal dysgenesis. While alobar and semilobar HPE are easily diagnosed by antenatal ultrasonograms, a prenatal Magnetic Resonance Imaging could be useful to differentiate between HPE and other conditions or in the diagnosis of lobar HPE. Other than routine antenatal screening for anomalies, mothers with diabetes, family history of HPE or those exposed to ionizing radiation and alkaloids would benefit from antenatal screening for HPE. The diagnosis of HPE should prompt a detailed anomaly scan to detect any extra-cranial abnormalities that may be indicative of an underlying genetic syndrome or aneuploidy. Karyotyping should also be performed. Termination of pregnancy should be offered in antenatally diagnosed alobar and semilobar HPE since these children tend to have severe developmental delay. Though a CT scan is adequate to make a diagnosis of HPE postnatally, neuroimaging evaluation of HPE is best accomplished by MRI.
Babies with HPE who survive infancy develop various complications, which include feeding difficulty, gastro-esophageal reflux, malnutrition, seizures, spasticity, infections and endocrine dysfunctions like diabetes insipidus. Long-term management would include screening for associated anomalies, treatment of complications, ventricular shunting for hydrocephalus and plastic surgery.
Recurrence rates vary, with a 1% chance of recurrence if chromosomal abnormalities are present which rises to 6% for sporadic cases. The recurrence rate is higher if the inheritance pattern is autosomal dominant or if HPE is part of a genetic syndrome.
This case highlights the importance for clinicians to suspect an intracranial malformation in the presence of a midline facial defect. Neuroimaging would confirm the diagnosis and aid in counselling the parents.
[Figure - 1], [Figure - 2]