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Down syndrome (trisomy 21) with premaxillary agenesis and semilobar holoprosencephaly

Down syndrome with trisomy 21 is one of the most common aneuploidy in humans associated with mental retardation and developmental delay with an incidence of 1 per 920 births in India [Sheth et al., 2007]. Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses [Dubourg et al., 2007]. Common associated anomalies include hydrocephaly, microcephaly, delay of growth and facial malformations including cyclopia [Lahmar-Boufaroua et al., 2008]. The etiology of HPE is heterogeneous including non-genetic factors such as maternal diabetes and genetic causes [Karmous-Benailly et al., 2005]. Although trisomy 13, 18, 22, and other structural chromosomal anomalies have been reported with HPE, association of classical trisomy 21 with typical phenotypical features of Down syndrome is rare [Pi et al., 1980; Epstein et al., 1988; Urioste et al., 1988; Martinez -Fr ıas, 1989; Hamada et al., 1991]. We report on a male neonate with trisomy 21 who presented with semilobar HPE, flat nose, premaxillary agenesis/cleft lip and palate, and phenotypic features of Down syndrome. A full-term male neonate, product of a non-consanguineous marriage, was delivered normally to a non-diabetic, non-alcoholic, multigravida (G3P3) mother, aged 28 years. The first two children were normal. In the current pregnancy, antenatal period was uneventful. Ultrasonography done at 34 weeks of gestation showed fetal hydrocephalus with cleft lip. The neonate cried immediately after birth. On examination, vitals of the neonate was stable, he had large head with wide open anterior and posterior fontanels, ocular hypotelorism, upslanted palpebral fissures, flat nose, complete midline cleft lip and palate with premaxillary agenesis, bilateral low set ears, low hair line, clinodactyly, single transverse crease, sandle gap and generalized hypotonia (Fig. 1). Systemic examination did not reveal any abnormality. Anthropometry showed a weight of 2,550 g, length of 48.2 cm, and a head circumference of 38.8 cm. A clinical diagnosis of Down syndrome with hydrocephalus was made. Hematological and biochemical investigations were within normal limits. TORCH profile was negative and thyroid function tests were normal. Computerized tomographic (CT) scan of brain (Fig. 2) showed semilobar HPE with common anterior ventricle with absent septum pellucidum, hypoplastic olfactory bulbs and tracts, fusion of frontal lobe, reduced bulk of cerebral parenchyma with small occipital lobe, partially fused basal thalami, absent falx and anterior cleft, and dysgenesis of corpus callosum. Echocardiography with color Doppler and ultrasonography of abdomen were normal. Karyotyping of the infant showed trisomy 21 (47,XYþ21). Prognosis was explained to the parents and they were offered genetic counseling, but they declined any further investigation or treatment of the infant. HPE (OMIM #236100) is characterized by an incomplete cleavage of the forebrain, with three classical levels of decreasing severity: lobar HPE, where the right and left ventricles are separated, but with some continuity across the frontal cortex; semilobar HPE, with a partial separation; and the most severe form, alobar HPE, with a single brain ventricle and no interhemispheric fissure. Another milder subtype of HPE called the middle interhemispheric variant (MIHF) or syntelencephaly has now been recognized [Dubourg et al., 2007]. Other anomalies like absent hydrocephalus/ microcephaly, olfactory tracts and bulbs (arrhinencephaly), agenesis of the corpus callosum, hypopituitarism, single maxillary central incisor, hypoplasia of the pyriform aperture, ocular anomalies like cyclopia or anomalies of the extremities have also been described in association with HPE [Lazaro et al., 2004; Cohen,