Orbital Hypotelorism

► [Decreased interorbital distance]

The diagnosis of hypotelorism is made clinically. On inspection, the interpupillary distance and the inner and outer canthal distances can be measured, allowing a meaningful appraisal of eye morphology and position (see next section).

A short interorbital distance can be a morpho-genetic variant in otherwise normal individuals. Hypotelorism also occurs as a result of premature closure of the metopic suture (see " Craniosynostosis") and in syndromes with midface hypoplasia, including Down syndrome. Varying degrees of hy-potelorism, ranging in degree from mild to the extreme form of cyclopia, are found in holoprosen-cephaly (arrhinencephaly, OMIM 236100, 142945, 142946,605934), an early developmental brain defect caused by failure of the prosencephalon to cleave into paired expansions that will form the cerebral hemispheres and lateral ventricles (the term 'arrhinencephaly' refers to absence of olfactory bulbs and tracts, a feature that is often associated). Holoprosen-cephaly is the most common structural anomaly of the human brain, occurring with a frequency of about 1 in 16,000 live births and 1 in 200 spontaneous abortions. The disorder is phenotypically and etio-logically heterogeneous. Three major types of decreasing severity are recognized: alobar holoprosen-cephaly (large monoventricle, small anterior rim of cerebral tissue without interhemispheric cleavage, single thalamic mass); semilobar holoprosencephaly (rudimentary cerebral hemispheres, absent anterior interhemispheric cleavage, single ventricle with in-

Craniosynostosis Micropenis
Fig. 1.39. Holoprosencephaly in an 18-day-old male neonate. There is marked orbital hypotelorism and premaxillary agenesis. The metopic suture is open

complete differentiation into occipital and temporal horns); and lobar holoprosencephaly (near-normal cerebral hemispheres, defective gray-white matter separation along the anterior aspect of the frontal lobes, and absent septum pellucidum) (Corsello et al. 1990). The facial features in holoprosencephaly vary in severity from mild ocular hypotelorism and single central upper incisor (Fig. 1.39) to cyclopia with a proboscis above the single eye (Fig. 1.40). These two phenotypes are the extremes of a wide spectrum of defects including premaxillary agenesis (median pseudocleft, agenesis of nasal bones and primary palate, and ocular hypotelorism), the most common facial appearance in holoprosencephaly; cebocephaly (orbital hypotelorism associated with single-nostril nose); and ethmocephaly (extreme orbital hypo-telorism, arrhinia, and a blind-ending proboscis located between the eyes) (DeMyer et al. 1963; Cohen and Gorlin 1969). However, the face of holoprosen-cephalic patients can be entirely normal (Barr and Cohen 2002). Absence of the pituitary gland or hypothalamus, adrenal dysgenesis, and micropenis may be associated features (Begleiter and Harris 1980). Hypotelorism, microcephaly, and unilateral cleft lip and palate can be manifestations in gene carriers

Craniosynostosis Micropenis
Fig. 1.40. Holoprosencephaly in a female newborn. Two orbits are fused into a median single cavity, and there is agenesis of the nasal bones and premaxilla

(Collins et al. 1993). Kallmann syndrome (OMIM 244200), consisting in anosmia and hypogonadism, may be related to holoprosencephaly. Etiologically, both teratogens and genetic factors have a major role in the causation of holoprosencephaly. Maternal diabetes increases the risk 200 fold. Congenital cyto-megalovirus infection has been implicated in some cases (Byrne et al. 1987). Familial occurrence of isolated holoprosencephaly, the occurrence of holoprosencephaly in some mendelian genetic disorders (e.g., Smith-Lemli-Opitz syndrome), and the association with nonrandom chromosomal aberrations (e.g.,imbalances involving chromosome 2,3,7,13,18, and 21) point to the genetic factors as important determinants of the anomaly (Odent et al. 1998). At least five chromosomes (2,3,7,13, and 18) and several distinct genes, including the SHH, ZIC2, SIX3, and TGIF genes, have been implicated in the genesis of holo-prosencephaly (Wallis and Muenke 2000; Orioli et al. 2001; Munke 1989). Thus, this condition is genetically heterogeneous. Sporadic cases account for about 68 %. Autosomal dominant inheritance with incomplete penetrance appears to be the most likely mode of inheritance in familial cases (Odent et al. 1998). Genoa syndrome (OMIM 601370) is an association of semilobar holoprosencephaly with nontypical face and primary craniosynostosis (Camera et al. 1993). Inheritance is possibly autosomal recessive.

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