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1.

Holoprosencephaly 1

Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain and occurs after failed or abbreviated midline cleavage of the developing brain during the third and fourth weeks of gestation. HPE occurs in up to 1 in 250 gestations, but only 1 in 8,000 live births (Lacbawan et al., 2009). Classically, 3 degrees of severity defined by the extent of brain malformation have been described. In the most severe form, 'alobar HPE,' there is a single ventricle and no interhemispheric fissure. The olfactory bulbs and tracts and the corpus callosum are typically absent. In 'semilobar HPE,' the most common type of HPE in neonates who survive, there is partial cortical separation with rudimentary cerebral hemispheres and a single ventricle. In 'lobar HPE,' the ventricles are separated, but there is incomplete frontal cortical separation (Corsello et al., 1990). An additional milder form, called 'middle interhemispheric variant' (MIHV) has also been delineated, in which the posterior frontal and parietal lobes are incompletely separated and the corpus callosum may be hypoplastic (Lacbawan et al., 2009). Finally, microforms of HPE include a single maxillary median incisor or hypotelorism without the typical brain malformations (summary by Mercier et al., 2011). Cohen (2001) discussed problems in the definition of holoprosencephaly, which can be viewed from 2 different perspectives: anatomic (fixed) and genetic (broad). When the main interest is description, the anatomic perspective is appropriate. In genetic perspective, a fixed definition of holoprosencephaly is not appropriate because the same mutational cause may result in either holoprosencephaly or some microform of holoprosencephaly. Cohen (2001) concluded that both fixed and broad definitions are equally valid and depend on context. Munke (1989) provided an extensive review of the etiology and pathogenesis of holoprosencephaly, emphasizing heterogeneity. See also schizencephaly (269160), which may be part of the phenotypic spectrum of HPE. Genetic Heterogeneity of Holoprosencephaly Several loci for holoprosencephaly have been mapped to specific chromosomal sites and the molecular defects in some cases of HPE have been identified. Holoprosencephaly-1 (HPE1) maps to chromosome 21q22. See also HPE2 (157170), caused by mutation in the SIX3 gene (603714) on 2p21; HPE3 (142945), caused by mutation in the SHH gene (600725) on 7q36; HPE4 (142946), caused by mutation in the TGIF gene (602630) on 18p11; HPE5 (609637), caused by mutation in the ZIC2 gene (603073) on 13q32; HPE6 (605934), mapped to 2q37; HPE7 (610828), caused by mutation in the PTCH1 gene (601309) on 9q22; HPE8 (609408), mapped to 14q13; HPE9 (610829), caused by mutation in the GLI2 gene (165230) on 2q14; HPE10 (612530), mapped to 1q41-q42; HPE11 (614226), caused by mutation in the CDON gene (608707) on 11q24; HPE12 (618500), caused by mutation in the CNOT1 gene (604917) on 16q21; HPE13 (301043), caused by mutation in the STAG2 gene (300826) on Xq25; and HPE14 (619895), caused by mutation in the PLCH1 gene (612835) on 3q25. Wallis and Muenke (2000) gave an overview of mutations in holoprosencephaly. They indicated that at least 12 different loci had been associated with HPE. Mutations in genes involved in the multiprotein cohesin complex, including STAG2, have been shown to be involved in midline brain defects such as HPE. Mutations in some of those genes cause Cornelia de Lange syndrome (CDLS; see 122470), and some patients with severe forms of CDLS may have midline brain defects. See, for example, CDLS2 (300590), CDLS3 (610759), and CDLS4 (614701). [from OMIM]

MedGen UID:
78617
Concept ID:
C0266667
Congenital Abnormality
2.

Arrhinia with choanal atresia and microphthalmia syndrome

Bosma arhinia microphthalmia syndrome (BAMS) is characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence (summary by Graham and Lee, 2006). Also see absence of nasal bones (161480). [from OMIM]

MedGen UID:
355084
Concept ID:
C1863878
Disease or Syndrome
3.

Holoprosencephaly 13, X-linked

X-linked holoprosencephaly-13 (HPE13) is a neurologic disorder characterized by midline developmental defects that mainly affect the brain and craniofacial structure. The severity and manifestations are variable: some patients may have full alobar HPE with cyclopia, whereas others have semilobar HPE or septooptic dysplasia. Dysmorphic features include microcephaly, hypotelorism, low-set ears, micrognathia, and cleft lip/palate. Patients with a more severe phenotype may die in the newborn period, whereas those with a less severe phenotype show global developmental delay. Additional variable features include congenital heart defects and vertebral anomalies. Phenotypic variability may be related to the type of mutation, X-inactivation status, and possible incomplete penetrance. The STAG2 protein is part of the multiprotein cohesin complex involved in chromatid cohesion during DNA replication and transcriptional regulation; HPE13 can thus be classified as a 'cohesinopathy' (summary by Kruszka et al., 2019). For a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100). [from OMIM]

MedGen UID:
1714826
Concept ID:
C5393308
Disease or Syndrome
4.

Holoprosencephaly-radial heart renal anomalies syndrome

This syndrome has characteristics of holoprosencephaly, predominantly radial limb deficiency (absent thumbs, phocomelia), heart defects, kidney malformations and absence of gallbladder. It has been described in two families (with at least seven affected persons). Variable manifestations include vertebral anomalies, cleft lip/palate, microphthalmia, absent nose, dysplastic ears, hearing loss, colobomas of the iris and retina and/or bifid uvula. Inheritance is likely to be autosomal dominant with variable expressivity. [from SNOMEDCT_US]

MedGen UID:
401047
Concept ID:
C1866649
Disease or Syndrome
5.

Aplasia of the nose

Complete absence of all nasal structures. [from HPO]

MedGen UID:
120555
Concept ID:
C0265740
Congenital Abnormality
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