Other entities represented in this entry:
SNOMEDCT: 718761007; ORPHA: 178364, 99001; DO: 0111806;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q22.3 | Microphthalmia, syndromic 5 | 610125 | Autosomal dominant | 3 | OTX2 | 600037 |
| 14q22.3 | Retinal dystrophy, early-onset, with or without pituitary dysfunction | 610125 | Autosomal dominant | 3 | OTX2 | 600037 |
A number sign (#) is used with this entry because of evidence that microphthalmia with associated features (MCOPS5), including pituitary dysfunction, is caused by heterozygous mutation in the OTX2 gene (600037) on chromosome 14q22. There is also evidence that early-onset retinal dystrophy with or without pituitary dysfunction is caused by heterozygous mutation in the OTX2 gene.
The term 'anophthalmia' has been misused in the medical literature. True or primary anophthalmia is rarely compatible with life; in such cases, the primary optic vesicle has stopped developing and the abnormal development involves major defects in the brain as well (Francois, 1961). The diagnosis can only be made histologically (Reddy et al., 2003; Morini et al., 2005; Smartt et al., 2005), but this is rarely done. In most published cases, the term 'anophthalmia' is used as a synonym for the more appropriate terms 'extreme microphthalmia' or 'clinical anophthalmia.'
Ragge et al. (2005) described affected members of 8 unrelated families with unilateral or bilateral microphthalmia/clinical anophthalmia and variable additional features including coloboma, microcornea, cataract, retinal dystrophy, hypoplasia or agenesis of the optic nerve, agenesis of the corpus callosum, developmental delay, joint laxity, hypotonia, and seizures. A mother of 2 patients, who was a gonosomal mosaic, had a later-onset phenotype resembling pigmentary retinopathy (see 193220).
Dateki et al. (2008) described an 8.5-year-old Japanese girl who was born with bilateral clinical anophthalmia and cleft palate. She underwent evaluation for short stature at 3.75 years of age and was found to have partial growth hormone (GH; 139250) deficiency. Brain MRI showed bilateral anophthalmia and optic nerve hypoplasia, but brain structure as well as the pituitary gland appeared normal, with an intact stalk and hyperintense signal in the posterior lobe. The patient also showed developmental retardation. Her parents and 2 older brothers were unaffected.
Tajima et al. (2009) reported a 6-year-old Japanese boy with bilateral clinical anophthalmia who upon examination for evaluation of short stature at 4 years of age was also found to have markedly delayed psychomotor retardation, a small penis, and bilateral undescended testes. Laboratory evaluation revealed central hypothyroidism and deficiencies of GH, gonadotropins, and cortisol. Brain MRI showed a small anterior pituitary, invisible pituitary stalk, ectopic posterior lobe, bilateral anophthalmia, absence of optic nerve and chiasm, and Chiari malformation (see 118420).
Chassaing et al. (2012) studied a large 4-generation French family in which 17 individuals had microphthalmia or clinical anophthalmia, 3 were diagnosed with otocephaly-dysgnathia complex (see 202650), and 2 exhibited an intermediate, overlapping phenotype. One affected woman had 2 sons with otocephaly, 1 of whom died soon after birth from respiratory distress and unsuccessful intubation; the second pregnancy was electively terminated after ultrasonography showed recurrence of facial malformations consistent with otocephaly. An affected male cousin also had a son who died soon after birth from respiratory distress with a probable diagnosis of otocephaly. The cousin's half sister exhibited an intermediate phenotype of unilateral anophthalmia and micrognathia. In addition, a half sister of the woman with the otocephalic sons gave birth to a boy who also had an intermediate phenotype and died at birth of respiratory distress with hypoplasia of maxilla and upper pharynx, noncommunication between proboscis and hypopharynx, and rudimentary tongue. Additional features revealed on autopsy included bilateral microphthalmia, absence of anterior ocular chamber, cataract, and focal retinal dysplasia, as well as microretrognathia, microglossia, thymic hyperplasia, 11 ribs, and micropenis. Detailed examinations of the patients with microphthalmia/clinical anophthalmia were not reported, although it was noted that in the fourth generation, 3 male cousins with bilateral clinical anophthalmia had moderate to severe mental retardation. Chassaing et al. (2012) also reported a 12-year-old Caucasian girl who had maxillary hypoplasia, microstomia, absent tongue, agnathia, and a long tubular nose. Her eyes and ears were normally formed, and she had patent external auditory canals. She had no known associated limb or internal organ anomalies or hormonal dysfunction. Her mother had 8 miscarriages, mostly in the first trimester, but there was no family history of ophthalmic or mandibular malformations.
Patat et al. (2013) reported a 4-generation family in which a mother, her father, and her paternal grandmother all had severe unilateral microphthalmia, and the mother terminated a pregnancy at 16 weeks of gestation because of agnathia associated with bilateral microphthalmia. The male fetus had agnathia, astomia, and aglossia, with low, posteriorly rotated, paramedian, and convergent ears. The pharyngeal floor was absent. He had bilateral microphthalmia with downslanted palpebral fissures, and the optic chiasm and pituitary gland could not be detected. X-rays confirmed the absence of mandibular bone. Abnormalities of the extremities included brachymesophalangy of the fifth finger and bilateral talus valgus. Patat et al. (2013) also described a male infant born at 30 weeks of gestation who died shortly after birth of respiratory insufficiency due to absence of the mandible and severe microstomia. He also had persistent buccopharyngeal membrane and dysmorphic anterocaudally positioned ears, as well as mild clubfeet, but his eyes appeared normal on external inspection.
Early-Onset Retinal Dystrophy with or without Pituitary Dysfunction
Vincent et al. (2014) studied 2 Caucasian Canadian families with pattern retinal dystrophy. One was a 3-generation family in which 5 affected individuals underwent detailed eye examination. All 5 presented with reduced distance vision and myopia with or without astigmatism. Color vision was mildly impaired only in the 2 older individuals (fifth decade of life). Horizontal corneal diameters and axial eye lengths were normal. The retina showed a butterfly pattern dystrophy with pigment deposition in 3 patients, an annular pigmentary pattern in 1, and a dull foveal reflex in 1. Optic nerve head dysplasia was noted in 3 patients, and 1 patient had unilateral macular scarring. Spectral-domain optical coherence tomography (SD-OCT) showed distinct areas of photoreceptor outer-segment separation from the retinal pigment epithelium (RPE), with deposition and clumping on the RPE in areas of pigmentation, but the external limiting membrane appeared preserved. The Arden ratio was normal in the 3 children but borderline or abnormally low in the 2 adults. Electroretinography (ERG) showed moderately decreased cone responses in an affected 13-year-old girl, and her 46-year-old father showed mildly reduced rod and cone responses; the other 3 patients had normal ERGs. Pituitary hormone, cortisol, and serum electrolyte levels were normal in the 6 affected individual in whom they were tested; brain MRI was normal in 4 patients and showed a 0.5-cm Rathke's cleft cyst displacing the posterior aspect of the pituitary in 1. Vincent et al. (2014) also studied a 39-year-old man and his 8-year-old son with pattern retinal dystrophy. The son had nystagmus and photophobia since 2 years of age, and both patients had reduced distance vision. The father had compound myopic astigmatism, whereas the son had myopia. The father also had microcornea, posterior embryotoxon, and optic nerve head dysplasia. The macula showed an atypical pattern with mild RPE changes in the father, and a grouped pigmentation pattern was seen in the son. SD-OCT changes were characteristic and identical to those of the first family. Growth and stature were normal in both father and son. Vincent et al. (2014) noted that, like pattern dystrophies associated with mutation in the PRPH2 (179605) or BEST1 (607854) genes, the phenotype appeared to be very slowly progressive, with only 1 patient from each family showing worsening of vision parameters over a 3- to 5-year follow-up period.
Deletions of chromosome 14q22-q23, frequently spanning both the BMP4 (112262) and OTX2 genes, have been reported in patients with microphthalmia/anophthalmia and pituitary anomalies, see CYTOGENETICS in MCOPS6 (607932).
Using a candidate gene approach, Ragge et al. (2005) analyzed 333 patients with ocular malformation spectrum defects and identified heterozygous mutations in the OTX2 gene in 11 affected individuals from 8 families. In 2 families, the mutations occurred de novo in severely affected offspring (600037.0001 and 600037.0002, respectively), and in 2 other families, the mutations were inherited from a gonosomal mosaic parent (600037.0003 and 600037.0004, respectively). Ragge et al. (2005) stated that data from these 4 families supported a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. The other 4 families displayed complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes.
Wyatt et al. (2008) analyzed the OTX2 gene in 165 patients with ocular malformations, primarily clinical anophthalmia, microphthalmia, and/or coloboma, and identified heterozygosity for 2 whole gene deletions and 4 truncating mutations in 8 patients from 6 families. Two of the patients, 1 with a whole gene deletion and 1 with a frameshift mutation, had developmental delay, but the other patients were apparently normal apart from the ocular phenotype.
In an 8.5-year-old Japanese girl with bilateral clinical anophthalmia, short stature, developmental delay, and partial GH deficiency, who was negative for mutation in the HESX1 (601802) and POU1F1 (173110) genes, Dateki et al. (2008) identified a de novo heterozygous frameshift mutation in the OTX2 gene (600037.0005).
In a 6-year-old Japanese boy with bilateral clinical anophthalmia, short stature, and combined pituitary hormone deficiency, Tajima et al. (2009) identified a de novo heterozygous frameshift mutation in the OTX2 gene (600037.0007).
Dateki et al. (2010) analyzed the OTX2 gene in 16 patients with ocular anomalies, short stature, and pituitary dysfunction, 12 patients with ocular anomalies with or without short stature in whom pituitary function was not investigated, and 66 patients with pituitary dysfunction without ocular anomalies. The patients were negative for mutation in genes known to be associated with their respective phenotypes. Dateki et al. (2010) identified 3 heterozygous OTX2-truncating mutations in 4 unrelated patients (see, e.g., 600037.0009 and 600037.0010) and a microdeletion involving the OTX2 gene in 1 patient. The authors concluded that OTX2 mutations are associated with variable pituitary phenotype, with no genotype-phenotype correlations.
In a 13.5-year-old boy of Sephardic Jewish descent who had unilateral clinical anophthalmia, short stature, and isolated GH deficiency, Ashkenazi-Hoffnung et al. (2010) analyzed the HESX1, SOX2 (184429), and OTX2 genes, and identified heterozygosity for a missense mutation in OTX2 (600037.0011). His father, who had short stature but normal eye structure and unknown endocrine status, was also heterozygous for the mutation. The proband had a younger brother with bilateral anophthalmia and normal height, and 2 clinically healthy sibs; his mother also reported 4 pregnancy terminations due to anophthalmia detected on fetal ultrasound. A paternal uncle and cousin both had bilateral clinical anophthalmia; a second cousin, who had severe microphthalmia, had hypoplastic pituitary with absence of optic nerves and chiasm on brain MRI, but endocrine evaluation at 4 months of age showed normal pituitary function. Mutation status of the relatives was unknown, as they refused genetic analysis. Ashkenazi-Hoffnung et al. (2010) reviewed the wide variability of phenotypes associated with previously published OTX2 mutations, even within families and in patients carrying identical mutations, and noted that the lack of genotype-phenotype correlation strengthened the need for continuous endocrine follow-up of affected patients, since the clinical course could not be anticipated.
In a large 4-generation French family in which 17 individuals had microphthalmia or clinical anophthalmia, Chassaing et al. (2012) identified a heterozygous 1-bp deletion in the OTX2 gene (c.316delC; 600037.0012) that segregated with disease. Included in the pedigree were 3 deceased offspring with otocephaly, from whom DNA was unavailable; however, a deceased male infant with an intermediate phenotype was also found to be heterozygous for the 1-bp deletion. In a 12-year-old girl with otocephaly, Chassaing et al. (2012) identified heterozygosity for a de novo 1-bp deletion in OTX2 (c.130delC). Because of the phenotypic variability observed in the 4-generation family, Chassaing et al. (2012) screened 5 additional candidate genes known to play a role in vertebrate otocephalic malformations, including PRRX1 (167420), but did not detect any likely pathogenic variants. The authors concluded that loss-of-function OTX2 mutations do not sufficiently explain the complex anatomic defects in patients with otocephaly/dysgnathia, suggesting the requirement for a second genetic hit.
In a male fetus with agnathia-otocephaly complex, known to be negative for mutation in the PRRX1 gene, Patat et al. (2013) identified heterozygosity for a nonsense mutation in the OTX2 gene (R97X; 600037.0013) that was inherited from his mother, who exhibited only unilateral severe microphthalmia. The fetus also carried a heterozygous synonymous OTX2 variant (c.525C-G) that was inherited from his asymptomatic father; however, the authors stated that it was unlikely that the silent variant explained the intrafamilial phenotypic variability. In an unrelated male infant who died at birth of respiratory insufficiency due to absence of the mandible and severe microstomia, who was also negative for mutation in PRRX1, Patat et al. (2013) identified an approximately 400-kb de novo deletion at 14q23.1 that involved the entire OTX2 gene but did not include any other genes.
Williamson and FitzPatrick (2014) reviewed the screening of the OTX2 gene in what they designated as cases of 'MAC' (microphthalmia-anophthalmia-coloboma) and stated that among over 1,000 MAC cases screened, a heterozygous OTX2 mutation was identified in 69 cases from 51 families. Forty-seven different variants were detected, including 9 nonsynonymous variants and 38 unequivocal loss-of-function alleles, 40% of which were de novo. Nonpenetrance and variable expressivity were observed; transmission of a heterozygous OTX2 mutation from an unaffected parent was reported on 10 occasions and from an affected parent on 8 occasions, and maternal gonosomal mosaicism was reported or suspected in 3 cases. Ocular phenotypes included various combinations of microphthalmia and/or clinical anophthalmia with or without coloboma, as well as 'atypical' eye defects, including optic nerve hypoplasia and early onset retinal dystrophy. Extraocular phenotypes included mild to severe learning disability in more than 40% of cases, pituitary abnormalities in 20% of cases, and motor delay in about 10% of cases. Williamson and FitzPatrick (2014) discussed the markedly variable expressivity of OTX2 haploinsufficiency, which has been associated with otocephaly-dysgnathia complex in some patients, as well as phenotypic and genotypic discordance of OTX2 mutations, illustrated by substitutions within the transactivation domain that have been associated with combined pituitary hormone deficiency without ocular defects (CPHD6; 613986) or optic nerve hypoplasia and pituitary dysfunction.
Sergouniotis et al. (2015) reported a family in which a 9-year-old girl had a small mandible, normal ears, and velopharyngeal insufficiency due to a short hemi-palate. She was found to be heterozygous for a 3-bp duplication in the OTX2 gene (c.271_273dupCAG; Gln91dup); however, the mutation was also present in her unaffected father. Family history was significant for 2 pregnancies exhibiting apparent agnathia-otocephaly complex on prenatal ultrasonography; fetal DNA from 1 of the pregnancies revealed heterozygosity for the 3-bp duplication.
Early-Onset Retinal Dystrophy with or without Pituitary Dysfunction
Henderson et al. (2009) analyzed DNA samples from 142 patients with Leber congenital amaurosis (LCA; see 204000) or severe childhood-onset retinal dystrophy (RD; see 613341) using an 'LCA chip' involving 8 LCA- and RD-associated genes, as well as screening the OTX2 gene. In a 7-year-old boy with RD who was negative for all variants assayed by the LCA chip, they identified heterozygosity for a de novo nonsense mutation in the OTX2 gene (S138X; 600037.0008). The patient, who was noted to have poor vision and nyctalopia during his first year of life, also had failure to thrive and subsequent short stature, and growth hormone deficiency was suggested indirectly due to low levels of IGF1 (147440) and IGFBP3 (146732). Electroretinography (ERG) at 6 years of age was markedly electronegative with additional a-wave reduction, suggesting dysfunction at the photoreceptor level and also post-phototransduction, likely to involve both ON- and OFF-bipolar cells.
In a 3-generation Caucasian Canadian family with pattern retinal dystrophy without pituitary dysfunction, Vincent et al. (2014) performed whole-genome SNP genotyping followed by exome sequencing and identified a heterozygous missense mutation in the OTX2 gene (E79K; 600037.0014) that was confirmed by Sanger sequencing to segregate with disease in the family. An affected father and son from a second Canadian family were also heterozygous for the E79K mutation. Haplotype analysis revealed a 19.68-cM shared haplotype between SNPs rs17107459 and rs710050; the number of generations between a common ancestor and affected individuals in the youngest generation in each family was estimated to be 5, making them fourth cousins.
Ashkenazi-Hoffnung, L., Lebenthal, Y., Wyatt, A. W., Ragge, N. K., Dateki, S., Fukami, M., Ogata, T., Phillip, M., Gat-Yablonski, G. A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency. Hum. Genet. 127: 721-729, 2010. [PubMed: 20396904] [Full Text: https://doi.org/10.1007/s00439-010-0820-9]
Chassaing, N., Sorrentino, S., Davis, E. E., Martin-Coignard, D., Iacovelli, A., Paznekas, W., Webb, B. D., Faye-Petersen, O., Encha-Razavi, F., Lequeux, L., Vigouroux, A., Yesilyurt, A., and 12 others. OTX2 mutations contribute to the otocephaly-dysgnathia complex. J. Med. Genet. 49: 373-379, 2012. [PubMed: 22577225] [Full Text: https://doi.org/10.1136/jmedgenet-2012-100892]
Dateki, S., Fukami, M., Sato, N., Muroya, K., Adachi, M., Ogata, T. OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: functional studies using the IRBP, HESX1, and POU1F1 promoters. J. Clin. Endocr. Metab. 93: 3697-3702, 2008. [PubMed: 18628516] [Full Text: https://doi.org/10.1210/jc.2008-0720]
Dateki, S., Kosaka, K., Hasegawa, K., Tanaka, H., Azuma, N., Yokoya, S., Muroya, K., Adachi, M., Tajima, T., Motomura, K., Kinoshita, E., Moriuchi, H., Sato, N., Fukami, M., Ogata, T. Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype. J. Clin. Endocr. Metab. 95: 756-764, 2010. [PubMed: 19965921] [Full Text: https://doi.org/10.1210/jc.2009-1334]
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