Microphthalmia, Syndromic 9

A number sign (#) is used with this entry because of evidence that both syndromic microphthalmia-9 (MCOPS9) and isolated microphthalmia with coloboma-8 (MCOPCB8) are caused by homozygous or compound heterozygous mutation in the STRA6 gene (610745) on chromosome 15q24.

Description

Syndromic microphthalmia-9, also referred to as pulmonary hypoplasia-diaphragmatic hernia-anophthalmia-cardiac defect, is characterized by bilateral clinical anophthalmia, pulmonary hypoplasia/aplasia, cardiac malformations, and diaphragmatic defects. The phenotype is variable, ranging from isolated clinical anophthalmia or microphthalmia to complex presentations involving the cardiac, pulmonary, diaphragmatic, and renal systems. At its most severe, infants are born without pulmonary structures and die soon after birth (Marcadier et al., 2015).

Clinical Features

Ostor et al. (1978) described a premature stillborn infant with bilateral anophthalmia and pulmonary agenesis. Spear et al. (1987) reported a full-term stillborn male infant with a birth weight of 2,760 g in whom autopsy revealed right anophthalmia and left clinical anophthalmia, bilateral pulmonary agenesis, overriding aorta with high ventricular septal defect, nodular vestige of the main pulmonary artery, and eventration of the left hemidiaphragm.

Smith et al. (1994) described a 9-year-old boy, born at term with a weight of 3,250 g, who had bilateral extreme microphthalmia and respiratory distress due to a right-sided diaphragmatic hernia which was surgically repaired in the first 24 hours of life. In infancy he was found to have a hiatal hernia and tetralogy of Fallot, both of which were corrected surgically at 5 years of age. Ultrasound at age 8 showed that the right kidney was smaller than the left. His teacher reported above-average intellectual skills, and he had mild bilateral nerve deafness. Examination at age 9 revealed short stature, low-set prominent ears with narrow sloping external auditory meatus, mild pectus carinatum, and long thin rocker-bottom feet. He had 2 healthy younger sisters.

Seller et al. (1996) reported a male newborn and a female fetus, sibs of nonconsanguineous parents, who had bilateral anophthalmia and pulmonary hypoplasia. The male infant, who had a birth weight of 2,860 g, survived for only 1 hour; autopsy revealed bilateral anophthalmia and unilobar lungs with no other abnormalities. A second pregnancy resulted in a normal boy, and a third pregnancy was terminated at 18 weeks of gestation because of bilateral anophthalmia and hypoplastic lungs seen on ultrasound scan. Autopsy of the female fetus confirmed bilateral anophthalmia and also revealed micrognathia, midline cleft of the secondary palate, low-set ears, brachycephaly, bilateral asymmetric hypoplasia of the lungs with no apparent lobulation, hypoplastic left atrium, single ventricle, enlarged pulmonary trunk, hypoplastic spleen, and hypoplastic bicornuate uterus. The authors referred to the disorder as the Matthew-Wood syndrome at the request of the parents, presumably the name of the first-born sib. Seller et al. (1996) reviewed syndromes that included a combination of anophthalmia/microphthalmia with pulmonary hypoplasia, and stated that their cases were most likely the same condition as that reported by Spear et al. (1987).

Berkenstadt et al. (1999) reported the prenatal diagnosis of a 22-week-gestation male fetus with bilateral microphthalmia with cyst, right diaphragmatic hernia, agenesis of the right lung and pulmonary vessels, and intrauterine growth retardation. They suggested that this was similar to the case of Spear et al. (1987) and the case of Engellenner et al. (1989).

Priolo et al. (2004) reported a male infant born at term with mild intrauterine growth retardation (birth weight, 2,580 g) and severe bilateral microphthalmia, left diaphragmatic hernia with eventration of stomach and spleen, marked bilateral pulmonary hypoplasia, secundum-type atrial septal defect, and malrotation of the left kidney. The infant died 2 days after birth.

Lee et al. (2006) reported a female infant, the only child of a nonconsanguineous Pakistani couple, who was born at term weighing 2,125 g but died 4 hours after birth from respiratory failure. There were no dysmorphic features or limb defects. Postmortem examination confirmed bilateral microphthalmia, left-sided diaphragmatic hernia, and bilateral lung hypoplasia. There was no structural heart lesion and pulmonary vessels were normal. Lee et al. (2006) noted that the coexistence of microphthalmia, pulmonary hypoplasia, and diaphragmatic defects had been reported in 4 previous patients (Spear et al., 1987, Engellenner et al., 1989, Berkenstadt et al., 1999, and Priolo et al., 2004), all of whom had intrauterine growth retardation.

Li and Wei (2006) reported a female infant, born of a Nigerian mother, who presented at birth with bilateral clinical anophthalmia and respiratory distress due to pulmonary hypoplasia and pulmonary artery hypoplasia. The infant, who weighed 3,350 g at birth, died at 43 hours of age. Postmortem examination showed hypoplastic optic nerves and absence of the ocular globes. There was a single small unlobed lung on each side of the thorax, marked dilation of the right atrium and ventricle with a small left atrium and ventricle, and a hypoplastic left kidney that was abnormally descended into the pelvis.

Pasutto et al. (2007) described 2 unrelated consanguineous Turkish families with a pleiotropic multisystem malformation syndrome characterized by bilateral clinical anophthalmia, mild facial dysmorphism, normal intrauterine growth, early lethality, and a variety of malformations of the lungs, diaphragm, heart, and urogenital systems. Bilateral anophthalmia had been diagnosed in the proband of the first family by ultrasound scans at 16 weeks' gestation. She had normal intrauterine growth, with normal birth length, weight, and head circumference. At birth, right-sided pelvic kidney, circulatory-nonrelevant pulmonic valve stenosis, and a patent ductus arteriosus, which was surgically closed at the age of 3 weeks, were found. At the age of 2 months, she had mild facial dysmorphism, with marked blepharophimosis with an unusual trichoglyphic pattern of the eyebrows, which were broad, flaring, and only upward growing. She had a broad nasal bridge, micrognathia, and large, low-set ears. Cerebral magnetic resonance imaging (MRI) showed no abnormality of brain structure and showed visible optic nerves and chiasm. Mechanical ventilatory support was required from birth because of persistent respiratory insufficiency. Open lung biopsy performed at the age of 2.5 months revealed a reduced number of alveolar units and pulmonary capillary vessels with thickening of the interalveolar septa, as well as medial thickening of small pulmonary arteries with muscularization, which are the key features of alveolar capillary dysplasia. She died at the age of 6 months from respiratory insufficiency. The paternal uncle of the proband, who was also married to a half cousin, had a daughter with bilateral clinical anophthalmia, who died at the age of 2 days from cyanotic congenital heart defect with atresia of the pulmonary artery and single ventricle. She had normal intrauterine growth. The 14-year-old proband of the second family was the oldest son of a healthy consanguineous couple of Turkish origin. He had bilateral clinical anophthalmia, diaphragmatic hernia, and severe short stature with relative preservation of head growth (occipitofrontal circumference of 51 cm, corresponding to the third percentile). He had profound mental retardation with no speech and no obvious receptive language skills. He had both an atrial and a ventricular septal defect which did not require therapy. Cerebral MRI performed at the age of 4 years showed a structurally normal brain, apart from absent optic nerves. He had mild facial dysmorphism with severe blepharophimosis and an unusual trichoglyphic pattern of both eyebrows similar to that seen in the proband from the first family. The mother had had termination of a 23-week gestation after diagnosis of bilateral clinical anophthalmia and severe diaphragmatic hernia on antenatal ultrastructural scan. The fetus showed mild facial dysmorphism similar to that of the probands in the 2 families.

Pasutto et al. (2007) also described 3 more patients with a similar phenotype, with bilateral clinical anophthalmia, diaphragmatic hernia or eventration, lung hypoplasia, and normal birth measurements as consistent features.

Chitayat et al. (2007) described 8 patients, including a living child, 3 sibs, and 4 isolated cases, with the triad of bilateral severe microphthalmia, pulmonary agenesis/hypoplasia, and diaphragmatic defect; 5 patients also had cardiac abnormalities. Two patients did not have the full triad, one lacking pulmonary hypoplasia and the other having no diaphragmatic defect; both survived longer than is typical with this syndrome. A female infant who was born to consanguineous Moroccan parents had bilateral microphthalmia, bilateral unilobar lungs, atrial septal defect with patent ductus arteriosus, and hypoplastic left pelvic kidney, but no diaphragmatic defect. She underwent surgery to expand the orbits at 19 months of age but died postoperatively for unknown reasons. Chitayat et al. (2007) proposed that the syndrome be designated PDAC, for pulmonary aplasia/dysgenesis/hypoplasia, diaphragmatic eventration/hernia, anophthalmia/microphthalmia/ocular dysplasia, and cardiac defect, representing the most important components of this condition.

West et al. (2009) reviewed the phenotypic features of 9 patients with known STRA6 mutations and 4 affected sibs of these patients. The authors noted that all 12 patients in whom the eye phenotype was reported had bilateral clinical anophthalmia. Cardiac defects were the second most common feature, present in 10 (77%) of the 13 patients, and were varied. Pulmonary agenesis or hypoplasia was noted in 8 (62%), and diaphragmatic hernia or eventration in 8 (62%). Intrafamilial variation was common for the cardiac, pulmonary, and diaphragmatic malformations. Beyond these 4 cardinal features, the phenotype was pleiotropic, with dysmorphic features found in 6 of the 13 patients and renal anomalies in 4; 2 individuals had genital anomalies, 2 had duodenal stenosis, and 2 had pancreatic malformations. Cerebral malformations were rare, with 1 occurrence of a thin corpus callosum and 2 instances of small or absent optic nerves. Survival was poor, with only 2 of the 13 patients alive at the ages of 3 months and 14 years, respectively.

Marcadier et al. (2015) reported 6 patients from 4 Hmong families with clinical anophthalmia and bilateral pulmonary agenesis as well as cardiac, diaphragmatic, renal, and urogenital anomalies. In addition, 3 of the 6 patients (patients 4, 5 and 6, from families 3 and 4) exhibited camptodactyly and digital contractures.

Cytogenetics

In a 9-year-old boy with bilateral clinical anophthalmia, diaphragmatic hernia, and tetralogy of Fallot, Smith et al. (1994) identified an apparently balanced reciprocal translocation t(1;15)(q41;q21.2). Parental karyotypes were normal.

Mapping

Pasutto et al. (2007) performed a genomewide linkage scan in both consanguineous Turkish families with syndromic clinical anophthalmia described by them. Parametric and nonparametric linkage analysis of both families together revealed a single maximum lod score of 4.8 for the region 15q23-q25.1; flanking markers narrowed the critical region to a 12-Mb interval between 65.21 and 77.85 Mb from pter.

In 2 Hmong families (families 3 and 4) showing clinical anophthalmia and bilateral pulmonary agenesis, in which affected individuals also had camptodactyly and digital contractures, Marcadier et al. (2015) performed SNP microarray and identified stretches of homozygosity overlapping STRA6 at chromosome 15q24.1.

Molecular Genetics

In 5 families with syndromic clinical anophthalmia, Pasutto et al. (2007) detected homozygosity for mutations in the STRA6 gene (610745). A homozygous deletion generating a premature stop codon (G50AfsX22; 610745.0002) led to absence of the immunoreactive protein in the patient's fibroblast culture. Structural analysis of 3 missense mutations (P90L, 610745.0005; P293L, 610745.0001; and T321P, 610745.0005) suggested significant effects on the geometry of the loop connecting the transmembrane helices of STRA6. Two further variations in the C terminus (T644M, 610745.0004 and R655C, 610745.0003) altered specific functional sites, an SH2-binding motif and a phosphorylation site, respectively. STRA6 mutations thus define a pleiotropic malformation syndrome representing the first human phenotype associated with mutations in a gene from the STRA group.

Pasutto et al. (2007) suggested that the clinical anophthalmia syndrome that they described and showed to be caused by mutations in the STRA6 gene may be the same disorder as that known as Matthew-Wood syndrome. Sequence analysis of STRA6 in a patient with the full clinical picture of Matthew-Wood syndrome, including cleft palate, hypoplastic alae nasi, hypoplastic spleen, and bicornuate uterus, revealed no mutation.

Martinovic-Bouriel et al. (2007) studied 2 familial cases of Matthew-Wood syndrome and excluded mutations in the FGF10 (602115) and FGFR2 (see 176943) genes. Golzio et al. (2007) restudied these 2 families as well as 5 fetuses presenting at least 1 of the 2 major signs of clinical anophthalmia or pulmonary hypoplasia and at least 1 of the 2 associated signs of diaphragmatic closure defect or cardiopathy for mutations in the STRA6 gene. The 2 fetuses from consanguineous families had either a homozygous insertion/deletion in exon 2 (610745.0007) or a homozygous insertion in exon 7 (610745.0008) predicting a premature stop codon in STRA6 transcripts. The other 5 fetuses had no STRA6 mutations.

Using DNA extracted from a paraffin block of autopsy tissue from a male infant with clinical anophthalmia and diaphragmatic eventration, who was originally reported by Steiner et al. (2002), West et al. (2009) identified compound heterozygosity for a 2-bp insertion and a nonsense mutation, both in exon 2 of the STRA6 gene (610745.0009 and 610745.0010).

Segel et al. (2009) reported a 2.5-year-old girl with clinical anophthalmia, bushy eyebrows, patent ductus arteriosus, and normal motor and cognitive development who was compound heterozygous for 2 missense mutations in the STRA6 gene (610745.0012 and 610745.0013). Noting the milder clinical phenotype in this patient compared to previously reported patients, the authors concluded that the phenotypic spectrum of STRA6 mutations might be broader than originally suspected, with clinical anophthalmia being the major phenotypic effect, which may be associated with normal psychomotor development.

In a large consanguineous Irish Traveller family with isolated microphthalmia and coloboma (MCOPCB8), Casey et al. (2011) performed genomewide SNP homozygosity analysis and identified 4 runs of homozygosity on chromosome 15q23-q24.1 that were exclusively shared by MCOPCB-affected family members. Sequencing of DNA in the interval of interest revealed a homozygous missense mutation in the STRA6 gene (G304K; 610745.0011) that segregated with disease in the family. There were 9 affected family members over 2 generations who had varying degrees of microphthalmia and coloboma. All had normal cranial and abdominal ultrasounds, normal intellectual development, and no extraocular defects were observed. Homozygosity for the same G304K mutation was identified in 2 more Irish Traveller probands, a boy with severe bilateral microphthalmia and dysplastic right kidney, and a girl who fulfilled the criteria for Matthew-Wood syndrome, with bilateral clinical anophthalmia, absent pulmonary valves, polysplenia, absent uterus, and hydronephrosis with ureteroceles. The girl had a brother who had only bilateral clinical anophthalmia, but he was not available for study.

Chassaing et al. (2013) analyzed the STRA6 gene in 28 cases with clinical anophthalmia, including 7 cases of isolated anophthalmia, 14 cases in which it was associated with 1 of the major features of PDAC, and 7 cases with other abnormalities. They identified 2 patients with bilateral anophthalmia and mutations in STRA6 (see, e.g., 610745.0014): the first, who was compound heterozygous for a missense mutation and a large intragenic deletion, showed some of the features of PDAC, whereas the second, who was homozygous for a splicing mutation, exhibited all the major features of PDAC.

In 2 unrelated Hmong patients (patients 5 and 6, from families 3 and 4) with clinical anophthalmia and bilateral pulmonary agenesis mapping to chromosome 15q24, Marcadier et al. (2015) sequenced the STRA6 gene and identified homozygosity in both patients for the same splice site mutation (610745.0015). Affected individuals from the 2 families also exhibited camptodactyly and digital contractures, expanding the phenotypic variability observed in patients with STRA6 mutations.

Heterogeneity

Chitayat et al. (2007) sequenced the STRA6 gene in a 9.5-year-old boy and in 1 of 3 sibs with PDAC syndrome but did not detect any mutations, suggesting genetic heterogeneity (see MCOPS12, 615524).

Animal Model

Using a retinoic acid (RA) synthesis inhibitor in zebrafish embryos, Casey et al. (2011) modeled different levels of RA and observed dose-dependent microphthalmia. The inhibitor produced developmental eye defects ranging from mild to severe microphthalmia as well as retinal pigment epithelium coloboma, also in a range of severity. Other developmental defects were visible, including defects in heart morphogenesis, consistent with the role of RA in multiple developmental processes.

Nomenclature

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.'