Otopalatodigital spectrum disorder (OPDSD) is a clinical umbrella term comprising a group of related syndromes distinguished primarily by skeletal dysplasias.1 OPD includes otopalatodigital syndrome type I (OPD1), otopalatodigital syndrome type II (OPD2), frontometaphyseal dysplasia (FMD), and Melnick–Needles syndrome. These disorders are highly associated with mutations of the FLNA gene on the X chromosome, which encodes the cytoskeletal protein filamin A.2 Ocular anomalies have been reported in confirmed cases of FLNA mutation.3–8 However, accessory iris membranes have not been described in OPD. We describe an infant with the FMD variant of OPD, anterior segment dysgenesis, and bilateral accessory iris membranes.
Institutional review board approval was waived for this retrospective case report study. The study was performed in accordance with Health Insurance Portability and Accountability Act guidelines and in compliance with the tenets of the Declaration of Helsinki.
A male infant born at 38 weeks' gestation presented at birth with multiple congenital anomalies. The neonate was intubated shortly after delivery for respiratory decompensation secondary to airway obstruction attributable to midface hypoplasia, macroglossia, retrognathia, and tracheomalacia.
Renal and urinary tract anomalies including bilateral dysplastic kidneys, bladder wall abnormalities, and posterior ureteral valves were noted on ultrasound imaging. Echocardiography demonstrated a small patent foramen ovale with small shunts and collateral vessels involving the descending aorta. In the setting of subclinical seizures, neuroimaging demonstrated hemorrhage in bilateral hemispheres, tortuous cranial arteries, focal venous sinus stenosis, widened cranial sutures, plagiocephaly, and a tethered cord. A presumed platelet dysfunction disorder necessitated multiple blood product transfusions. Orthopedic examination was notable for butterfly scapulae and abnormally long bones. The long bones were dysplastic in appearance with metaphyseal broadening, prominent diaphyseal cortical remodeling, hypostosis, contractures, mild bowing deformities, and relative foreshortened femurs.
Ophthalmic examination documented anterior segment dysgenesis, bilateral microcornea, anterior tunica vasculosa lentis, posterior subcapsular and lamellar cataracts, and pale optic nerves. The irides were thought to be atrophic bilaterally.
Exome sequencing identified a de novo pathogenic missense variant (p.A1175P) involving the FLNA gene, associated with OPDSD. The combined clinical and molecular genetic findings were consistent with the FMD variant of the disorder spectrum.
Throughout a prolonged and complicated clinical course, the infant failed multiple attempts at extubation. Respiratory decompensation and poor prognosis in the setting of an adenovirus infection led to compassionate extubation.
Gross examination of post-mortem eyes was notable for bilateral small corneas and pupils with a scalloped appearance. The anterior surface of the iris was smooth and lacked normal architectural landmarks including the crypts, contraction furrows, and collarette (Figure 1). Prominently evident was the presence of bilateral duplication of the iris stroma. Central, peripupillary clefts were noted, separating the anterior lamellae of pigmented iris stroma from posterior lamellae in both irides (Figure 1). In the right eye, a thickened mass of iris tissue adhered to the surface of the posterior cornea. In the left eye, the anterior lamella was notably longer than the posterior lamella, which overhung the pupil margin. The ciliary processes were poorly formed (Figure 1) and the ora serrata in both eyes were smooth, lacking dentate processes and oral bays.
Gross and microscopic features of the post-mortem eyes. (A) The anterior surface of the iris is smooth and lacks normal architectural landmarks, including crypts, contraction furrows, and collarette. (B) A cleft (arrow) separates the two layers of the iris stroma. The anterior layer of the iris stroma (asterisk) lacks the iris pigment epithelium. (C) Anterior segment at a scanning magnification manifests the incompletely cleaved anterior chamber angle with peripheral iridocorneal attachment (arrow) and a central duplication of the iris stroma (hematoxylin–eosin stain; original magnification ×5). (D) The anterior layer of the duplicated iris stroma is composed of thick-walled iris stromal blood vessels surrounded by the normal iris stromal constituents and lacks the smooth muscle and iris pigment epithelium. A cleft separates the anterior duplicated iris stroma from the underlying iris tissue with smooth muscle (arrow) and iris pigment epithelial bilayer (arrowhead) (hematoxylin–eosin stain; original magnification ×50). (E) The crystalline lens demonstrates fragmentation and liquefaction of cortical lens fibers (arrow), compatible with cataract formation (hematoxylin–eosin stain; original magnification ×25). (F) The ciliary body processes are markedly hypoplastic (arrow).
Microscopic examination confirmed two separate layers of iris stroma divided by a cleft occupying approximately half of the central portion of the irides (Figure 1). The anterior lamella thickness was 70% of that of the posterior lamella in the right eye, whereas the layers were approximately equal in the left eye. Prominent iris vessels, some with perivascular cuffs of connective tissue, were noted within anterior stromal lamellae bilaterally. In both eyes, the trabecular meshwork and anterior chamber angles were malformed and incompletely cleaved (Figure 1). In the right eye, an increased number of lens epithelial nuclei were present equatorially in the region of the lens bow. In the left eye, irregular clefts surrounded by bladder cells with degenerate nuclei were seen in the center of the lens. Pools of liquefied cortical material also were seen in this area (Figure 1). Atrophic ganglion cell and nerve fiber layers were present in the retinas. Mild to moderate optic nerve atrophy and swollen gliotic optic nerve heads were noted bilaterally.
The accessory iris membrane is an uncommon ocular congenital anomaly.9–14 Duke-Elder15 initially proposed that accessory iris membrane is a clinical entity that is distinct from persistent pupillary membrane, which is much more common. It was postulated that accessory iris membrane arises from hyperplasia of the superficial mesenchymal layer of the developing iris. This lamina, which typically terminates at the iris collarette, becomes thickened and extends beyond the pupillary border. Defects in the membrane can give the appearance of a secondary pupillary aperture, or a pseudopupil, that lacks muscular activity.
In contrast, persistent pupillary membrane is described as a remnant of the tunica vasculosa lentis, a capillary network that nourishes the early developing lens and typically atrophies between 6 and 9 months of gestation. These remnants can persist postnatally as fine strands or sheets of tissue containing empty thin blood vessels that attach to the iris collarette and span the pupil. There is often a clinical overlap between the accessory iris membrane and persistent pupillary membrane and inconsistent differentiation between the two presentations is apparent in the literature.16 It is uncertain whether accessory iris membrane is etiologically distinct from persistent pupillary membrane or whether the two entities arise from developmentally related processes.
Histopathologic documentation of accessory iris membrane has been limited to one case report by Luxenberg,14 who described abnormal hyperplastic iris stromal tissue consisting of connective tissue, uveal melanocytes, and small thick-walled blood vessels extending from the iris collarette in an adult male patient presenting with corneal opacities and cataracts. These findings are histopathologically similar to the accessory iris tissue and cataract noted in our patient. In addition, we document a more extensive spectrum of malformations involving the anterior chamber angle and ciliary body that likely comprise additional stigmata of the anterior segment dysgenesis.
Familial cases of accessory iris membrane have been reported, but there is controversy regarding whether the phenotypes are most accurately classified as persistent pupillary membrane or accessory iris membrane.16 It is also notable that although accessory iris membrane has been typically described in adult males, suggestive of an X-linked inheritance, this condition has not been previously reported in an infant and in the setting of extraocular anomalies suggestive of a syndromic association.
The finding of accessory iris membrane in the setting of a congenital syndrome with an identifiable genetic mutation is noteworthy. OPDSD is rare, with an estimated prevalence of less than 1 in 100,000.1 The reported ocular anomalies associated with OPDSD include congenital glaucoma, congenital cataracts, anterior chamber cleavage defects, sclerocornea, microcornea, and hypertelorism.3–8 Missense mutations in the FLNA gene underlie the majority of OPDSD cases.1
The FLNA gene encodes filamin A, a cytoskeletal actin-binding protein that regulates cell shape and movement and scaffolds critical transmembrane receptors and signaling molecules.16 Filamin A interacts with more than 90 diverse protein partners, including FOXC1, which has a well-known association with anterior segment dysgenesis.17,18 The mutations in the FLNA gene are clustered, leading to a close link between genotype and syndromic phenotype.2 Specifically, the ocular anomalies in OPDSD have been associated with FLNA mutations in exon 22, which encodes the adjacent ninth and tenth repeat domains.19 The functional consequence of these mutations is poorly understood, although studies suggest possible reduced stability or impaired translation of filamin A.20
Our patient similarly had a pathogenic mutation in the FLNA gene in the exon 22 encoding the tenth repeat domain of filamin A, which likely accounts for the spectrum of ocular and systemic malformations. Although accessory iris membrane has not been previously described in association with FLNA gene mutations, the recognized importance of filamin A in anterior segment development and the expression of filamin A in a normal human iris suggest that the ocular phenotype in FLNA mutation–induced OPDSD may be expanded to include accessory iris membrane.
- Robertson SP. Otopalatodigital syndrome spectrum disorders: otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia and Melnick-Needles syndrome. Eur J Hum Genet. 2007;15(1):3–9. doi:10.1038/sj.ejhg.5201654 [CrossRef]
- Robertson SP, Twigg SRF, Sutherland-Smith AJ, et al. OPD-spectrum Disorders Clinical Collaborative Group. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet. 2003;33(4):487–491. doi:10.1038/ng1119 [CrossRef]
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- Santos HH, Garcia PP, Pereira L, et al. Mutational analysis of two boys with the severe perinatally lethal Melnick-Needles syndrome. Am J Med Genet A. 2010;152A(3):726–731. doi:10.1002/ajmg.a.33260 [CrossRef]
- Xie H, Xue L, Hua W, Jia B, Zhang L, Li L. Whole genome sequencing and 6-year follow-up of a mother and daughter with frontometaphy-seal dysplasia associated with keratitis, xerosis, poikiloderma, and acroosteolysis: a case report. Medicine (Baltimore). 2018;97(28):e11283. doi:10.1097/MD.0000000000011283 [CrossRef]
- Bakhoum MF, Alexander JM, Perry HDA. A pseudopupil: anterior iris stroma hyperplasia. Ophthalmology. 2017;124(6):775. doi:10.1016/j.ophtha.2016.11.027 [CrossRef]
- Bhatti SM, Kapoor HK. Bilateral accessory iris membrane. Indian J Ophthalmol. 1998;46(2):110–111.
- Espandar L, Allingham RR, Afshari NA. Stromal duplication of the iris. JAMA Ophthalmol. 2013;131(11):1442. doi:10.1001/jamaophthalmol.2013.2592 [CrossRef]
- Gavris M, Horge I, Avram E, Belicioiu R, Olteanu IA, Kedves H. Persistent pupillary membrane or accessory iris membrane?Rom J Ophthalmol. 2015;59(3):184–187.
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- Luxenberg MN. Hyperplasia of the anterior layer of the iris stroma. Br J Ophthalmol. 1965;49(10):516–520. doi:10.1136/bjo.49.10.516 [CrossRef]
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- Cassady JR, Light A. Familial persistent pupillary membranes. AMA Arch Opthalmol. 1957;58(3):438–448. doi:10.1001/archopht.1957.00940010450021 [CrossRef]
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- Berry FB, O'Neill MA, Coca-Prados M, Walter MA. FOXC1 transcriptional regulatory activity is impaired by PBX1 in a filamin A-mediated manner. Mol Cell Biol. 2005;25(4):1415–1424. doi:10.1128/MCB.25.4.1415-1424.2005 [CrossRef]
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