OBJECTIVE: Microphthalmia is a severe congenital ocular disease featured by abnormal ocular development. The aim of this study was to detail the genetic and clinical characteristics of a large cohort of Chinese patients with microphthalmia related to MFRP variants, focusing on uncovering genotype-phenotype correlations.
METHODS: Fifty microphthalmia patients from 44 unrelated Chinese families were recruited. Whole-exome sequencing (WES) was conducted to analyze the coding regions and adjacent intronic regions of MFRP. Axial lengths (AL) were measured for all probands and available family members. Protein structures of mutations with high frequency in our cohort were predicted. The genotype-phenotype correlations were explored by statistical analysis.
RESULTS: Sixteen MFRP variants were detected in 17 families, accounting for 38.64 % of all microphthalmia families. There were 9 novel mutations (c.427+1G>C, c.428-2A>C, c.561_575del:p.A188_E192del, c.836G>A:p.C279Y, c.1010_1021del:p.H337_E340del:p.Y479*, c.1516_1517del:p.S506Pfs*66, c.1561T>G:p.C521G, c.1616G>A:p.R539H, and c.1735C>T:p.P579S) and six previously reported variants in MFRP, with p.E496K and p.H337_E340del being highly frequent, found in eight (47.06 %) and two families (11.76 %), respectively. Seven variants (43.75 %) were located in the C-terminal cysteine-rich frizzled-related domain (CRD) (7/16, 43.75 %). Protein prediction implicated p.E496K and p.H337_E340del mutations might lead to a destabilization of the MFRP protein. The average AL of all 42 eyes was 16.02 ± 1.05 mm, and 78.36 % of eyes with AL < 16 mm harbored p.E496K variant. Twenty-six eyes with variant variant had shorter AL than that of the other 16 eyes without this variant (p = 0.006), highlighting a novel genotype-phenotype correlation.
CONCLUSIONS: In this largest cohort of Chinese patients with microphthalmia, the 9 novel variants, high frequency of p.E496W, and mutation hotspots in CRD reveals unique insights into the MFRP mutation spectrum among Chinese patients, indicating ethnic variability. A new genotype-phenotype correlation that p.E496K variant associated with a shorter AL is unveiled. Our findings enhance the current knowledge of MFRP-associated microphthalmia and provide valuable information for prenatal diagnosis as well as future therapy.

Genetic perturbations influencing early eye development can result in microphthalmia, anophthalmia, and coloboma (MAC). Over 100 genes are associated with MAC, but little is known about common disease mechanisms. In this study, we generated induced pluripotent stem cell (iPSC)-derived optic vesicles (OVs) from two unrelated microphthalmia patients and healthy controls. At day 20, 35, and 50, microphthalmia patient OV diameters were significantly smaller, recapitulating the \"small eye\" phenotype. RNA sequencing (RNA-seq) analysis revealed upregulation of apoptosis-initiating and extracellular matrix (ECM) genes at day 20 and 35. Western blot and immunohistochemistry revealed increased expression of lumican, nidogen, and collagen type IV, suggesting ECM overproduction. Increased apoptosis was observed in microphthalmia OVs with reduced phospho-histone 3 (pH3+) cells confirming decreased cell proliferation at day 35. Pharmacological inhibition of caspase-8 activity with Z-IETD-FMK decreased apoptosis in one patient model, highlighting a potential therapeutic approach. These data reveal shared pathophysiological mechanisms contributing to a microphthalmia phenotype.

Congenital arhinia-microphthalmos syndrome or BOSMA syndrome is an exceptionally rare clinical syndrome characterized by unilateral or bilateral complete absence of the nasal cavity associated with several craniofacial, ocular, and systemic anomalies. Lacrimal drainage anomalies are secondary to absent nasolacrimal duct and usually present as dilated lacrimal sac or mucoceles. While navigation-guided dacryocystorhinostomies into the contralateral nasal cavity are described for unilateral arhinia, the way forward for the complete absence of the nose and nasal cavity is still unclear. A multidisciplinary team from the specialties of genetics, plastic surgery, ophthalmic plastics and reconstructive surgery, otorhinolaryngology, and endocrinology should get involved very early on for better continuity of care.

OBJECTIVE: To describe multiple congenital ocular anomalies in three litters of Jack Russell Terrier puppies.
METHODS: Seven purebred Jack Russell Terrier puppies from three related litters and their four parents.
METHODS: Medical records of the puppies and their parents were evaluated. All dogs underwent a complete ophthalmic examination, followed by bilateral ocular ultrasonography in two of the puppies with complete corneal opacity. One eye from an affected puppy was subjected to histopathology. A complete database of pedigrees was built, and individual inbreeding was evaluated.
RESULTS: The most commonly diagnosed ocular anomalies in the puppies were: various anomalies of the fundus (12/14 eyes); microphthalmia (10/14 eyes); sclerocornea (8/14 eyes); and persistent pupillary membranes (7/14 eyes). Six out of seven puppies had at least two ocular abnormalities, and only one puppy was normal. Four out of seven puppies had sclerocornea, a particular corneal opacity to date described only in Spanish Podenco dogs. No ocular abnormalities were found in the parents examined (4/4). Analysis of the pedigrees showed that all the puppies and two parents were inbred, and the individual values of the inbreeding puppies were greater than 6.25% in two litters.
CONCLUSIONS: Inbreeding with closely related Jack Russell Terriers may result in severe congenital eye abnormalities in puppies.

In humans, the prevalence of congenital microphthalmia is estimated to be 0.2-3.0 for every 10,000 individuals, with nonocular involvement reported in ∼80% of cases. Inherited eye diseases have been widely and descriptively characterized in dogs, and canine models of ocular diseases have played an essential role in unraveling the pathophysiology and development of new therapies. A naturally occurring canine model of a syndromic disorder characterized by microphthalmia was discovered in the Portuguese water dog. As nonocular findings included tooth enamel malformations, stunted growth, anemia, and thrombocytopenia, we hence termed this disorder Canine Congenital Microphthalmos with Hematopoietic Defects. Genome-wide association study and homozygosity mapping detected a 2 Mb candidate region on canine chromosome 4. Whole-genome sequencing and mapping against the Canfam4 reference revealed a Short interspersed element insertion in exon 2 of the DNAJC1 gene (g.74,274,883ins[T70]TGCTGCTTGGATT). Subsequent real-time PCR-based mass genotyping of a larger Portuguese water dog population found that the homozygous mutant genotype was perfectly associated with the Canine Congenital Microphthalmos with Hematopoietic Defects phenotype. Biallelic variants in DNAJC21 are mostly found to be associated with bone marrow failure syndrome type 3, with a phenotype that has a certain degree of overlap with Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and reports of individuals showing thrombocytopenia, microdontia, and microphthalmia. We, therefore, propose Canine Congenital Microphthalmos with Hematopoietic Defects as a naturally occurring model for DNAJC21-associated syndromes.

OBJECTIVE: To evaluate axial length (AL), orbital width (OW) and height (OH) development in congenital microphthalmia and anophthalmia (MICA) using serial ultrasonography measurements.
METHODS: A longitudinal prospective cohort (n = 74) of unilaterally and bilaterally affected MICA patients was followed from 2013 to 2022 at the university hospital in Amsterdam, the Netherlands. Clinical entity, age, severity category based on axial length, conformer treatment and intra-orbital cysts were registered. The main outcome measures were the absolute and relative growth of AL, OW and OH. Surgical and intra-orbital cyst cases were described separately.
RESULTS: Absolute microphthalmic eye size increased in 27/49 (55%) unilateral MICA eyes, but growth arrest/decrease in the remaining could shift the case to a more severe category over time. A final affected/unaffected orbital symmetry ≥80% was seen in the large majority of unilateral cases (45/46 for OW, 43/46 for OH). Cases with AL < 10.5 mm had orbital symmetry <80% more often. Most orbital symmetry changes were seen in moderate and severe unilateral cases treated with 3D-printed conformer therapy starting at age <1 year, with 6/10 (60%) symmetry increase, 30% unchanged symmetry and 10% symmetry decrease. All cases older than 6.5 years (n = 6) did not show any change anymore, regardless of treatment. For bilateral and unilateral mild cases, orbital dimensions kept the same proportions during follow-up, with or without conformer treatment.
CONCLUSIONS: Using severity categories in MICA based on relative AL may aid the decision to start conformer treatment, as most orbital symmetry changes were seen in moderate and severe unilateral cases receiving 3D-printed conformer therapy that started under age 1.

OBJECTIVE: To estimate the prevalence and trend of congenital eye anomalies (CEAs) and the rate of prenatal diagnosis over a 10-year period.
METHODS: Retrospective population-based registry study.
METHODS: All maternity units in Paris, France, from 2010 to 2020.
METHODS: A cohort of 115 cases of CEA detected among all live births or stillbirths, after 22 weeks of gestation, and terminations of pregnancy.
METHODS: The total prevalence of CEAs and prevalence of each specific CEA were calculated using 95% Poisson exact confidence intervals.
METHODS: The total prevalence of CEAs and the proportion of prenatal diagnosis of CEAs, and their evolution.
RESULTS: The prevalence of CEAs was 4.1 (95% CI 3.4-5.0) cases, ranging between 3.1 and 5.7 cases, per 10 000 births. CEAs were prenatally diagnosed in 23.5% of cases. CEAs were bilateral in 51 cases (44.3%), unilateral in 43 cases (37.4%) and missing or unknown in 21 cases (18.3%). Of those with CEAs, 20.9% had genetic anomalies and 53.0% had at least one other extraocular anomaly. When detected prenatally, CEAs were bilateral in 15 cases (55.6%), unilateral in eight cases (29.6%) and missing in the four remaining cases. The prenatal diagnosis rate of CEAs associated with genetic anomalies, CEA cases with at least one other malformation and isolated CEA cases were 29.2%, 26.2% and 13.3%, respectively.
CONCLUSIONS: In total, 115 cases of CEAs were observed during the study period, representing a total prevalence of 4.1 cases per 10 000 births. The overall prenatal detection rate of CEAs in our population was 23.5%, which dropped to 13.3% for isolated cases of CEAs.

The development and growth of the eye depends on normal lens morphogenesis and its growth. This growth, in turn, is dependent on coordinated proliferation of the lens epithelial cells and their subsequent differentiation into fiber cells. These cellular processes are tightly regulated to maintain the precise cellular structure and size of the lens, critical for its transparency and refractive properties. Growth factor-mediated MAPK signaling driven by ERK1/2 has been reported as essential for regulating cellular processes of the lens, with ERK1/2 signaling tightly regulated by endogenous antagonists, including members of the Sprouty and related Spred families. Our previous studies have demonstrated the importance of both these inhibitory molecules in lens and eye development. In this study, we build on these findings to highlight the importance of Spreds in regulating early lens morphogenesis by modulating ERK1/2-mediated lens epithelial cell proliferation and fiber differentiation. Conditional loss of both Spred1 and Spred2 in early lens morphogenesis results in elevated ERK1/2 phosphorylation, hyperproliferation of lens epithelia, and an associated increase in the rate of fiber differentiation. This results in transient microphakia and microphthalmia, which disappears, owing potentially to compensatory Sprouty expression. Our data support an important temporal role for Spreds in the early stages of lens morphogenesis and highlight how negative regulation of ERK1/2 signaling is critical for maintaining lens proliferation and fiber differentiation in situ throughout life.

BACKGROUND: Self-inflating hydrogel expanders have been used to treat anophthalmia and blind microphthalmia. This study aimed to investigate the long-term outcomes of treatment with self-inflating hydrogel expanders for congenital anophthalmia and blind microphthalmia.
METHODS: In this retrospective study, the medical records of 161 patients with anophthalmia and blind microphthalmia who underwent hydrogel expansion were reviewed. We measured the palpebral fissure height (PFH), palpebral fissure length (PFL), and distance between the inner canthal and mid-nasal line (ICMN) before and after surgery. Cox regression analysis was conducted to determine which variables were related to the implantation of spherical expanders following hemispherical expander implantation.
RESULTS: After treatment, the PFH and PFL increased significantly (p < 0.001). Complications including expander migration and extrusion occurred in 15 cases. Five patients needed enucleation or further dermis fat graft implantation because of insufficient expansion. The necessity for further spherical expansion was substantially related to a relative axial length (rAL) <0.5 (p = 0.007).
CONCLUSIONS: Self-inflating hydrogel expansion can significantly increase the lid fissure. The occurrence of complications is rare, and surgical intervention can effectively address them. Abnormal eyes with a rAL of less than 0.5 demonstrate a higher possibility of needing additional orbital expansion.

UNASSIGNED: Stickler syndrome (STL) is a collagenopathy caused by pathogenic variants in collagen-coding genes, mainly COL2A1 or COL11A1 associated with Stickler syndrome type 1 (STL1) or type 2 (STL2), respectively. Affected individuals manifest ocular, auditory, articular, and craniofacial findings in varying degrees. Previous literature and case reports describe high variability in clinical findings for patients with STL. With this case report, we broaden the clinical spectrum of the phenotype.
UNASSIGNED: Case report on two members of a family (mother and son) including clinical examination and genetic testing using targeted trio whole exome sequencing (trio-WES).
UNASSIGNED: A boy and his mother presented with microphthalmia, congenital cataract, ptosis, and moderate-to-severe sensorineural hearing loss. Trio-WES found a novel heterozygote missense variant, c.4526A>G; p(Gln1509Arg) in COL11A1 in both affected individuals.
UNASSIGNED: We report a previously undescribed phenotype associated with a COL11A1-variant in a mother and son, expanding the spectrum for phenotype-genotype correlation in STL2, presenting with microphthalmia, congenital cataract, and ptosis not normally associated with Stickler syndrome.