Background: Type II DNA topoisomerases (EC5.99.1.3) are enzymes that catalyze topological changes during DNA replication and gene transcription in an ATP-dependent manner. Vertebrates have two isoforms: topoisomerase IIα and β. Type II topoisomerase β is encoded by TOP2B. For TOP2B, a number of germline pathogenic variants have been identified as causative for human diseases, including Hoffman syndrome, ablepharon-macrostomia syndrome with immunodeficiency, B-cell immunodeficiency, distal limb anomalies, and urogenital malformations syndrome. To date, only 14 patients with the above diseases from seven families have been reported in PubMed. Herein, we describe an additional case of a child who presented with "infantile epileptic spasms syndrome" (IESS) as the first symptom, B-cell immunodeficiency, dysmorphic facial features, and a pathogenic variant in TOP2B. The c.1901A > G variant in TOP2B is new to our study, which further enriches the genotype of TOP2B deficiency. Our patient manifested as a typical triad: infantile spasms, hypsarrhythmia on electroencephalogram, and developmental arrest at the age of 7 months. Although epilepsy and neurodevelopmental disorders have been reported in patients with TOP2B deficiency, typical IESS has not been described previously. IESS in our patient further expands the phenotype of TOP2B. The patient was started on monthly intravenous immunoglobulin replacement therapy after being diagnosed with TOP2B deficiency and since then has not suffered from severe infections. TOP2B deficiency is a group of heterogeneous diseases, which is ultrarare. The results from our study extend the phenotype and genotype spectrum of TOP2B deficiency. TOP2B may be a causative gene for IESS.

Ablepharon macrostomia syndrome is a rare congenital disorder caused by autosomal-dominant TWIST2 mutations. This condition is characterized by redundant skin, low-set ears, macrostomia, ambiguous genitalia, and underdevelopment of the both upper and lower eyelids. The shortening of the anterior lamella, septum and levator aponeurosis lead to a severe corneal exposure within the first hours of life. Since McCarthy and West's first report in 1977, 21 AMS cases have been documented. We report a new AMS case with a quantitative analysis of palpebral fissure changes following skin grafts over the upper and lower smooth tarsal muscles and lateral tarsorrhaphy.

Ablepharon-macrostomia syndrome is a rare disorder characterized by TWIST2 mutations and anterior lamellar dysgenesis. Timely intervention is critical to prevent exposure keratopathy, corneal ulceration, and permanent vision loss. We report a novel approach to multiplanar eyelid reconstruction in ablepharon-macrostomia syndrome involving use of a modified reverse hatchet flap in 1 lower eyelid along with division at the eyelid margin, recession of the eyelid retractors in conjunction with preputial skin grafting for anterior lamellar restoration in the other 3 eyelids.

Cryptophthalmos is a rare congenital condition caused by anomalous eyelid development where the eyelid folds do not develop or fail to separate. Cryptophthalmos can be unilateral or bilateral and can occur in isolation or as part of an underlying syndrome. We aim to identify genetic syndromes associated with cryptophthalmos to facilitate genetic diagnosis. We performed a retrospective medical record review of all patients diagnosed with cryptophthalmos followed at a single center between 2000 and 2020. The analysis included medical history, clinical examination findings, and genetic testing results. Thirteen patients were included, 10 (77%) males, mean age of 2.4 years. Eight (61%) had bilateral cryptophthalmos, and 4 (31%) had complete cryptophthalmos. Associated ocular abnormalities included corneal opacities (13/13, 100%), upper eyelid colobomas (12/13, 92%), and microphthalmia/clinical anophthalmia (3/13, 23%). All cases of complete cryptophthalmos had bilateral disease. An underlying clinical or molecular diagnosis was identified in 10/13 (77%) cases, including Fraser syndrome (n = 5), amniotic band syndrome (n = 1), FREM1-related disease (n = 1), Goldenhar versus Schimmelpenning syndrome (n = 1), MOTA syndrome (n = 1), and CELSR2-related disease (n = 1). This is the first report of a possible association between cryptophthalmos and biallelic CELSR2 variants. Children with cryptophthalmos, especially those with extra-ocular involvement, should be referred for comprehensive genetic evaluation.

Ablepharon-macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are congenital ectodermal dysplasias associated with mutations in the TWIST2 gene. Among the ophthalmic anomalies that occur in these syndromes, underdevelopment of the anterior lamella of the eyelid is a defining feature. Reports of mosaic expression of TWIST2 mutations are extremely rare, with only five confirmed or suspected cases described to date. Mosaic expression of TWIST2 variants is correlated with a less severe phenotype than that reported for the typical expression of TWIST2 variants associated with BSS or AMS. Abnormal development of the anterior lamella appears to be a common feature in all cases of AMS with mosaic expression. Here, we describe the phenotype of a patient with mosaic expression of a TWIST2 mutation that is typically associated with AMS. We additionally describe the surgical approach employed in the treatment of this patient.