Cleft palate and hypopituitarism in a patient with Noonan-like syndrome with loose anagen hair-1.

Noonan syndrome (NS), the most common of the RASopathies, is a developmental disorder caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Noonan-like syndrome with loose anagen hair (NSLH, including NSLH1, OMIM #607721 and NSLH2, OMIM #617506) is characterized by typical features of NS with additional findings of macrocephaly, loose anagen hair, growth hormone deficiency in some, and a higher incidence of intellectual disability. All NSLH1 reported cases to date have had an SHOC2 c.4A>G, p.Ser2Gly mutation; NSLH2 cases have been reported with a PPP1CB c.146G>C, p.Pro49Arg mutation, or c.166G>C, p.Ala56Pro mutation. True cleft palate does not appear to have been previously reported in individuals with NS or with NSLH. While some patients with NS have had growth hormone deficiency (GHD), other endocrine abnormalities are only rarely documented. We present a female patient with NSLH1 who was born with a posterior cleft palate, micrognathia, and mild hypotonia. Other findings in her childhood and young adulthood years include hearing loss, strabismus, and hypopituitarism with growth hormone, thyroid stimulating hormone (TSH), and gonadotropin deficiencies. The SHOC2 mutation may be responsible for this patient's additional features of cleft palate and hypopituitarism.

Camptodactyly and the 22q11.2 deletion syndrome.

We describe a 5-day-old male with minor facial anomalies, a congenital laryngeal web, severe laryngomalacia, and prominent fixed flexion of the proximal interphalangeal joints of digits 2 through 5 bilaterally. A whole genome SNP microarray analysis identified a 2.55 Mb interstitial deletion of 22q11.21, typical of that seen in the DiGeorge and Velocardiofacial syndromes. A review of the literature identifies 10 other cases with camptodactyly. Camptodactyly appears to be an associated but rarely reported anomaly in patients with the 22q11.2 microdeletion syndrome. © 2016 Wiley Periodicals, Inc.

Mild achondroplasia/hypochondroplasia with acanthosis nigricans, normal development, and a p.Ser348Cys FGFR3 mutation.

Pathogenic allelic variants in the fibroblast growth factor receptor 3 (FGFR3) gene have been associated with a number of phenotypes including achondroplasia, hypochondroplasia, thanatophoric dysplasia, Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal syndrome), and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans). Crouzon syndrome with acanthosis nigricans is caused by the pathogenic variant c.1172C>A (p.Ala391Glu) in the FGFR3 gene. The p.Lys650Thr pathogenic variant in FGFR3 has been linked to acanthosis nigricans without significant craniofacial or skeletal abnormalities. Recently, an infant with achondroplasia and a novel p.Ser348Cys FGFR3 mutation was reported. We describe the clinical history of an 8-year-old child with a skeletal dysplasia in the achondroplasia-hypochondroplasia spectrum, acanthosis nigricans, typical development, and the recently described p.Ser348Cys FGFR3 mutation.

Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion syndrome.

Mitochondrial DNA depletion syndrome 5 (MIM 612073) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the beta subunit of the succinate-CoA ligase gene located within the 13q14 band. We describe two siblings of Hispanic descent with SUCLA2-related mitochondrial depletion syndrome (encephalomyopathic form with methylmalonic aciduria); the older sibling is additionally affected with trisomy 21. SUCLA2 sequencing identified homozygous p.Arg284Cys pathogenic variants in both patients. This mutation has previously been identified in four individuals of Italian and Caucasian descent. The older sibling with concomitant disease has a more severe phenotype than what is typically described in patients with either SUCLA2-related mitochondrial depletion syndrome or Down syndrome alone. The younger sibling, who has a normal female chromosome complement, is significantly less affected compared to her brother. While the clinical and molecular findings have been reported in about 50 patients affected with a deficiency of succinate-CoA ligase caused by pathogenic variants in SUCLA2, this report describes the first known individual affected with both a mitochondrial depletion syndrome and trisomy 21.

The phenotype of multiple congenital anomalies-hypotonia-seizures syndrome 1: report and review.

The Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 1 (MCAHS1) has been described in two families to date. We describe a 2-year-old Mexican American boy with the syndrome and additional manifestations not yet reported as part of the phenotype. The patient presented with severe hypotonia, microphallus and left cryptorchidism, and was later diagnosed with epilepsy and severe cortical visual impairment. He also had supernumerary nipples, pectus excavatum, a short upturned nose, fleshy ear lobes, and a right auricular pit. Massively parallel exome sequencing and analysis revealed two novel compound heterozygous missense (Trp136Gly and Ser859Thr) variants in the PIGN gene. This report extends and further defines the phenotype of this syndrome.

Genotype-phenotype analysis of ocular findings in Rubinstein-Taybi syndrome - A case report and review of literature.

BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a rare genetic syndrome with a wide range of phenotypic presentations, including characteristic facial features. A variety of ocular abnormalities have been described in patients with RSTS. The genetic etiology of RSTS is heterogeneous but often involves two major genes, CREBBP (cAMP-response element binding protein-binding protein) and EP300 (E1A binding protein p300), with CREBBP variants responsible for the majority of the cases. MATERIALS AND METHODS: We report a new case of female patient with a novel variant in CREBBP (c.4495C>G), with clinical features consistent with RSTS. We performed a literature review to search for possible genotype-phenotype relationships between the type of variant in CREBBP and frequency of ocular presentations. A PubMed search generated 12 articles that met our inclusion criteria. With the addition of our patient, there were a total of 163 patients included for mutation analysis (164 variants given one patient had two different variants). RESULTS: Our review revealed that the most common variant types were frameshift (25%), gross deletion (23%), nonsense (18%), and intragenic deletions (13%). There does not appear to be an obvious hot spot location. A total of 127 patients were included for genotype-phenotype analysis of ocular features (36 patients were excluded as unable to discern variant type). The most frequent ocular features in patients with RSTS were down-slanting palpebral fissure (74%), arched eyebrows (56%), long eyelashes (52%), and strabismus (23%). CONCLUSIONS: Our results suggest that currently there is no clear genotype-phenotype relationship between the type of variant and frequency of associated ocular features in RSTS patients.

Magnetic Resonance Imaging Findings and Genetic Testing Results in Children With Congenital Corneal Opacities.

PURPOSE: This study investigates brain and globe abnormalities identified on magnetic resonance imaging (MRI) in children with congenital corneal opacities (CCO). DESIGN: Retrospective cohort study. METHODS: Clinical notes, radiology records, and genetic testing results were reviewed for patients diagnosed with corneal opacification within the first 6 months of life at a tertiary referral academic center between August 2008 and January 2018. Ocular findings, systemic anomalies, neuroimaging, and genetic testing results were summarized. RESULTS: A total of 135 patients presenting at age 1 day to 12 years (mean age, 1 year) were identified. Children with bilateral CCO were more likely to have systemic disease (P = 0.018). Of the entire cohort, 43 (31.8%) patients received MRI, of whom 27 (62.8%) had abnormal brain findings and 30 (69.7%) had abnormal orbital findings. The most common abnormal brain findings were ventriculomegaly (n = 16, 59.2%) and corpus callosum abnormalities (n = 10, 37.0%) followed by brainstem/pons anomalies (n = 5, 18.5%), and cerebellar anomalies (n = 2, 7.4%). Abnormal brain MRI findings were associated with the presence of neurologic (P = .003) and craniofacial (P = .034) disease. A total of 44 (32.1%) patients underwent genetic testing, of whom 29 (65.9%) had pathogenic results. CONCLUSIONS: More than 60% of the children with CCO who underwent MRI had abnormal brain and orbit findings that were correlated with significant neurologic disease. Furthermore, almost two-thirds of patients with CCO who underwent genetic testing had pathogenic results. These data demonstrate the value of systemic workup in children with CCO, and highlight the role of ophthalmologists in facilitating the diagnosis of systemic comorbidities associated with CCO.

Facial and ocular manifestations of male patients affected by the HUWE1-related intellectual developmental disorder.

Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a rare neurodevelopmental disorder. MRXST is caused by pathogenic variants in the HUWE1 gene on chromosome Xp11.22. The HUWE1 gene encodes a ubiquitin ligase, which has downstream effects on the n-MYC protein and DLL3 Notch ligand, ultimately affecting neuronal differentiation. In addition to intellectual disability and developmental delay, other clinical features such as absent or delayed speech, skeletal abnormalities, abnormalities in hands or feet, seizures, and hypotonia have been described in case reports. Facial dysmorphic features and eye manifestations have been reported in patients with MRXST, but have not been identified as distinctive to this condition. We report two cases of individuals affected by HUWE1-Related Intellectual Developmental Disorder and present a review of literature of male patients affected by this disorder. Based on the literature review and findings in our two patients, it is our observation that patients with MRXST present with distinctive features, which include broad nasal tip, root, or prominent nose (39%), blepharophimosis (27%), epicanthic folds (25%), ear abnormalities (25%), thin upper lip (23%), and deep set eyes (23%). Furthermore, we note that oculofacial abnormalities are seen more frequently in patients with missense variants than patients with duplications in the HUWE1 gene. The findings noted in this paper may help clinicians suspect a diagnosis of MRXST when presented with these distinctive ocular and facial features.

A New Case and Comprehensive Review of the Ophthalmic Manifestations of 172 Individuals With Branchio-Oculo-Facial Syndrome.

PURPOSE: To review the literature on branchio-oculo-facial syndrome and describe a new case. METHODS: A girl presented with a de novo pathogenic mutation in the TFAP2A gene consistent with branchio-oculo-facial syndrome. A systematic review was also performed to characterize the eye manifestations associated with the syndrome. RESULTS: A total of 172 total patients were identified from the literature. Among these, 102 patients received molecular confirmation. The most common pathogenic variants reported were p.R255G, p.A256V, p.R254W, and p.G251E. Common eye abnormalities associated with the syndrome in total combined cases (represents individuals with a clinical diagnosis only of branchio-oculo-facial syndrome plus those who additionally had molecular confirmation of the syndrome from genetic testing) were nasolacrimal duct stenosis (n = 98, 57%), coloboma (n = 76, 46%), anophthalmia/microphthalmia (n = 64, 37%), and cataracts (n = 27, 16%). CONCLUSIONS: This analysis provides a comprehensive review of genetic variants and ophthalmic findings to characterize the most common eye manifestations associated with branchio-oculo-facial syndrome. The report provides incentive to further investigate TFAP2A variants and identify genotype-phenotype correlations. [J Pediatr Ophthalmol Strabismus. 2023;60(4):295-301.].

The Role of Genetic Testing in Avoiding Diagnostic Delays in Inherited Retinal Disease.

PURPOSE: To identify and highlight potential delays in diagnosis and improve the characterization of the providers referring individuals affected with suspected IRDs for specialty care, we performed an analysis of the patients with IRDs seen by an ophthalmic genetics specialty service. In addition, we analyzed the diagnostic yield of genetic testing in patients with IRD in our series and compared this information with other previous studies. METHODS: We analyzed 131 consecutive patients with suspected IRDs referred to an ophthalmic genetics specialty service at a tertiary hospital. Provider referral patterns, delays in diagnosis and the diagnostic yield of genetic testing were evaluated. RESULTS: Mean age in the cohort was 24 years. From the 51 patients that underwent genetic testing, the diagnostic yield was 69%. Of these, genetic testing revealed 51% of patients had an incorrect initial referral clinical diagnosis. The average delay to reach a correct diagnosis was 15 years. Ophthalmologists represented the largest referral base at 80%, followed by neurologists representing 5% of referrals. Pediatric and retinal specialists were the largest referral of ophthalmic subspecialties at 44% and 35%, respectively. CONCLUSION: A significant number of patients experienced a prolonged delay in reaching a correct diagnosis largely due to a delay in initiating the genetic evaluation and testing process. The initial suspected clinical diagnosis was incorrect in a significant number of cases, revealing that affected patients were potentially denied from appropriate recurrence risk counseling, relevant educational resources, specialty referrals in syndromic cases, and clinical trial eligibility in a timely manner.

The epidemiology of strabismus and cataracts within a pediatric population in Saint Vincent and the Grenadines: an analysis of 201 consecutive cases.

PURPOSE: Childhood cataracts and strabismus are among the most common causes of visual impairment in children worldwide, and prompt diagnosis and correction can significantly reduce disease burden. In certain regions, including the Eastern Caribbean, access to adequate treatment can be limited and epidemiological data scarce. This study aims to analyze the epidemiological data of pediatric strabismus and cataract cases in St. Vincent and the Grenadines. METHODS: The setting of the study is a clinical practice including 201 patients between the age of 0 to 19 who received care with World Pediatric Project (WPP). Factors analyzed include patient age, sex, and type of cataract or strabismus. The findings were compared to publicly available demographic information. RESULTS: The cases were divided into cataract (n=51), strabismus (n=134), and both strabismus and cataract (n=16). Mean ages (years) were 5.96, 5.54, and 4.50, respectively. The most frequent type of cataract and strabismus were congenital (n=25) and esotropia (n=95), respectively. The highest annual cumulative incidence was 31 and 49 cases per 100,000 people for cataracts and strabismus, respectively. CONCLUSION: This study provides regional epidemiological data on pediatric strabismus and cataracts. Further studies can expand the patient population by increasing collaboration with local providers. Ultimately, these findings can offer a basis for which additional epidemiological studies can be performed and help guide public health efforts to prevent visual impairment in St. Vincent and the Grenadines.

Ocular manifestations of Nabais Sa-de Vries Syndrome type 1.

Nabais Sa-de Vries syndrome (NSDVS) is a neurodevelopmental disorder first described in 2020. The syndrome is caused by de novo missense mutations in speckle-type pox virus and zinc finger protein (SPOP) on chromosome 17q21. The syndrome is divided into two forms (NSDVS Type 1 and NSDVS Type 2) based on the consequence of the mutation involved. In this report, we present the clinical features in a young male patient with suspected NSDVS1 and summarize the features of the reported affected individuals thus far, with a focus on the ophthalmic manifestations. Similar to other individuals with NSDVS1, he had features of congenital microcephaly, developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphisms. Ocular and periorbital manifestations in this patient included thick high-arched eyebrows, mild synophrys, long eyelashes, ptosis, and downslanting palpebral fissures; comparable to features described in other individuals with NSDVS1. In addition, this patient had esotropia that required multiple strabismus surgeries and a refractive error that required the use of corrective lenses. Although the consequences of specific mutations may result in a portion of the phenotypic differences between NSDVS1 and NSDVS2, the ophthalmic abnormalities between the two types may have significant overlap not explained by these bidirectional mutational effects.

Eye and ocular adnexa manifestations of MED12-related disorders.

BACKGROUND: MED12-related disorders are a rare group of intellectual disability syndromes with a broad range of phenotypic characteristics. The phenotypic spectrum of MED12-related disorders currently includes X-Linked Ohdo Syndrome, Lujan-Fryns Syndrome (LS), and FG syndrome type 1 (FG), also known as Opitz-Kaveggia Syndrome. The MED12 gene encodes the largest component of the mediator complex of RNA polymerase II, which is critical for recruiting activators and repressors to regulate the transcription of genes critical to growth, development, and differentiation. METHODS: We performed a systematic literature review of previously published cases to highlight the key ocular features in individuals with MED12-related disorders. In addition, we present a new case of a female patient with a de novo pathogenic c. 3866A>G, p.Q1289R variant. Ocular manifestations are not uncommon in MED12-related disorders, but have not been characterized in literature reports. Commonly reoccurring reported eye and ocular adnexa features within the spectrum include ptosis, downslanting palpebral fissures, and hypertelorism. Other less common findings include strabismus, astigmatism, and optic nerve hypoplasia. RESULTS: Our patient presented with developmental delay, mild hypotonia and dysmorphic features including frontal bossing, high arched palate, and syndactyly of the 2nd and 3rd toes bilaterally. DISCUSSION: Ocular manifestations identified in this patient included intermittent esotropia, hyperopic astigmatism, epicanthal folds and ptosis bilaterally.

Ophthalmia neonatorum due to Escherichia coli: A rare cause or an emerging bacterial etiology of neonatal conjunctivitis?

Since the introduction of universal gonococcal and chlamydia prophylaxis, other etiologies for neonatal conjunctivitis such as Escherichia coli have become more common. Early eye culturing as part of the management plan could provide swifter treatment and preservation of vision potential in affected neonates.

Eye manifestations in the NSUN2 intellectual disability syndrome.

The NSUN2-intellectual disability syndrome is a rare disorder of the cellular transcriptome that prevents proper t-RNA splicing. This disorder interrupts cellular function and leads to an accumulation of RNA fragments, producing a constellation of symptoms including dysmorphic facies, hypotonia, microcephaly, and short stature. Eye manifestations have been reported but not well characterized. Our study presents a new case involving a 4-year-old boy with novel NSUN2 variants and clinical features consistent with the syndrome. In addition, through a systemic review, we discuss the 24 previously reported cases of the syndrome with an emphasis on the eye and ocular adnexa clinical features.

The evolving role of genetics in ophthalmology.

Advances in molecular genetics over the past three decades have helped identify a substantial number of genetic variants causing inherited eye diseases that can be identified rapidly by appropriate genetic tests in a clinically useful window. With this progression of knowledge, the roles of genetics and ophthalmology in patient care have become increasingly intertwined, and the necessity for subspecialists in the field of ophthalmic genetics is of paramount importance. As a result of continual medical specialization, technological progress in genetics and knowledge garnered by over a century and a half of cataloguing eye pathology, ophthalmic genetics has become an emerging subspecialty within ophthalmology. By virtue of its rapidly changing advances, genetics and genomics serves a large role within ophthalmology, and subspecialists with the same level of detailed and broad knowledge as any other ophthalmology subspecialty are now required in order to meet the growing needs of the expanding population.

The First Cataract Surgeons in the British Isles.

PURPOSE: To describe the entry of cataract surgery into the British Isles. METHODS: Handbills, books, and other historical sources were reviewed to determine when cataract surgery was first performed in the region. RESULTS: Roman artifacts suggest that couching was performed in the British Isles in antiquity. Seemingly miraculous cures of blindness during the early Middle Ages might be consistent with couching. However, there is no strong evidence of medieval cataract surgery in the region. Cataract couching probably arrived in England by the 1560s, in Scotland by 1595, in Ireland by 1684, and in Anglo-America by 1751. Before the 18th century, cataract surgery was taught within families, apprenticeships, and mountebank troupes. Beginning in the 17th century, congenital cataract surgery permitted surgeons to tout their skills and to explore visual perception. However, in some cases, such as the couching of the 13-year-old Daniel Dolins by surgeon William Cheselden in 1727, whether the cataracts were truly congenital, and whether vision improved in any way, remain in doubt. Beginning in the 1720s, cataract surgery began to be performed by traditional surgeons in hospitals. However, for most of the century, the highest-volume cataract surgeons continued to be itinerant oculists, including those who performed cataract extraction in the latter half of the century. CONCLUSIONS: Cataract surgery might have been performed in Roman Britain. Specific evidence of cataract surgery emerges in the region in the Elizabethan era. Cataract extraction was performed in the British Isles by 1753, but couching remained popular throughout the 18th century. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Corrigendum #2 to "Eye Manifestations of Shprintzen-Goldberg Craniosynostosis Syndrome: A Case Report and Systematic Review".

[This corrects the article DOI: 10.1155/2020/7353452.].

An Adult Loa loa Worm in the Upper Eyelid: An Atypical Presentation of Loiasis in the United States.

Purpose. To report a case of ocular involvement of Loa loa parasite. Observations. We present a rare case report of a Loiasis diagnosed in the United States from a patient presenting with subcutaneous migration of an adult worm within an eyelid who was found to have systemic disease with microfilaria in his blood. This is the second report in the United States and the eighth case in published literature worldwide. Conclusions and Importance. Due to the relatively mild disease course, Loiasis is relatively ignored in public health in low resource health districts. Understandably, the focus of public health in endemic areas must focus on basic health needs like malnutrition and diseases that entail a greater disease burden. As globalization has increased the amount of trade of physical goods, the effect of immigration also has implications for the spread of infectious disease. Medical practitioners in the United States should be aware of endemic diseases from foreign lands.

Eye, Ocular Adnexa, and Facial Manifestations of Tetrasomy 18p.

Tetrasomy 18p is often the result of an additional isochromosome for the short arm of chromosome 18. Although many organ systems are affected phenotypically, the ocular manifestations associated with tetrasomy 18p have not been well characterized in the literature. This case report presents the ocular and facial features associated with tetrasomy 18p in a 4-year-old Black girl, along with a review of clinical presentations previously reported in the literature. A systematic review of the literature in PubMed was conducted to summarize the reported eye, ocular adnexa, and distinctive facial features in individuals with confirmed tetrasomy 18p. Searching "Tetrasomy 18p" generated 65 article results, of which 28 articles had sufficient eye and facial descriptions. Including the patient in this report, 90 patients had confirmed tetrasomy 18p. The most common features noted in these 90 patients, with a roughly equal male-to-female ratio of impact (7:8), were as follows: microcephaly (57%), triangular facies (18%), anomalous palpebral fissures (31%), strabismus (48%), low-set ears (52%), hearing loss to some extent (16%), depressed or flat nasal bridge (18%), smooth philtrum (41%), thin upper lip (27%), and highly arched palate (21%). Additionally, many were noted to have feeding difficulties (28%), developmental delay (58%), and abnormal brain findings on imaging (20%). Muscle tone was abnormal in 23% of the patients. This report elucidates the reoccurring eye, ocular adnexa, and distinctive facial features associated with tetrasomy 18p. This knowledge may assist in timely diagnosis and encourage providers to use a multidisciplinary approach for the treatment of affected individuals. [J Pediatr Ophthalmol Strabismus. 2021;58(6):e44-e48.].