Identification of Codon 146 KRAS Variants in Isolated Epidermal Nevus and Multiple Lesions in Oculoectodermal Syndrome: Confirmation of the Phenotypic Continuum of Mosaic RASopathies.

Mosaic RASopathies are a molecularly heterogeneous group of (neuro)cutaneous syndromes with high phenotypical variability. Postzygotic variants in KRAS have been described in oculoectodermal syndrome (OES), encephalocraniocutaneous lipomatosis (ECCL) and epidermal nevus syndrome (ENS). This study confirms the continuum of mosaic neurocutaneous RASopathies showing codon 146 KRAS variants in an individual with OES and, for the first time, in an individual with (isolated) epidermal nevus. The presence of a nevus psiloliparus in individuals with OES indicates that this finding is not specific for ECCL and highlights the phenotypical overlap between ECCL and OES. The presence of the somatic KRAS variant in the nevus psiloliparus resolves the underlying molecular etiology of this fatty-tissue nevus. In addition, this finding refutes the theory of non-allelic twin-spotting as an underlying hypothesis to explain the concurrent presence of two different mosaicisms in one individual. The identification of codon 146 KRAS variants in isolated epidermal nevus introduces a new hot spot for this condition, which is useful for increasing molecular genetic testing using targeted gene sequencing panels.

DETAILED CLINICAL PHENOTYPING OF OXALATE MACULOPATHY IN PRIMARY HYPEROXALURIA TYPE 1 AND REVIEW OF THE LITERATURE.

PURPOSE: To describe the structural and functional characteristics of oxalate retinopathy. METHODS: Five patients with molecularly confirmed primary hyperoxaluria (PH) Type 1 underwent multimodal retinal imaging (spectral-domain optical coherence tomography, white light, and HRA multispectral imaging) and functional testing, including color vision testing, Goldmann perimetry, and International Society for Clinical Electrophysiology of Vision standard electrophysiological testing. RESULTS: Four distinct retinal phenotypes are presented. One patient with a c.[33dupC]; c.[731T>C] mutation showed bilateral perifoveal retinal pigment epithelium hyperplasia. The fundus in the four other patients, all of whom share an identical homozygous c.[33dupC] mutation, ranged from normal to bilateral widespread distribution of retinal crystals and confluent macular retinal pigment epithelium hyperplasia with subfoveal fibrosis. All patients who had developed end-stage renal disease showed some sign of retinopathy, more severe with earlier onset. CONCLUSION: Retinopathy in PH Type 1 shows considerable interindividual variation. No correlation between genotype and retinal phenotype was detected. Oxalate crystals at the level of the retinal pigment epithelium seem to be irreversible. A proposed clinical grading system of oxalate maculopathy, based on a literature review, may provide clinicians with a tool to better predict visual function and prognosis.

Severe congenital neutropenia with neurological impairment due to a homozygous VPS45 p.E238K mutation: A case report suggesting a genotype-phenotype correlation.

VPS45 mutations cause severe congenital neutropenia (SCN). We report on a girl with SCN and neurological impairment harboring a homozygous p.E238K mutation in VPS45 (vacuolar sorting protein 45). She successfully underwent hematopoietic stem cell transplantation. Our findings delineate the phenotype and indicate a possible genotype-phenotype correlation for neurological involvement.

Congenital fixed dilated pupils due to ACTA2- multisystemic smooth muscle dysfunction syndrome.

Congenital fixed dilated pupils (congenital mydriasis) is characterized by hypoplasia or aplasia of the iris muscles, with absence of iris between the collarette and pupillary border, creating a scalloped pupillary margin. This condition has been reported in a multisystemic smooth muscle cell dysfunction syndrome, combined with congenital patent ductus arteriosus, cerebrovascular disease (Moya-moya-like), coronary artery disease, thoracic aorta aneurysm, and dysfunction of smooth muscle cells in organs throughout the body. All affected individuals carry a p.R179H heterozygous mutation in the ACTA2 gene. We add to the ophthalmologic involvement with 3 more patients. Congenital fixed dilated pupils is a rare condition and should alert ophthalmologists to the possibility of the coexistence of systemic life-threatening disorders.

Defining a therapeutic range for adalimumab serum concentrations in the management of pediatric noninfectious uveitis, a step towards personalized treatment.

BACKGROUND: Adalimumab is currently considered the most efficacious anti-TNFα agent for childhood noninfectious uveitis (NIU). The objective of this study was to define a therapeutic range for adalimumab trough levels in the treatment of childhood NIU. METHODS: A retrospective, observational, pilot study of 36 children with NIU aged < 18 years, treated with adalimumab. Serum adalimumab through levels and adalimumab anti-drug antibodies (ADA) were analysed at least 24 weeks after start adalimumab. RESULTS: Adalimumab trough levels were significantly higher in complete responders 11.8 µg/mL (range 6.9-33.0) compared to partial or non-responders 9,2 µg/mL (range 0-13.6) (p = 0,004). Receiver-operator characteristics analyses with an area under the curve of 0,749 (95% CI, 0,561-0,937) defined 9.6 µg/mL as the lower margin for the therapeutic range. This cut-off corresponds with a sensitivity of 88% and a specificity of 56% (positive predictive value, 85%; negative predictive value, 62.5%). A concentration effect curve defined 13 µg/mL as the upper margin. Approximately one-third (30.5%) of patients had an adalimumab trough concentration exceeding 13 µg/mL. Free ADA were observed in 2 patients (5.5%). CONCLUSIONS: A therapeutic range of adalimumab trough levels of 9.6 to 13 µg/mL, which corresponds with an optimal clinical effect, was identified. Therapeutic drug monitoring may guide the optimisation of treatment efficacy in children with NIU in the treat-to-target era.

Paediatric cataract surgery with 27G vitrectomy instrumentation: the Ghent University Hospital Experience.

Objective: To describe a cohort of paediatric patients who underwent unilateral or bilateral lens extractions at Ghent University hospital using the Dutch Ophthalmic Research Center (D.O.R.C.) ultra-short 27G vitrectomy system. Methods: Retrospective analysis of the medical and surgical records of all children that underwent lens extraction between September 2016 and September 2020 using the D.O.R.C. ultra-short 27G vitrectomy system. Results: Seventy-two eyes of 52 patients were included. The most important aetiologies in this study were of secondary (25.5%), developmental (13.7%), or genetic (13.7%) nature. No definitive cause could be established in more than a quarter of cases (27.5%) despite extensive work-up, them being deemed idiopathic. The remainder of cases (19.6%) was not assigned a final aetiologic designation at the time of the study due to contradicting or missing diagnostic data. This study could not identify any cataract cases related to infection or trauma. Surgical complications rate was 61.1% of which posterior capsule opacification was the most frequent with a rate of 25%. A significant short-term postoperative best-corrected visual acuity gain (≤ -0.2 LogMAR) was observed in 60.5% of eyes for which usable acuity data were available (n = 38). Conclusion: Many different instruments and techniques have been described and used in the context of paediatric lens extractions, each with its advantages and disadvantages. This study illustrates that an ultra-short 27G vitrectomy system can be used to perform paediatric lens extractions with good surgical outcomes. Further studies and comparative trials are needed to ascertain this further.

Extraocular muscle hypoplasia associated with Axenfeld-Rieger syndrome.

We describe a four-year-old girl with bilateral severe iris hypoplasia and secondary ocular hypertension. Genetic testing revealed a de novo deletion in the FOXC1 gene, establishing the diagnosis of Axenfeld-Rieger syndrome (ARS). The girl developed a gradually increasing exotropia, up to 95 prism diopters by the age of 3 years wherefore strabismus surgery was performed. Intra-operatively, only very rudimentary developed medial and lateral rectus muscles were found. This is the first observation of pronounced hypoplasia of both medial and lateral rectus muscles associated with ARS.

Identification of 34 novel and 56 known FOXL2 mutations in patients with Blepharophimosis syndrome.

Blepharophimosis syndrome (BPES) is caused by loss-of-function mutations in the single-exon forkhead transcription factor gene FOXL2 and by genomic rearrangements of the FOXL2 locus. Here, we focus on 92 new intragenic FOXL2 mutations, 34 of which are novel. Specifically, we found 10 nonsense mutations (11%), 13 missense mutations (14%), 40 deletions or insertions leading to a frameshift (43%), and 29 in-frame changes (32%), of which 28 (30%) lead to a polyalanine expansion. This study confirms the existence of two previously described mutational hotspots. Moreover, we gained novel insights in genotype-phenotype correlations, emphasizing the need to interpret genotype-phenotype correlations individually and always in the context of further clinical observations.

Novel FRMD7 Mutations and Genomic Rearrangement Expand the Molecular Pathogenesis of X-Linked Idiopathic Infantile Nystagmus.

PURPOSE: Idiopathic infantile nystagmus (IIN; OMIM 31700) with X-linked inheritance is one of the most common forms of infantile nystagmus. Up to date, three X-linked loci have been identified, Xp11.4-p11.3 (calcium/calmodulin-dependent serine protein kinase [CASK]), Xp22 (GPR143), and Xq26-q27 (FRMD7), respectively. Here, we investigated the role of mutations and copy number variations (CNV) of FRMD7 and GPR143 in the molecular pathogenesis of IIN in 49 unrelated Belgian probands. METHODS: We set up a comprehensive molecular genetic workflow based on Sanger sequencing, targeted next generation sequencing (NGS) and CNV analysis using multiplex ligation-dependent probe amplification (MLPA) for FRMD7 (NM_194277.2) and GPR143 (NM_000273.2). RESULTS: In 11/49 probands, nine unique FRMD7 changes were found, five of which are novel: frameshift mutation c.2036del, missense mutations c.801C>A and c.875T>C, splice-site mutation c.497+5G>A, and one genomic rearrangement (1.29 Mb deletion) in a syndromic case. Additionally, four known mutations were found: c.70G>A, c.886G>C, c.910C>T, and c.660del. The latter was found in three independent families. In silico predictions and segregation testing of the novel mutations support their pathogenic effect. No GPR143 mutations or CNVs were found in the remainder of the probands (38/49). CONCLUSIONS: Overall, genetic defects of FRMD7 were found in 11/49 (22.4%) probands, including the first reported genomic rearrangement of FRMD7 in IIN, expanding its mutational spectrum. Finally, we generate a discovery cohort of IIN patients potentially harboring either hidden a variation of FRMD7 or mutations in genes at known or novel loci sustaining the genetic heterogeneity of IIN.

Triad of torticollis, photophobia and epiphora in a child with a posterior fossa tumor.

A 7-month-old Caucasian girl presented with an acquired, spasmodic torticollis to the right side with the head tilted downwards, photophobia and epiphora. Diagnostic work-out revealed a posterior fossa pilocytic astrocytoma. The symptoms improved after surgical resection. There is evidence of internuclear connections between cranial nerves II, V and VII acting as important mechanisms in this triad (Okamoto et al. 2010).