Autosomal Recessive NOTCH3-Related Leukodystrophy in Two Siblings and Review of the Literature.

BACKGROUND: NOTCH3, a large type I transmembrane receptor expressed on arterial smooth muscle cells and capillary pericytes, features a diverse extracellular domain with 34 epidermal growth factor-like repeats. It exhibits distinct phenotypes due to variant zygosity and type; missense mutations cause CADASIL with cerebral vasculopathy, while null mutations lead to severe congenital manifestations. METHODS: This report describes two cases with homozygous loss- of- function variants in NOTCH3 along with their clinical manifestations. RESULTS: These patients presented with a severe congenital phenotype, including eye misalignment, visual impairment, epilepsy, global developmental delay, and subsequent development of pyramidal signs. Biallelic nonsense variants were discovered in both the cases (NM_000435.3:c.2203 C > T (p. [Arg735Ter]). Livedo reticularis was not reported in our cases, although it was present in previously reported patients. Autosomal recessive NOTCH3-related leukodystrophy is usually caused by biallelic null mutations in NOTCH3. CONCLUSIONS: The phenotype of biallelic null variants is associated with a more severe phenotype than the dominantly inherited form of the disease.

Unilateral Proptosis: A Rare Presenting Sign of Acute Myeloid Leukemia.

Unilateral proptosis is a rare initial presenting sign of acute myeloid leukemia (AML). We report a case of unilateral proptosis in a six-year-old girl as the initial manifestation of AML. The cancer link was initially missed and the case was investigated as one of hyperthyroidism. Peripheral blood smear and bone marrow aspirate evaluation showed signs diagnostic of AML. Computed tomography scan of orbits showed infiltrative process in the right orbit, right maxillary, and right ethmoidal sinuses. Unilateral proptosis as an extramedullary first presenting feature of AML is very rare; however, it should always be considered in the differential diagnosis of proptosis in pediatric age group.

Further phenotypic delineation of Alazami syndrome.

Alazami syndrome (AS) is an autosomal recessive condition characterized by the cardinal features of severe growth restriction, moderate to severe intellectual disability, and distinctive facial features. Biallelic pathogenic variants of the LARP7, encoding a chaperone of 7SK noncoding RNA, is implicated in this disease. There are <35 reported cases in the literature. All reported cases share the same three cardinal features of the syndrome. Herein, we report on 12 patients with a confirmed diagnosis of AS from eight unrelated families. The cohort shares the same key feature of the syndrome. Moreover, we report additional phenotypic features, including genito-renal anomalies, ophthalmological abnormalities, and congenital heart disease. Whole-exome sequencing was used in all reported cases, implicating a clinical under-recognition of the syndrome. This report further expands the clinical and molecular characteristics of Alazami syndrome.

THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.

Covalent tRNA modifications play multi-faceted roles in tRNA stability, folding, and recognition, as well as the rate and fidelity of translation, and other cellular processes such as growth, development, and stress responses. Mutations in genes that are known to regulate tRNA modifications lead to a wide array of phenotypes and diseases including numerous cognitive and neurodevelopmental disorders, highlighting the critical role of tRNA modification in human disease. One such gene, THUMPD1, is involved in regulating tRNA N4-acetylcytidine modification (ac4C), and recently was proposed as a candidate gene for autosomal-recessive intellectual disability. Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1. Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities. We demonstrate that the bi-allelic variants identified cause loss of function of THUMPD1 and that this defect results in a loss of ac4C modification in small RNAs, and of individually purified tRNA-Ser-CGA. We further corroborate this effect by showing a loss of tRNA acetylation in two CRISPR-Cas9-generated THUMPD1 KO cell lines. In addition, we also show the resultant amino acid substitution that occurs in a missense THUMPD1 allele identified in an individual with compound heterozygous variants results in a marked decrease in THUMPD1 stability and RNA-binding capacity. Taken together, these results suggest that the lack of tRNA acetylation due to THUMPD1 loss of function results in a syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphism.

Mucolipidosis Type IV in Omani Families with a Novel MCOLN1 Mutation: Search for Evidence of Founder Effect.

Mucolipidosis Type IV (MLIV) is caused by a deficiency of the mucolipin cation channel encoded by Mucolipin TRP Cation Channel 1 gene (MCOLN1). It is a slowly progressive neurodevelopmental and neurodegenerative disorder causing severe psychomotor developmental delay and progressive visual impairment, which is often misdiagnosed as cerebral palsy. We describe six patients with MLIV from two Omani families with a novel c.237+5G>A mutation in the MCOLN1 gene predicted to affect mRNA splicing. Mutation screening with a high-resolution melting (HRM) assay in a large population sample did not detect this mutation in control subjects. This report highlights the importance of considering MLIV in the differential diagnosis of patients in a pediatric age group with cerebral palsy-like presentation. Although the same rare mutation was seen in two apparently unrelated families, this was not seen in the sample screened from the general population. The HRM assay provides a cost-effective assay for population screening for the c.237+5G>A mutation.

Accommodative esotropia: An outcome analysis from a tertiary center in Oman.

AIM: The aim of this study is to determine the outcome of accommodative esotropia (ET) and influencing factors in young Omani children. SUBJECTS AND METHODS: In this retrospective cohort, children diagnosed with accommodative ET who had followed up in a tertiary hospital from 2006 to 2011 were identified. Parameters studied included cycloplegic refraction and its change with time, ocular alignment, binocularity, visual acuity (VA), amblyopia, and requirement for surgery. RESULTS: A total of 51 patients were identified. Twenty-four patients were diagnosed with fully accommodative ET (FAET) and 27 with partially accommodative ET (PAET). The mean (± standard deviation [SD]) age of onset and reporting were 2.6 (±1.58) and 3.2 (±1.84) years in the two groups, respectively. The mean (SD) cycloplegic refraction at presentation was 4.50 (±1.66) in the FAET group and 3.65 (±1.67) in the PAET group. Anisometropia was present in 28% of patients. The mean follow-up period was 4.9 years. The following were detected in the final visit. A reduction in amblyopia from 43% to 6% of patients, binocularity in 75% of patients, and a mean increase of 0.64 (±1.3) D in cycloplegic refraction from the first visit (P = 0.005). The mean angle of deviation at near and distance was 29.86 (±15.21) and 17.80 (±10.14) prism diopters, respectively, in FAET patients and 30.15 (±14.83) and 29.53 (±15.53), respectively, in PAET patients. Thirty-seven percent of the PAET patients underwent surgery within 5 years from diagnosis. All participants in this cohort continued to wear glasses in the last follow-up visit. CONCLUSION: Most children with refractive accommodative ET have an excellent outcome in terms of VA and binocular vision. The PAET group was characterized by delayed reporting, the presence of anisometropia, and lower hypermetropia. Further study is required to determine the possibility of weaning glasses in FAET patients.

Secondary intracranial hypertension in aplastic anemia: A case report and review of current concepts.

Intracranial hypertension (IH) when detected mandates prompt and appropriate therapy to avoid permanent visual impairment. We report a 7-year-old boy who presented to the emergency services with purpuric rashes and bruises. Peripheral blood smear and bone marrow aspiration confirmed the diagnosis of aplastic anemia. During admission, the child developed headache, nausea, vomiting, and diplopia. Ophthalmic examination revealed intermittent esotropia and bilateral papilledema. The findings on neuroimaging and lumbar puncture led to the diagnosis of secondary IH (SIH). The intracranial pressure normalized on treatment with oral acetazolamide, oral furosemide, and intravenous dexamethasone.

Chronic myelogenous leukemia in a child following treatment for bilateral retinoblastoma.

A 3-year-old child was incidentally found to have chronic myelogenous leukemia (CML) during an admission for a routine ophthalmic examination under anesthesia. The child had received systemic chemotherapy and focal treatment for Groups C and D retinoblastoma in the right and left eye, respectively, when she was 7 months old. CML was treated with dasatinib, and the child attained a major molecular response. The child is now 3 years after treatment of CML, and the retinoblastoma remains inactive. CML following treatment of retinoblastoma is a rare occurrence. Long term and close monitoring of retinoblastoma patients who received systemic chemotherapy using serial blood tests is essential.

Ophthalmic findings as clues for early diagnosis of Vici syndrome in a neonate.

AIM: To report the earliest diagnosis of Vici syndrome in a three-week-old Omani girl. METHODS: A three-week-old baby girl with blond hair and agenesis of the corpus callosum was born to consanguineous parents. An older sibling with similar findings had died at the age of six months with recurrent seizures and aspiration pneumonia without a diagnosis of the underlying systemic condition. After a standard ophthalmic and comprehensive systemic evaluation, full sequencing of the EPG5 gene was carried out. RESULTS: The findings of bilateral anterior polar cataracts and oculocutaneous albinism in the child with agenesis of corpus callosum raised a suspicion of Vici syndrome. Immunology, neurology, cardiology, and genetic consultations were requested and revealed the presence of immunodeficiency, psychomotor retardation, and hypertrophic cardiomyopathy. Full sequencing of the EPG5 gene led to the detection of a homozygous c.6084 G > A (Trp2028Ter) mutation, confirming the diagnosis of Vici syndrome. Parental heterozygosity was confirmed. On follow-up, progressive microcephaly, failure to thrive, and significant developmental delay were noted, and a clinical decision not to resuscitate was made at the age of 22 months. CONCLUSIONS: We report the earliest diagnosis of Vici syndrome in the literature. Ophthalmic findings are a cardinal feature of this condition. The diagnosis should be considered in infants with hallmark features of oculocutaneous albinism, cataracts, and agenesis of the corpus callosum. Vici syndrome has a very poor prognosis due to progressive neuroregression superimposed on the neurodevelopmental anomaly.

Congenital Eyelid Anomalies: What General Physicians Need To Know.

The eyelids are important structures that maintain the health of the ocular surface and have an important role in facial esthetics. Any interruption in eyelid development can lead to congenital eyelid deformities. Eyelid abnormalities in children may present at birth due to abnormal embryogenesis (congenital) or may occur at a later stage as the child matures (developmental). These abnormalities, in general, can be classified into three different categories depending on the location: malformation of the margins, malformation of the folds, and malformation of the position. Congenital and developmental eyelid abnormalities are among the most challenging problems encountered by ophthalmic reconstructive surgeons. Additional considerations include social factors regarding the patient's self-awareness of their deformities and associated medical issues, which often coexist and maybe multisystem in nature. This article briefly reviews eyelid embryology, the most common congenital eyelid anomalies, and the management options available to address these conditions.

Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects.

Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic-intestinal and retinal-disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

Development and validation of an instrument to measure physician awareness of bioethics and medical law in Oman.

BACKGROUND: A different ethos with respect to the perception of medical ethics prevails in societies in transition such as those in the Arabian Peninsula, which makes it difficult to apply international principles of bioethics in medical practice. This study aimed to develop and psychometrically test an instrument that measures physicians' awareness of bioethics and medical law and their attitudes towards the practice of medical ethics. Additionally, it examined physician correlates influencing the awareness of bioethics. METHODS: Following a rigorous review of relevant literature by a panel of experts, a 13-item instrument, the Omani physicians' bioethics and medical law awareness (OBMLA) questionnaire was developed with the aim of assessing physicians' awareness of bioethics and medical law. The study tool's construct validity and internal consistency reliability were examined by exploratory factor analysis (EFA) and Cronbach's alpha. In a cross-sectional study, the questionnaire was distributed among a random sample of 200 physicians at a tertiary hospital in Muscat, Oman. Participant characteristics that may influence awareness of bioethics and medical law were explored. RESULTS: The EFA of the OBMLA questionnaire resulted in three well-loading factors: (1) Physicians' bioethics practice subscale (2) incentive related bioethics subscale and (3) medical law awareness subscale. Internal consistency reliability ranged between Cronbach's α: 0.73-0.8. Of the total 200 participants, 52% reported that teaching medical ethics during medical school was inadequate. The overall mean (standard deviation, SD) of the bioethics awareness score and Omani medical law awareness were 27.6 (3.5) and 10.1 (2.1) respectively. The majority of physicians (73%) reported that they frequently encountered ethical dilemmas in their practice and 24.5% endorsed the view that unethical decisions tended to occur in their practice. CONCLUSION: The study provides an insight into the practice of bioethics, and the awareness of bioethics and medical law among physicians in a teaching hospital in Oman. The OBMLA questionnaire appears to be a valid and reliable tool to assess a physician's awareness of bioethics and medical law. In this preliminary study, it appears that participants have suboptimal scores on the indices which measure practice and awareness of bioethics and medical law.

CNP deficiency causes severe hypomyelinating leukodystrophy in humans.

Myelin pathologies are an important cause of multifactorial, e.g., multiple sclerosis, and Mendelian, e.g., leukodystrophy, neurological disorders. CNP encodes a major component of myelin and its CNS expression is exclusive to myelin-forming oligodendrocytes. Deficiency of CNP in mouse causes a lethal white matter neurodegenerative phenotype. However, a corresponding human phenotype has not been described to date. Here, we describe a multiplex consanguineous family from Oman in which multiple affected members display a remarkably consistent phenotype of neuroregression with profound brain white matter loss. A novel homozygous missense variant in CNP was identified by combined autozygome/exome analysis. Immunoblot analysis suggests that this is a null allele in patient fibroblasts, which display abnormal F-actin organization. Our results suggest the establishment of a novel CNP-related hypomyelinating leukodystrophy in humans.

Microphthalmos-anophthalmos-coloboma (MAC) spectrum in two brothers with Renpenning syndrome due to a truncating mutation in the polyglutamine tract binding protein 1 (PQBP1) gene.

Background: Patients with intellectual disability syndromes frequently have coexisting abnormalities of ocular structures and the visual pathway system. The microphthalmos, anophthalmos, and coloboma (MAC) spectrum represent structural developmental eye defects that occur as part of a syndrome in one-third of cases. Ophthalmic examination may provide important diagnostic clues in identifying these syndromes.Purpose: To provide a detailed and comprehensive description of the microphthalmos, anophthalmos, and coloboma (MAC) spectrum in two brothers with intellectual disability and dysmorphism.Methods: The two brothers underwent a detailed ophthalmic and systemic evaluation. A family pedigree was obtained and exome sequencing was performed in the proband.Results: The two brothers aged 4 and 7 years had intellectual disability, microcephaly, short stature, and characteristic dysmorphic features. Ophthalmic evaluation revealed the presence of the MAC spectrum in both boys. Genetic testing led to the detection of an X-linked hemizygous truncating mutation in the nuclear polyglutamine-binding protein 1 (PQBP1) gene confirming the diagnosis of X-linked recessive Renpenning syndrome.Conclusion: The presence of X-linked intellectual disability and characteristic dysmorphism, in a patient with the MAC spectrum should raise the suspicion of Renpenning syndrome. PQBP1 mutation testing is confirmatory. A comprehensive systemic evaluation is mandatory in all patients with the MAC spectrum and intellectual disability.

An update of ophthalmic management in craniosynostosis.

Craniosynostosis has a varied clinical spectrum, ranging from isolated single suture involvement to multisutural fusions. Syndromic and nonsyndromic patients require orchestrated and multidisciplinary care from birth to adulthood. Advances in our understanding of craniosynostosis over the last quarter-century have resulted in more systematic management of the problems associated with the syndromic and nonsyndromic forms of this condition. This review provides an update on the genetic basis of, management of strabismus and oculoplastic manifestations in, and visual surveillance of patients with craniosynostosis.

Normal electro-oculography in a young Omani male with genetically confirmed best disease complicated by choroidal neovascularization.

Best vitelliform macular dystrophy (VMD) is an autosomal dominant macular dystrophy caused by heterozygous mutations in the bestrophin1 gene. Patients with this condition typically have an abnormal electrooculogram. We report a case of a 16-year-old male who presented with gradual progressive vision loss in the right eye. Ophthalmic assessment included funduscopy, optical coherence tomography (OCT), fluorescein angiography, electro-oculography, electroretinography, and genetic testing. Visual acuity was 20/500 and 20/20 in the right and left eyes, respectively. Ophthalmoscopy revealed round yellow lesions in both foveae similar to what is typically seen in Best disease. A subretinal hemorrhage surrounding the right foveal lesion was also noted. OCT demonstrated an elevated neurosensory retina with a subretinal lesion in the right macula. Fluorescein angiography of the right eye confirmed the presence of choroidal neovascularization. Genetic analysis of VMD2/BEST1 sequences confirmed the diagnosis of Best disease. However, contrary to what was expected, the patient's electro-oculography was normal. The findings of this case support a small number of previous reports demonstrating cases of Best disease with normal electro-oculography. While an abnormal electro-oculography along with the typical features of Best disease confirms the diagnosis, a normal result may not exclude the diagnosis. Genetic testing is probably the most important test for establishing the diagnosis of Best disease.

Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.

Ligneous conjunctivitis is a rare form of chronic recurrent membranous conjunctivitis with reduced plasminogen activity. It is characterized by the formation of characteristic firm ("woody") membranes on the tarsal conjunctiva. Similar lesions may occur on other mucous membranes. When treated with local excision, ligneous conjunctivitis is invariably associated with recurrences. Various therapeutic modalities, including topical heparin, cyclosporine, fresh frozen plasma (FFP), plasminogen, and amniotic membrane transplantation have been reported to reduce postoperative recurrences. We present 2 cases of recurrent ligneous conjunctivitis in children successfully managed with surgical excision under cover of FFP transfusion, amniotic membrane grafting, and combined with concomitant postoperative administration of topical heparin, steroids.