Co-occurring Usher syndrome Type 1 and Renal Failure.

PURPOSE: To describe a patient with a rare co-occurrence of Usher syndrome type 1C (USH1C) and renal disease, suspected to be secondary to Alport syndrome. METHOD: Case report and literature review of cases with Usher syndrome and renal failure. Clinical examination, color fundus photography, visual field tests, electroretinography and whole exome sequencing were used to diagnose and document the patient's clinical presentation. RESULTS: An 18-year-old female with known history of congenital hearing loss and chronic renal failure, presents with progressive night and peripheral visual impairment suspicious for an inherited retinal disease. Visual field testing, fundus exam and electroretinography findings supported the diagnosis of Usher syndrome. Whole exome sequencing (WES) identified a novel homozygous frameshift variant (c.238del) in USH1C. WES also identified a homozygous COL4A3 variant of unknown significance, which may be responsible for concomitant Alport syndrome. CONCLUSION: By presenting this rare case of co-occurring Usher syndrome Type 1 and renal failure, we highlight the importance of conducting further investigations that could reveal an additional underlying etiology when these entities are present.

De novo variants in DENND5B cause a neurodevelopmental disorder.

The Rab family of guanosine triphosphatases (GTPases) includes key regulators of intracellular transport and membrane trafficking targeting specific steps in exocytic, endocytic, and recycling pathways. DENND5B (Rab6-interacting Protein 1B-like protein, R6IP1B) is the longest isoform of DENND5, an evolutionarily conserved DENN domain-containing guanine nucleotide exchange factor (GEF) that is highly expressed in the brain. Through exome sequencing and international matchmaking platforms, we identified five de novo variants in DENND5B in a cohort of five unrelated individuals with neurodevelopmental phenotypes featuring cognitive impairment, dysmorphism, abnormal behavior, variable epilepsy, white matter abnormalities, and cortical gyration defects. We used biochemical assays and confocal microscopy to assess the impact of DENND5B variants on protein accumulation and distribution. Then, exploiting fluorescent lipid cargoes coupled to high-content imaging and analysis in living cells, we investigated whether DENND5B variants affected the dynamics of vesicle-mediated intracellular transport of specific cargoes. We further generated an in silico model to investigate the consequences of DENND5B variants on the DENND5B-RAB39A interaction. Biochemical analysis showed decreased protein levels of DENND5B mutants in various cell types. Functional investigation of DENND5B variants revealed defective intracellular vesicle trafficking, with significant impairment of lipid uptake and distribution. Although none of the variants affected the DENND5B-RAB39A interface, all were predicted to disrupt protein folding. Overall, our findings indicate that DENND5B variants perturb intracellular membrane trafficking pathways and cause a complex neurodevelopmental syndrome with variable epilepsy and white matter involvement.

Hereditary motor and sensory neuropathy type VIA with optic nerve pallor in two sisters with pathologic myopia: a case series and review.

PURPOSE: Hereditary Motor Sensory Neuropathy Type VIA with Optic Atrophy (HMSN6A) is a rare variant subtype of mitofusin 2 (MFN2) associated Charcot-Marie-Tooth disease, with ophthalmic manifestations largely limited to optic atrophy. We report a case series of two sisters with HMSN6A corresponding to known variants in the MFN2 gene. The proband's mother, maternal aunt, and maternal grandfather were also reportedly affected with the condition, although not examined at our institution. The clinical presentations of the proband and her sister are reviewed in detail. In addition, a comprehensive review of ophthalmic findings from prior reported cases of HMSN6A is provided. OBSERVATIONS: HMSN6A is a neurologic disorder characterized by a motor sensory axonal neuropathy and optic atrophy. A range of additional ophthalmic manifestations have been reported in the literature. We highlight the proband and her sister who demonstrate this phenotype but also manifested other ocular abnormalities from an early age. In addition to optic nerve pallor, both sisters had additional ophthalmic features of bilateral pathologic myopia, limited vision, nystagmus, and strabismus. CONCLUSIONS AND IMPORTANCE: This case series and review describe the ophthalmologic findings of HMSN6A and provides incentive to further investigate the correlation between molecular findings and the phenotype.

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.].

Ophthalmologic and facial abnormalities of Nicolaides-Baraitser syndrome.

BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS), first described in 1993, is a rare autosomal dominant disease caused by pathogenic variants in the SMARCA2 gene on chromosome 9p24.3. NCBRS typically presents with dysmorphic facial features, seizures, intellectual disability, and developmental delays. Abnormal findings of the eye and ocular adnexa associated with NCBRS have not been systematically evaluated and summarized in literature. This report presents the case of a 4-year-old male with NCBRS along with a systematic review of literature of the abnormal ophthalmologic and facial features of NCBRS cases. METHODS: A systematic review of literature of published cases of molecularly confirmed NCBRS was performed and the frequencies of eye, ocular adnexa, and facial abnormalities were calculated. RESULTS: Our patient's abnormal eye features include myopia, down slanting palpebral fissures, sagging inferior periorbital skin, hypertelorism, and long eyelashes. From the systemic review of literature, the most common abnormal eye and ocular adnexa features include prominent/long eyelashes, thick eyebrows, sagging periorbital skin, down slanting palpebral fissures, and ptosis. The most common facial dysmorphic features include thick/everted lower lip, coarse facial features, wide/large mouth, and thin upper lip. Dental abnormalities are also commonly reported. CONCLUSIONS: NCBRS frequently presents with well-defined ophthalmic and facial abnormalities. Prompt ophthalmologic evaluation following NCBRS diagnosis may be recommended to screen for several eye disorders. Surgical correction of ptosis may be indicated for NCBRS patients. This report may help further delineate the phenotype of this condition, which may allow for more rapid identification of those affected and provide incentive for additional studies.

Ophthalmic abnormalities in Wieacker-Wolff syndrome.

Wieacker-Wolff syndrome is an X-linked condition caused by variants of the ZC4H2 gene that results in in utero muscular weakness that manifests clinically as arthrogryposis congenita as well as facial and bulbar weakness. We report the case of a young girl with a de novo pathogenic deletion in the ZC4H2 gene and clinical features consistent with Wieacker-Wolff syndrome. Common eye manifestations of the syndrome reported in the literature include ptosis, strabismus, and oculomotor apraxia. The overall incidence of these manifestations is 56%.

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.

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.].

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

A Chromosomal Deletion and New Frameshift Mutation Cause ARSACS in an African-American.

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare, progressive, neurodegenerative disease characterized by ataxia, spasticity and polyneuropathy. First described in the French-Canadian population of Quebec in 1978, ARSACS has since been identified in multiple patients worldwide. In this clinical case report, we describe the evaluation of an 11-years-old African-American male who presented to neuromuscular clinic for assessment of a gait abnormality. He had a history of gross motor delay since early childhood, frequent falls and a below average IQ. Chromosomal microarray revealed a 1.422 megabase loss in the 13q12.12 region, which includes the SACS gene. Next Generation Sequencing then showed a novel, predicted to be pathogenic missense mutation (c.11824dup) of this gene. His clinical presentation and neurological imaging further confirmed the diagnosis of ARSACS. To our knowledge, this is the first reported case of this disease in the African-American population of the United States. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide.

A Rare Case of Unilateral Morning Glory Disc Anomaly in a Patient with Turner Syndrome: Report and Review of Posterior Segment Associations.

Turner syndrome is a common sex chromosome disorder affecting females. The disorder is caused by a partial loss, complete absence, or structural abnormality of one X chromosome. The clinical presentation is broad and ranges from the classic phenotype to minimal clinical manifestations. Ocular abnormalities associated with the syndrome are common. Reports describing abnormal eye features in individuals with Turner syndrome generally involve refractive errors (myopia or hyperopia), strabismus, and external or anterior segment abnormalities including hypertelorism, epicanthal folds, and ptosis. Posterior ocular segment anomalies involving the optic nerve and retina in Turner syndrome have been rarely reported. We report a rare presentation of an 11-year-old female with Turner syndrome and unilateral morning glory disc anomaly.

Multiloculated Cavitary Primary Pulmonary Hodgkin Lymphoma: Case Series.

Primary pulmonary Hodgkin lymphoma (PPHL) is very rare and typically involves the superior portion of the lung. Pulmonary involvement is observed in 15-40% of Hodgkin lymphoma patients. Three such patients who presented with an unusual form of PPHL in radiological studies, i.e., multiloculated cavitary lesions, were admitted to our hospital. These lesions represent a new pathological and radiological feature of PPHL.

Hodgkin's Lymphoma as a Multiloculated Lung Cavity Lesion.

BACKGROUND: Pulmonary manifestation of Hodgkin's lymphoma is common, and recently, single and/or multiple lung cavities with air-fluid levels has been reported as a primary manifestation of Hodgkin's lymphoma. However, the unusual presentation of the lung cavity itself has not been previously reported for Hodgkin's lymphoma, especially as the first presentation of the disease. CASE PRESENTATION: We report a 16-year-old male who presented to the emergency department with chief complaints of fever, unintentional 10-kilogram weight loss, a productive cough and pulmonary cavity for investigation. The patient's CT scan indicated multiloculated cavity lesions in the middle lobe with an air-fluid level and multiple enlarged mediastinal lymph nodes, which have not been previously reported as a primary presentation for Hodgkin's lymphoma or in the histopathology of the nodular sclerosing type of classical Hodgkin's lymphoma. CONCLUSION: Pulmonary manifestation of Hodgkin's lymphoma has already been reported and must be part of the differential diagnosis of lung cavity lesions, even if the likelihood is low based on previous reports, especially in younger individuals. Multiloculated lung cavities can be the first presentation of Hodgkin's lymphoma.

Morphometric evaluation of the foramen magnum for sex determination: A study from Saudi Arabia.

The present study provides a database of various morphometric dimensions of the foramen magnum region in the Saudi population. The objective of this study was to evaluate various measurements of the foramen magnum region for sex determination in the Saudi population by using computed tomography (CT) images. The various radiological measurements of the foramen magnum region were measured in a total of 200 adult subjects of Saudi origin including 100 males and 100 females. Sexual dimorphism was observed in five parameters related to the foramen magnum, namely length of the right occipital condyle (LROC), length of the left occipital condyle (LLOC), width of the foramen magnum (WFM), area of the foramen magnum (AFM) and length of the foramen magnum (LFM). The accuracy to discriminate sex ranged from 65.5% to 62.5% when LROC, LLOC, WFM, AFM, and LFM were considered as individual parameters. When multiple parameters were combined to discriminate sex, the highest accuracy of 71% was achieved.

Uterine and Tubal Abnormalities in Infertile Saudi Arabian Women: A Teaching Hospital Experience.

BACKGROUND AND OBJECTIVE: Hysterosalpingography (HSG) is commonly used in the evaluation of the subfertile and infertile women. This study was undertaken to assimilate the findings observed during HSG in Saudi Arabian infertile patients and to find the most common pathology identified by the HSG. PATIENTS AND METHODS: A retrospective analysis was conducted of subfertile and infertile patients who had undergone HSG between June 2007 and May 2012. Patients' demographic data were collected from the medical records of the King Fahd Hospital of the University, Al Khobar, Saudi Arabia. The data included age, years of marriage, menstrual history either regular or irregular, primary/secondary infertility, hormonal profile, previous infection or pelvic surgery, and diagnostic laparoscopy. Radiographic reports of HSG were collected from the IPAC system and analyzed for fimbrial findings, tubal patency, and cervical and uterine cavitary pathology. The data were entered in the database and analyzed using a t-test to compare means between the age, type of infertility, different pathologies and for all the parameters assessed. All tests were performed using Statistical Package for the Social Sciences, version 14.0, Chicago, Illinois, USA. A P < 0.05 was considered statistically significant with a confidence interval of 95%. RESULTS: Data from the medical records of 117 patients with an average age of 32.59 ± 5.48 years were analyzed. Of this total, 48 (41%) had been diagnosed as having primary infertility. In 95 (81.2%) patients, there was an abnormality in the fallopian tubes and in 27 (23%) patients, there was an abnormality in the uterus. Patients with primary infertility were significantly younger (29.7 ± 5.6 vs. 34.58 ± 4.75; P < 0.001), and tubal and uterine pathology was more common (P < 0.08 and 0.01). CONCLUSIONS: Our review indicates that the most common pathology found through HSG in women presenting with infertility is tubal blockage.