Holt-Oram Syndrome; A Case report

Holt-Oram syndrome is a rare genetic autosomal dominant disorder which affects the preaxial radial ray of the upper limbs and septation of the heart and/or cardiac conduction. The present article describes the clinical and radiological features of Holt–Oram syndrome in a Tanzanian patient. This case emphasises the importance of proper prenatal screening for congenital anomalies and counselling of the parents.   &nbsp

Tuberculous Meningitis Presenting with Stroke in an Immunocompetent Adolescent: A Case Report

Background: Tuberculous meningitis (TBM) is a severe infection of the central nervous system that has high mortality. The disease predominantly affects young children and those who are immuncompromised. Strokes have been reported in about one-third of children with tuberculous meningitis and are associated with poor clinical outcomes.Case report: A previously healthy 14-year-old girl living in Dar es Salam, Tanzania presented with one month history of weight loss associated with weakness, loss of appetite, apathy; without respiratory symptoms. Anti-TB therapy was started, based on radiological findings of the chest which showed multiple patchy centrilobular nodules with linear branching pattern bilaterally, mediastinum lymph node enlargement with punctate calcification. She then became aphasic and developed right-sided hemiparesis. Brain imaging showed infarction, hydrocephalus and meningeal enhancement. Diagnosis of tuberculous meningitis (TBM) with left sided ischaemic stroke was made and dexamethasone was added to her regimen. Treatment and rehabilitation was continued for 12 months with minimal improvement.Conclusion: Tuberculous meningitis can present with non-specific features and has grave outcomes. Stroke is an uncommon complication in older immunocompetent children and results in severe morbidity. A high index of suspicion is required in adolescents with neurological symptoms that can be confused with behavioural symptoms

Tuberculous Meningitis Presenting with Stroke in an Immunocompetent Adolescent: A Case Report

Background: Tuberculous meningitis (TBM) is a severe infection of the central nervous system that has high mortality. The disease predominantly affects young children and those who are immuncompromised. Strokes have been reported in about one-third of children with tuberculous meningitis and are associated with poor clinical outcomes. Case report: A previously healthy 14-year-old girl living in Dar es Salam, Tanzania presented with one month history of weight loss associated with weakness, loss of appetite, apathy; without respiratory symptoms. Anti-TB therapy was started, based on radiological findings of the chest which showed multiple patchy centrilobular nodules with linear branching pattern bilaterally, mediastinum lymph node enlargement with punctate calcification. She then became aphasic and developed right-sided hemiparesis. Brain imaging showed infarction, hydrocephalus and meningeal enhancement. Diagnosis of tuberculous meningitis (TBM) with left sided ischaemic stroke was made and dexamethasone was added to her regimen. Treatment and rehabilitation was continued for 12 months with minimal improvement. Conclusion: Tuberculous meningitis can present with non-specific features and has grave outcomes. Stroke is an uncommon complication in older immunocompetent children and results in severe morbidity. A high index of suspicion is required in adolescents with neurological symptoms that can be confused with behavioural symptoms

Novel likely pathogenic variant in NR5A1 gene in a Tanzanian child with 46,XY differences of sex development, inherited from the mosaic father

Pathogenic variants in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1), which encodes steroidogenic factor 1 (SF1), result in 46,XY and 46,XX differences of sex development (DSD). In 46,XY individuals with a pathogenic variant in the NR5A1 gene a variable phenotype ranging from mild to severe is seen, including adrenal failure, testis dysgenesis, androgen synthesis defects, hypospadias and anorchia with microphallus and infertility. We report the clinical, endocrinological and genetic characteristics of a patient with 46,XY DSD with a novel likely pathogenic missense variant in the NR5A1 gene. A retrospective evaluation of the medical history, physical examination, limited endocrinological laboratory analysis and genetic analysis with DSD gene panel testing was performed. A 1.5-month-old individual was referred with ambiguous genitalia. The karyotype was 46,XY. The endocrinological analyses were within normal male reference including a normal response of cortisol within an adrenocorticotropic hormone test. A novel heterozygous missense variant c.206G&gt;C p.(Arg69Pro) in the NR5A1 gene was detected. This variant was present in mosaic form (~20%) in his unaffected father. Because another missense variant at the same position and other missense variants involving the same highly conserved codon have been reported, we consider this NR5A1 variant in this 46,XY DSD patient as likely pathogenic in accordance with the ACMG/AMP 2015 guidelines causing ambiguous genitalia but no adrenal insufficiency. This variant was inherited from the apparently unaffected mosaic father, which might have implications for the recurrence risk in this family.Learning pointsThe importance of performing trio (patient and parents) sequencing is crucial in pointing out the origin of inheritance.In a 46,XY differences of sex development patient, a normal adrenal function does not rule out an NR5A1 mutation.With the support of a dedicated overseas institute partnership, we could solve this complex clinical case by molecular diagnosis in a resource-limited setting.</p

Leber\u27s congenital amaurosis with anterior keratoconus in Pakistani families is caused by the Trp278X mutation in the AIPL1 gene on 17p

Background: Leber\u27s congenital amaurosis (LCA) represents the earliest and severest form of retinal dystrophy leading to congenital blindness. A total of 20% of children attending blind schools have this disease. LCA has a multigenic basis and is proving central to our understanding of the development of the retina. We describe the clinical and molecular genetic features of four inbred pedigrees from neighbouring remote villages in northern Pakistan, in which some of the affected members have concurrent keratoconus.Methods: History-taking and physical and eye examinations were performed in the field. Venipuncture, DNA extraction, studies of linkage to known LCA genes, automated sequencing and polymorphism analyses for haplotype assessments were done.Results: We examined 12 affected and 15 unaffected family members. By history, there were an additional nine blind people in the four pedigrees. In each pedigree a consanguineous marriage was evident. We found a homozygous nonsense mutation in the AIPL1 gene, which replaces a tryptophan with a stop codon (Trp278X). The phenotype is severe and variable, despite the common molecular genetic etiology in each family. Affected patients had hand motion to no light perception vision and fundus findings ranging from maculopathy to diffuse pigmentary retinopathy. Three affected members had definite keratoconus, and two were suspects based on mild cone formation in the cornea of at least one eye.Interpretation: We have identified four Pakistani families with a severe form of LCA that is associated with severe keratoconus in some affected members. The molecular etiology in all four families is a homozygous nonsense mutation, Trp278X, in the photoreceptor-pineal gene AIPL1. To our knowledge, this is one of the first phenotype-genotype correlations of AIPL1-associated LCA