First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known worldwide, but evidence is accumulating that the disorder is substantially under-diagnosed. Clinical features include variable combinations of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems, failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder which may be first seen by many different specialists or generalists. Phenotypic breadth and variability present a major challenge to the diagnostician: some children with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical test, based on detecting abnormal ratios of different cardiolipin species, was first described in 2008. Key areas of differential diagnosis include metabolic and viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots. TAZ sequencing also allows female carrier detection and antenatal screening. Management of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are essential for minimising hospital attendances and allowing many more individuals with BTHS to live into adulthood.
Our cohort demonstrated clinical variability, but most had cardiomyopathy and diminished growth velocity, with a propensity toward neutropenia and low cholesterol. There was increased incidence of ventricular arrhythmia, predominantly in adolescents and young adults. Barth syndrome should be considered when boys present with cardiomyopathy, especially when associated with increased left ventricular trabeculations, neutropenia, skeletal muscle weakness, or family history indicating an X-linked pattern of inheritance.
Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed mutation analysis in 34 North American and 6 European (total 40) patients with Costello syndrome, and detected missense mutations in HRAS in 33 (82.5%) patients. All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases. In two patients, we found a mutation resulting in an alanine substitution in position 12 (G12A), and in one patient, we detected a novel mutation (G13C). Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete.
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