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We report a young woman with dilated cardiomyopathy, severe visual dysfunction, and short stature secondary to a previously unrecognised skeletal dysplasia. Her mother and sister died before we met the proband; both had had a sudden cardiac death and both also had impaired vision and we include the information gleaned from their hospital records.
The proband's mother had attended a school for the partially sighted and was of normal intelligence. Her visual acuities as an adult were 6/60 in her right eye and 3/60 in her left eye. Unfortunately, there is no information regarding the appearance of her optic discs or retinae. She was of average build, with an adult height of 163 cm (50th centile). There was no clinical indication for skeletal radiographs to be taken. She had two pregnancies, leading to the proband and her sister who are described below. A heart murmur noted during childhood had persisted into adult life and an ECG showed frequent ectopic beats. She died suddenly and unexpectedly aged 30, while sitting in a motor vehicle. There was no history of prodromal symptoms or previous episodes of syncope or presyncope. Necropsy showed slight hypertrophy of both ventricles with a congested myocardium. The cardiac histology was consistent with a diagnosis of dilated cardiomyopathy. The proband's father has not been examined by us but has no history of visual, cardiac, or skeletal problems.
The proband's sister's visual acuities were 4/60 in the right eye and 6/36 in her left eye at 6 years of age. She had nystagmus and a high myopic refractive error. Examination under anaesthesia showed hypoplastic discs with an oblique/inverse appearance and myopic peripapillary atrophy. Her macula and retinal vessels were normal and her electroretinogram (ERG) was within normal limits. She attended a school for the blind from the age of 7 years and was intellectually normal. At 12 years, her height was 148 cm (25th centile) and weight was 47 kg (50-75th centile). She had no clinical indication to have skeletal radiographs taken. A heart murmur had been noted during childhood, but not investigated. She collapsed and died suddenly and unexpectedly at a school disco, aged 12 years. There was no history of previous symptoms or episodes of syncope or presyncope. Necropsy showed some thickening of the left ventricular free wall with extreme thinning and fibrosis of the interventricular septum and some thickening of the septum in the subaortic area.
The proband was a term delivery, weighing 2700 g (10th centile). At the age of 5 years, her visual acuity was of perception of light in her right eye and 6/36 in her left eye. She had hypoplastic optic discs, a right divergent squint, nystagmus, and was mildly myopic. Her ERG was very reduced. She attended a school for the blind and her situation remained stable until the age of 15 years when she complained of deterioration of vision in her left eye. A retinal detachment was repaired surgically and she retains visual acuity of 6/60 in that eye. Examination under anaesthesia at this time showed tilted/colobomatous optic discs with full thickness retinal folds, vitreous veils, temporal peripheral retinal scarring, but normal vasculature in both eyes. She also had a shallow tractional retinal detachment and a dragged disc. Her ERG showed low amplitude responses. At this time, a diagnosis of familial exudative vitreoretinopathy was made.
During childhood, she had six fractures of her long bones and she has a mild idiopathic non-progressive scoliosis. Her height and weight were <3rd centile throughout childhood, and she attained an adult height of 152 cm (3rd centile) and weight of 47 kg (10th centile). There was no joint hypermobility or skin laxity. She is of normal intelligence. She has a short philtrum and thin upper lip (fig 1).
She had a number of faints when aged 12 years. An ECG at that time was normal apart from a prominent “u” wave in the precordial leads. The symptoms resolved and no further investigations were instituted. She was well up until her second pregnancy, when she had a number of episodes of dizziness associated with palpitations and two episodes associated with loss of consciousness which were not investigated. A few months following delivery, she had an episode of collapse followed by palpitations. Clinical examination showed a murmur of mitral regurgitation which was clinically mild. There was no evidence of heart failure. Her resting ECG at this point showed sinus rhythm with inferolateral repolarisation abnormalities. Exercise test showed a number of short episodes of ventricular tachycardia and a 24 hour tape showed numerous ventricular ectopic beats with one eight beat run of ventricular tachycardia. Her echocardiogram showed moderate global left ventricular dilatation and impaired function, without hypertrophy. MRI scan showed areas of thinning of the free wall of the right ventricle and a fine line of subendocardial infiltrate in the lateral wall of the left ventricle. Cardiac biopsy of the interventricular septum was carried out and the histology was consistent with a diagnosis of dilated cardiomyopathy. She was started on angiotensin converting enzyme inhibitors but was intolerant of beta blockers. Amiodarone exacerbated the arrhythmia and she was unable to tolerate Mexiletine. She continued to have non-sustained ventricular tachycardia following exercise. An automatic defibrillator was implanted and she was also started on Nicorandil. The defibrillator discharged three months following implantation suggesting that a life threatening arrythmia had occurred.
Chromosome analysis showed an apparently normal 46,XX female karyotype. Analysis of cultured fibroblasts indicated a normal collagen profile. A skeletal survey showed abnormally short long bones, with flared metaphyses and patchy areas of sclerosis and lysis within the metaphyses and metadiaphyses (fig 2). These findings did not fit into a recognised pattern. A full blood count, electrolytes, calcium, phosphate, liver function tests, and amino urinary acids were normal. Alkaline phosphatase was slightly raised at 133 U/l (reference range 41-117 U/l).
A mitochondrial aetiology was considered and a quadriceps muscle biopsy taken. Histological and histochemical examination of the muscle biopsy showed minor abnormalities (type 2B fibre atrophy). There was no histological or histochemical evidence of mitochondrial disease: there were no ragged red fibres and no cytochrome c oxidase negative fibres seen. Respiratory chain studies were undertaken on mitochondria isolated from a fresh muscle biopsy. The activity of respiratory chain complexes I, II, and IV fell comfortably within the age and sex matched control range. No mtDNA rearrangements were identified by Southern blot analysis of skeletal muscle DNA. Three mitochondrial genes in which mutations have been associated with cardiomyopathy (tRNAleu(UUR), tRNAIlle, tRNAleu(CUN)) were sequenced and only well established polymorphisms were identified.
The common findings in this family are dilated cardiomyopathy and visual impairment. It seems likely that the cause of death in both the mother and older daughter was an arrhythmia, secondary to their cardiomyopathy, as the proband had ventricular dysrhythmia necessitating defibrillator implantation. This striking combination of features has not been described previously.
The proband has an unidentified skeletal dysplasia with short stature. Unfortunately, no information is available on whether the mother or older sister had these features as neither had any radiological examination. The changes are not those of a recognised dysplasia. Retinal and skeletal abnormalities are often associated with collagen disorders, but there was a normal collagen profile in cultured fibroblasts from the proband. Dilated cardiomyopathy consists of ventricular enlargement, abnormal systolic and diastolic left ventricular function, symptoms of congestive heart failure, and premature death resulting predominantly from heart failure and cardiac arrythmias.1 The aetiologies are varied, and although frequently idiopathic, a familial basis has been identified in 20-30%. Genes implicated to date in dilated cardiomyopathy are of two types: those which encode structural proteins such as dystrophin and muscle LIM protein, and those encoding transcription factors which control the expression of cardiac myocyte genes, such as the cyclic AMP response element binding protein (CREB).1 While the vast majority of familial forms of dilated cardiomyopathy appear to be autosomal dominant, autosomal recessive, X linked recessive, and mitochondrial inheritance have all been described.2 This family pedigree is not consistent with autosomal recessive or X linked recessive inheritance and, in the light of the investigations of mitochondrial function, mitochondrial inheritance is unlikely.
Although a diagnosis of familial exudative vitreoretinopathy had been made in the proband, this seems unlikely as there was no evidence of retinovascular abnormalities in either the proband or her sister at a time when both had poor acuity. A diagnosis of Wagner's vitreoretinal dystrophy, with features of myopic refractive error, and inverse, pale optic discs and retinal detachment was considered. However, the ERG in this condition shows subnormal b waves, which were not a feature in these patients, and the temporal retinal scarring with dragged optic discs seen in the family are not features of Wagner's vitreoretinal dystrophy.3 Some of the Wagner-like syndromes (Kniest dysplasia, diastrophic variant and spondyloepiphyseal dysplasia congenita) have short stature as one of their characteristics, but the normal collagen profile and atypical x rays exclude these diagnoses.4–6 The appearance of retinopathy of prematurity is similar to that in the proband, but she was not born prematurely and did not receive oxygen supplementation neonatally. Thus, the visual problems are not typical of any recognised condition.
In conclusion, this family represents a distinct entity consisting of dilated cardiomyopathy, arrhythmia predisposing to sudden death, visual impairment, and possibly skeletal dysplasia. The most likely inheritance pattern in this family is autosomal dominant.
We would like to thank Dr Mike Pope for analysing the cultured fibroblasts.