A girl with 1p36 deletion syndrome and congenital fiber type disproportion myopathy

Chromosome 1p36 deletion syndrome is characterized by hypotonia, moderate to severe developmental and growth retardation, and characteristic craniofacial dysmorphism. Muscle hypotonia and delayed motor development are almost constant features of the syndrome. We report a 4-year-old Japanese girl with 1p36 deletion syndrome whose muscle pathology showed congenital fiber type disproportion (CFTD) myopathy. This is the first case report of 1p36 deletion associated with CFTD. This association may indicate that one of the CFTD loci is located at 1p36. Ski proto-oncogene −/− mice have phenotypes that resemble some of the features observed in patients with 1p36 deletion syndrome. Because fluorescent in situ hybridization analysis revealed that the human SKI gene is deleted in our patient, some genes in 1p36, including SKI proto-oncogene, may be involved in muscle hypotonia and delayed motor development in this syndrome. Received: March 4, 2002 / Accepted: July 7, 2002     

Expression of growth associated protein 43 and neural cell adhesion molecule in congenital fibre type disproportion with interstitial myositis

We report on the expression of growth associated protein (GAP)43 and neural cell adhesion molecule (NCAM) in congenital fibre type disproportion (CFTD) with myopathological additional signs of interstitial myositis. We assume that sarcolemmal GAP43 in developmental disordered myocytes plays a role in maintenance of growth morphology. In muscular dystrophy light microscopical evaluation reveals no GAP43 immunoreactivity in regenerating fibres. The expression of GAP43 seems to be a characteristic feature of CFTD. The expression of NCAM, particularly in the sarcolemma of small muscle fibres of CFTD, indicates a functional state of permanent partial denervation. Whether the steroid-responsive interstitial myositis is pathogenetically related to CFTD or a coincidental inflammation is not known. Because of the clinical and myopathological data the differential diagnosis of Emery-Dreifuss muscular dystrophy is considered.     

Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy

Cardiac ankyrin repeat protein (CARP), which is structurally characterized by the presence of four ankyrin repeat motifs in its central region, is believed to be localized in the nucleus and to participate in the regulation of cardiac-specific gene expression in cardiomyocytes. However, we recently found that CARP was induced in skeletal muscle by denervation, leading us to speculate that CARP may be induced under some pathological conditions. In the present study, we immunohistochemically analyzed the expression of CARP in 11 cases of spinal muscular atrophy (SMA) and 14 cases of congenital myopathy. In SMA, CARP was expressed selectively in severely atrophic myofibers, suggesting that CARP expression may reflect the status of muscle atrophy. Furthermore, in the congenital myopathies, the expression patterns of CARP were distinct among the subtypes, which included nemaline myopathy, myotubular myopathy, central core disease, and congenital fiber type disproportion. Although CARP was preferentially expressed in severely damaged myofibers in nemaline myopathy, it was not detected in central core disease. These findings suggest that immunohistochemical evaluation of CARP may be helpful in the diagnosis of SMA and the congenital myopathies.     

RYR1-related congenital myopathy with fatigable weakness,responding to pyridostigimine

The spectrum of RYR1 mutation associated disease encompasses congenital myopathies, exercise induced rhabdomyolysis, malignant hyperthermia susceptibility and King-Denborough syndrome. We report the clinical phenotype of two siblings who presented in infancy with hypotonia and striking fatigable ptosis. Their response to pyridostigimine was striking, but genetic screening for congenital myasthenic syndromes was negative, prompting further evaluation. Muscle MRI was abnormal with a selective pattern of involvement evocative of RYR1-related myopathy. This directed sequencing of the RYR1 gene, which revealed two heterozygous c.6721C>T (p.Arg2241X) nonsense mutations and novel c.8888T>C (p.Leu2963Pro) mutations in both siblings. These cases broaden the RYR1-related disease spectrum to include a myasthenic-like phenotype, including partial response to pyridostigimine. RYR1-related myopathy should be considered in the presence of fatigable weakness especially if muscle imaging demonstrates structural abnormalities. Single fibre electromyography can also be helpful in cases like this.     

Frequency and phenotype of patients carrying TPM2 and TPM3 gene mutations in a cohort of 94 patients with congenital myopathy

Congenital myopathies are difficult to classify correctly through molecular testing due to the size and heterogeneity of the genes involved. Therefore, the prevalence of the various genetic causes of congenital myopathies is largely unknown. In our cohort of 94 patients with congenital myopathy, two related female patients and two sporadic, male patients were found to carry mutations in the tropomyosin 2 (TPM2) and tropomyosin 3 (TPM3) genes, respectively. This indicates a low (4.3%) frequency of TPM2 and TPM3 mutations as a cause of congenital myopathy. Compared to previously described patients carrying the same mutations as found in our study (c.503G > A, and c.502C > T in TPM3, and c.415_417delGAG in TPM2), clinical presentation and muscle morphological findings differed in our patients. Differences included variation in distribution of muscle weakness, presence of scoliosis and ptosis, physical performance and joint contractures. The variation in clinical profiles emphasizes the phenotypic heterogeneity. However, common features were also present, such as onset of symptoms in infancy or childhood, musculoskeletal deformities and normal or low plasma levels of creatine kinase.One patient had nemaline myopathy and fiber size disproportion, while three patients had congenital fiber type disproportion (CFTD) on muscle biopsies. TPM2-related CFTD has only been described in two cases, indicating that mutations in TPM2 are rare causes of CFTD.     

Height, Sitting Height and Leg Length in Patients with Hypophosphataemic Rickets

ABSTRACT. Height, sitting height (SH) and subischeal leg length (SLL) were determined in 5 boys and 11 girls with hypophosphataemic (vitamin D-resistant) rickets, aged 4–14 years. Their average height was -2.05 ± 1.22 SDS, and SLL (average value: -2.59 ± 1.18 SDS) was more reduced than SH (average value: -0.91 ± 1.37 SDS). SLL and SH were abnormally low in 11 and 3 of the patients respectively. The difference between SLL and SH was abnormally low in only 4 of the children, indicating a mild degree of disproportion. None of the patients had relatively long legs. There was no relation between height and the degree of disproportion, a finding which tallied with the relatively mild degree of disproportion. This indicated that the normal interindividual differences in proportion were more important than a preferential effect of rickets on leg length.     

Does growth hormone therapy harmonize distorted morphology and body composition in chronic renal failure?

Recombinant human growth hormone (rhGH) therapy of growth retardation in chronic renal failure (CRF) has become well established. While there are ample data about its effectiveness in restoring longitudinal growth delay, data on complex anthropometry are scarce. Twenty-three children with CRF (6 after renal transplantation) were investigated using 24 different parameters. The analysis revealed disproportionate growth in CRF. While parameters of the trunk and transverse dimension of the head were preserved, the extremities were affected more severely. Bone dimensions of the legs and arms as well as muscle mass were affected the most. RhGH therapy was effective in restoring impaired longitudinal dimensions of the body in CRF. The restoration of growth retardation occurred predominantly in the extremities. This was accompanied by an increase in transversal dimensions, circumferences and soft tissue of the extremities, as well as an increase in bone and muscle volume, indicating harmonization of the total body shape. The dimensions of trunk, forehead diameter and morphological face height remained within the normal range. There was no evidence of acromegaly in children with CRF and rhGH therapy. We conclude that rhGH therapy at a dose of 28 iU/m²/week is effective in restoring previously disproportional body structure and shape in children with CRF. Received: 3 December 1999 / Revised: 27 July 2000 / Accepted: 1 August 2000     

Final height and body disproportion in thalassaemic boys and girls with spontaneous or induced puberty

The aim of the study was to evaluate whether sex hormone replacement therapy adversely affected final height and body disproportion in thalassaemic boys and girls. Thirty-six patients with spontaneous (SP) or induced puberty (IP) were studied in order to define the pattern of height growth through three observations: the first (A) at the age of 7-9; the second (B) at onset of spontaneous or induced puberty; and the third (C) when final height was reached. We examined 14 females with SP (f-SP) and 8 with IP (f-IP); 7 males with SP (m-SP) and 7 with IP (m-IP). Girls with IP reached the same final height of girls with SP (f-IP 153.8 (4.3) versus f-SP 154.4 (5.5) cm); p > 0.05) close to target height (f-IP 155.9 (5.2) cm versus f-SP 155.5 (3.6) cm). Girls with IP reached the final height at older chronological age (CA) (17.0 (0.6) y) than girls with SP (CA of 15.3 (0.7) y), but at the same bone age (BA) (f-IP 15.1 (0.9) y versus f-SP 14.8 (0.6) y). There was no difference between the two groups for pubertal growth (f-SP 16.2 (7.7) cm versus f-IP 12.2 (7.4) cm (p > 0.05)) that was negatively correlated with both prepubertal growth and BA at onset of puberty in both groups. Values of sitting height (sds) with respect to BA (SHsdsBA) were not significantly different between the two groups, and showed a worsening from the first observation to final height, reaching values around -2 SD, in both groups. Values of subischial leg length (sds) with respect to BA (SLLsdsBA) were in the normal range at both observations in all girls. High serum ferritin levels were observed in both groups (f-SP 3189 (2296) ng/ml and f-IP 3998 (2545) ng/ml; p > 0.05). Also boys with induced puberty reached the same final height of those with spontaneous one (m-IP 160.9 (5.5) cm versus m-SP 161.8 (2.4) cm; p > 0.05), but it was lower than target height in both groups (m-IP 168.1 (4.1) cm versus m-SP 169.6 (3.2) cm). Boys with IP reached final height at CA of 18.6 (1.1) y slightly older than boys with SP (CA 17.2 (0.9) y), but at the same BA (m-IP 15.9 (1.5) y versus m-SP 16.3 (0.8) y). Pubertal growth values were significantly different between boys with SP 18.9 (5.3) cm and those with IP 13.8 (4.9) cm (p < 0.05), but they were negatively correlated with prepubertal growth values in both groups (m-SP r = -0.91; p < 0.002 and m-IP r = -0.51; p < 0.05). SHsdsBA showed a worsening from the first observation to final height, reaching values around -3 SD in both groups, while SLLsdsBA were always in the normal range in all patients. Serum ferritin levels were higher in boys with IP (3400 (1179) ng/ml) than in those with SP (2020 (496) ng/ml). Conclusions: Our data showed that: (a) patients of both sexes with induced puberty reached the same final height of patients with spontaneous puberty; (b) all patients showed a body disproportion with truncal shortening and normal leg length that was more severe in boys of both groups at final height; (c) body disproportion was independent of pubertal or prepubertal period of greater height gain, suggesting that sexual steroids replacement therapy did not adversely affect either final height or body disproportion. Further studies, focused on the pathogenesis of the truncal shortening, are necessary in order to acquire more insight into the causes of this impairment.     

先天性肌纤维类型不均的临床表现和病理特点（附1例报道）

目的：探讨先天性肌纤维类型不均（CFTD）的临床表现和病理特点。方法：回顾复旦大学附属华山医院神经科收治的1例CFTD患者的临床表现和肌肉病理改变,并结合国外文献报道的3组共21例病例进行分析比较。结果：21例CFrD患者中,男11例,女10例。平均发病年龄为2．84岁,约28．6％的患者有家族史。除四肢无力及肌张力低下外,伴面肌无力者42．9％,喂养困难者19．0％,呼吸肌受累者38．1％,约1／3患者有高腭穹、脊柱侧凸、关节挛缩等骨骼畸形,所有病例认知功能均正常。约71．43％的患者病情稳定,28．6％的患者病情缓慢加重。与文献报道比较,本文所报道的病例临床表现具有肌无力和肌萎缩进展缓慢,而呼吸肌和骨骼不受累等肌营养不良样的特点。结论：CFTD作为先天性肌病的一种,可有肌营养不良样的临床表现,明确诊断有赖于肌肉活检。