Najjar et al. (1973) reported 3 sibs with genital anomaly, mental retardation, and cardiomyopathy. Najjar et al. (1984) reported a second unrelated family in which 2 brothers had severely hypoplastic genitalia and cardiomyopathy. The parents were consanguineous in ... Najjar et al. (1973) reported 3 sibs with genital anomaly, mental retardation, and cardiomyopathy. Najjar et al. (1984) reported a second unrelated family in which 2 brothers had severely hypoplastic genitalia and cardiomyopathy. The parents were consanguineous in both instances. The genital anomaly appeared to be due to primary testicular failure. The testes were very small. Sacks et al. (1980) described 3 brothers with cardiomyopathy and hypergonadotropic hypogonadism. The proband was a 48-year-old man with tricuspid regurgitation and, at autopsy, cardiomyopathy involving both ventricles but with predominant involvement of the right ventricle. He also had primary testicular failure and a distinctive type of cutaneous collagenoma (see 115250) of the occipital scalp. The patient's 2 brothers were found to have testicular failure and signs of mild to moderate cardiomyopathy, as well as similar scalp lesions. All 3 brothers had elevated serum levels of the gonadotropins follicle stimulating hormone (FSH) and luteinizing hormone (LH). Their father had died at 68 years of age with cardiomegaly, atrial fibrillation, and chronic congestive heart failure. From birth he also had a posterior occipital scalp lesion devoid of hair, similar to that of his 3 sons. Malouf et al. (1985) reported 2 sisters, born of first-cousin Lebanese Moslem Shiite parents, who had congestive cardiomyopathy associated with ovarian dysgenesis and secondary hypergonadotropic hypogonadism. Other features included bilateral ptosis and prominent nasal bones. They had 2 brothers who had died suddenly at the age of 18 years with normal secondary sexual characteristics and no clinical evidence of heart failure. Malouf et al. (1985) suggested that males with this syndrome may have cardiomyopathy but not testicular dysgenesis. Harbord et al. (1989) described cardiomyopathy in association with Martsolf syndrome (212720), which has hypogonadism as a feature. Narahara et al. (1992) described the sporadic case of an 18-year-old girl with ovarian dysgenesis (resulting in hypergonadotropic hypogonadism), dilated cardiomyopathy, mild mental retardation, broad nasal base, bilateral blepharoptosis, and minor skeletal anomalies, including arachnodactyly and mild thoracic scoliosis. She died at age 19 years due to intractable congestive heart failure. At autopsy, histologic examination of the myocardium showed diffuse cellular degeneration and interstitial fibrosis with no evidence of inflammation; there was no degeneration of elastic fibers in the aortic media. Gonadal tissue consisted only of stromal cells and mullerian tube remnants, with virtually absent oocytes. Thomas et al. (1993) described 2 brothers with cardiomyopathy and genital anomalies. One brother was born with micropenis and bilateral cryptorchidism but seemed otherwise well until age 5 weeks when he developed congestive heart failure leading to death at age 7 months. The other affected brother was the product of a pregnancy that ended in miscarriage after 17 weeks. Autopsy showed hypoplastic penis and markedly edematous myocardial interstitium with areas of myofiber disarray. Chen et al. (2003) studied a 23-year-old Iranian woman who presented in her early teens with short stature and was referred for evaluation of progeroid features. She had scleroderma-like skin, graying and thinning of hair, increased urinary hyaluronic acid, osteoporosis, osteosclerosis, hypogonadism, dilated cardiomyopathy, and sloping shoulders. Gursoy et al. (2006) reported 3 Turkish sibs with cardiomyopathy and hypergonadotropic hypogonadism. The 19-year-old male proband, who had hemiagenesis of the thyroid gland discovered during endocrine evaluation for delayed puberty, also had cardiomyopathy diagnosed in childhood that was complicated by ventricular tachycardia and recurrent cardiac decompensation. He underwent orthotopic cardiac transplantation at age 15. His 2 older sisters had echocardiographically confirmed cardiomyopathy, and 1 sister died as a result of cardiomyopathy at age 13. The affected living sister had hypergonadotropic hypogonadism with a normal thyroid by ultrasound and was under consideration for cardiac transplantation. The nonconsanguineous parents and a younger sister were clinically and echocardiographically normal. None of the family members had mental retardation or dysmorphic features. Nguyen et al. (2007) described a 17-year-old Caucasian female of northern European origin who developed recurrent shoulder dislocations and joint contractures of her fifth digits at 5 years of age. Osteoporosis was diagnosed at 8 years of age, along with abnormal skin findings including telangiectases, sclerodactyly, and poikiloderma, and she had a history of poor wound healing. Height and weight were both below the second percentile. She had unusual facial features, including small ears, narrow beaked nose, and very small chin. A soft tissue calcification on the left elbow was noted. Echocardiogram showed mild to moderate mitral valve regurgitation, and she was later diagnosed with dilated cardiomyopathy. Nguyen et al. (2007) stated that the features of this patient were consistent with atypical Werner syndrome (see 277700). McPherson et al. (2009) restudied the patient originally described by Nguyen et al. (2007) and reported additional features, including premature ovarian failure with secondary amenorrhea at 15 years of age. She had pubic hair but no breast development and elevated serum levels of FSH and LH, and pelvic ultrasound showed infantile uterus and small ovaries. McPherson et al. (2009) described a second patient with a similar phenotype, a girl who underwent orthopedic evaluation at age 10 years and was found to have sloping shoulders, clavicular hypoplasia, osteopenia, and acrogeric appearance of hands and feet, the skin of which showed prominent vasculature and lack of subcutaneous tissue. Mitral regurgitation was diagnosed at 10 years of age and she had dilated cardiomyopathy by 12 years of age. Menarche occurred at age 12 years, followed by secondary amenorrhea at age 13; pubertal development was incomplete with minimal breast development on the right side. Hormone analysis showed low estradiol and elevated FSH and LH, consistent with ovarian failure. Osteopenia was noted, as was lipodystrophy, with disproportionately full cheeks and loss of fat in the upper body. At age 15 years, her cardiac function deteriorated and she died from an arrhythmia while awaiting cardiac transplantation.
In a 23-year-old Iranian woman referred for evaluation of short stature and progeroid features, who also had dilated cardiomyopathy, hypogonadism, and sloping shoulders, Chen et al. (2003) identified a heterozygous missense mutation in the LMNA gene (A57P; 150330.0030). ... In a 23-year-old Iranian woman referred for evaluation of short stature and progeroid features, who also had dilated cardiomyopathy, hypogonadism, and sloping shoulders, Chen et al. (2003) identified a heterozygous missense mutation in the LMNA gene (A57P; 150330.0030). Although Chen et al. (2003) designated the patient as having 'atypical Werner syndrome' (see 277700), Hegele (2003) suggested that the patient more likely had late-onset Hutchinson-Gilford progeria syndrome (see 176670). However, McPherson et al. (2009) noted the phenotypic similarity between this patient and 2 unrelated girls with cardiomyopathy and hypergonadotropic hypogonadism, studied by Nguyen et al. (2007) and McPherson et al. (2009), respectively, who were found to be heterozygous for an adjacent L59R mutation in LMNA (150330.0052). In a 17-year-old Caucasian female with premature ovarian failure and dilated cardiomyopathy, who had features consistent with atypical Werner syndrome (see 277700) but who was negative for mutation in the RECQL2 gene (604611), Nguyen et al. (2007) identified heterozygosity for a missense mutation in the LMNA gene (L59R; 150330.0052). The authors suggested the diagnosis of a laminopathy, most likely an atypical form of mandibuloacral dysplasia (see 248370). In a 15-year-old Caucasian girl with premature ovarian failure and dilated cardiomyopathy, McPherson et al. (2009) identified heterozygosity for the L59R mutation in the LMNA gene. McPherson et al. (2009) noted phenotypic similarities between this patient and the patient previously reported by Nguyen et al. (2007), who carried the same mutation, as well as a patient originally described by Chen et al. (2003) with an adjacent A57P mutation in LMNA (150330.0030). Features common to these 3 patients included premature ovarian failure, dilated cardiomyopathy, lipodystrophy, and progressive facial and skeletal changes involving micrognathia and sloping shoulders, but not acroosteolysis. Although the appearance of these patients was somewhat progeroid, none had severe growth failure, alopecia, or rapidly progressive atherosclerosis, and McPherson et al. (2009) suggested that the phenotype represents a distinct laminopathy involving dilated cardiomyopathy and hypergonadotropic hypogonadism.