We describe a large Acadian kindred including 8 Alstrom Syndrome (AS) patients, with an age range of 4 to 26 at the time of clinical assessment. The affected subjects come from 5 nuclear families within this kindred. The phenotype includes early childhood retinopathy, progressive sensorineural hearing loss, truncal obesity, and acanthosis nigricans. In addition, hyperinsulinemia and hypertriglyceridemia with normal cholesterol levels were observed in most affected individuals tested. Non-insulin dependent diabetes mellitus and growth retardation appear to be age-related manifestations that occur post-adolescence. Younger affected children are not overtly hyperglycemic and are normal or above average height for age. Although the AS patients in kindred 1 presumably carry the same mutation, many manifestations of the disease are variable. For example, of the 8 children in the Acadian kindred, 4 have scoliosis, 2 have had infantile cardiomyopathy, 2 are hypothyroid, 1 has had hepatic dysfunction and is hypertensive, and 4 have developed asthma. Seven subjects described in this kindred exhibit developmental delay. One additional manifestation not described widely in the literature, advanced bone age, was observed in all subjects tested. The clinical data from this large Acadian kindred, together with information obtained from 4 additional AS patients in 3 unrelated kindreds, confirm and extend clinical observations previously described. In addition, the Acadian kindred with multiple affected individuals, probably arising from a common founder, should allow for identification of the chromosomal localization of a gene causing AS.
Osteoporosis causes significant morbidity for boys with Duchenne muscular dystrophy. Corticosteroid therapy given to prolong mobility may increase the rate of osteoporosis and risk of fracture. This study of 33 boys with Duchenne muscular dystrophy determined retrospectively the incidence of vertebral fractures particularly after initiation of corticosteroids. A latency period of 40 months after commencement of steroids occurred before the first vertebral fracture appeared. However, by 100 months of treatment approximately 75% had sustained a vertebral fracture.
Neonatal severe hyperparathyroidism (NSHPT) is considered an autosomal-recessive disorder, attributable in many cases to homozygous inactivating mutations of the Ca++-sensing receptor (CASR) gene at 3q13.3-21. Most heterozygotes are clinically asymptomatic but manifest as familial (benign) hypocalciuric hypercalcemia (FHH) with a laboratory profile that is variably and sometimes only marginally different from normal. In 5 NSHPT cases from 3 Nova Scotian families, we found homoallelic homozygosity for an insertion mutation in exon 7 of CASR that includes an Alu repeat element with an exceptionally long polyA tract. Four of the 5 NSHPT infants were treated by parathyroidectomy more than a decade ago and are well now. A fifth went undiagnosed until adulthood and has profound musculoskeletal and neurobehavioral deficits. Among 36 identified FHH heterozygotes are 3 individuals with an unexpected degree of hypercalcemia and elevated circulating parathyroid hormone levels consistent with secondary hyperparathyroidism. Two are obligately heterozygous offspring of NSHPT mothers with surgical hypoparathyroidism and variable compliance with vitamin D therapy. The other is an adult with coexistent celiac disease in whom hyperparathyroidism, probably secondary to vitamin D deficiency, led to surgery. In counseling affected families, the heterozygous state should not be considered entirely benign, since FHH heterozygotes, particularly infants, may be prone to secondary hyperparathyroidism and symptomatic hypercalcemia. In such families, molecular diagnosis will allow for unambiguous identification of at-risk individuals.
Peer relationships, social skills, self-esteem, parental psychopathology, and family functioning of children with Tourette's disorder and a chronic disease control group of children with diabetes mellitus were compared. Children with Tourette's disorder had poorer peer relationships than their classmates and were more likely to have extreme scores reflecting increased risk for peer relationship problems than children with diabetes mellitus, but did not report self-esteem problems or social skills deficits. Measures of peer relationships were not related to severity or duration of tics. Children with Tourette's disorder and Attention Deficit Hyperactivity Disorder were at increased risk for poor peer relationships. The psychosocial problems of children with Tourette's disorder do not appear to be the generic result of having a chronic disease.
Peer relationships, social skills, self-esteem, parental psychopathology, and family functioning of children with Tourette's disorder and a chronic disease control group of children with diabetes mellitus were compared. Children with Tourette's disorder had poorer peer relationships than their classmates and were more likely to have extreme scores reflecting increased risk for peer relationship problems than children with diabetes mellitus, but did not report self-esteem problems or social skills deficits. Measures of peer relationships were not related to severity or duration of tics. Children with Tourette's disorder and Attention Deficit Hyperactivity Disorder were at increased risk for poor peer relationships. The psychosocial problems of children with Tourette's disorder do not appear to be the generic result of having a chronic disease.
Familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism (NSHPT), and autosomal dominant hypocalcemia (ADH), in which calcium homeostasis is disordered, are associated with mutations in the calcium-sensing receptor (CASR). Six unrelated kindreds with FHH and/or NSHPT and two unrelated kindreds with ADH were studied. Direct sequence analysis of the exons of the CASR gene identified heterozygous mutations in six of the kindreds with FHH and in one of those with ADH. We performed functional analyses on the novel missense and insertion/frameshift mutants by transiently transfecting wild-type and mutant CASRs tagged with a c-Myc epitope in human embryonic kidney (HEK293) cells. All mutant receptors were expressed at a similar level to that of the wild type; however, whereas mutants R220W and A835T (the ADH mutant) were fully glycosylated and were visualized on the cell surface, glycosylation of mutants G549R and C850-851 ins/fs was impaired, resulting in reduced cell surface staining. In fura-2-loaded HEK293 cells expressing the wild-type or mutant receptors, the inactivating R220W mutant produced a significant shift to the right relative to the wild-type CASR in the cytosolic calcium response to increasing extracellular calcium concentrations and the G549R and C850-851 ins/fs mutants were without detectable activity. The activating A835T mutation resulted in a shift to the left in the cytosolic calcium response to extracellular calcium concentrations relative to the wild type. Our studies have identified novel CASR mutations that alter the function of the CASR in several different ways.
Primary massive ovarian edema is uncommon, particularly when it involves both ovaries before puberty. Ovarian edema secondary to a preexisting ovarian lesion is one of the postulated mechanisms. A prepubertal girl presented with bilateral massive ovarian edema with stromal hyperthecosis, which may have predisposed both ovaries to undergo partial torsion. The associations with Meig's syndrome, greatly elevated hormone levels and presence of omental and retroperitoneal nodules, raised a suspicion of malignancy.
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