Is familial hyperparathyroidism a unique disease?

BACKGROUND: Familial hyperparathyroidism is a rare condition reported to behave more aggressively than sporadic hyperparathyroidism. METHODS: A retrospective (1975 to 1995) analysis was performed on 30 such patients. All patients had at least one first-degree relative with surgically treated hyperparathyroidism and no personal or family history of multiple endocrine neoplasia. RESULTS: There were 19 women and 11 men with a mean age of 39 years (range, 13 to 78 years). Fourteen patients (47%) had nephrolithiasis. The mean serum calcium level was 11.6 mg/dl (range, 10.5 to 15.3 mg/dl). Twenty-three primary and 15 repeat explorations (eight recurrent and seven persistent disease) were performed during the study period. Follow-up was obtained on all patients and ranged from 1 to 21 years (mean, 12 years). At the conclusion of the study, hypercalcemia (five recurrent and one persistent) was present in six patients (20%). CONCLUSIONS: Familial hyperparathyroidism is a distinct and unique entity. Patients are diagnosed at a young age and have a high incidence of nephrolithiasis. Long-term follow-up is mandatory because of the high incidence of both recurrent and persistent hyperparathyroidism. Surgical treatment should include subtotal parathyroidectomy and routine transcervical thymectomy performed in centers with experience in the management of multiple-gland parathyroid disease.     

Is attention deficit hyperactivity disorder familial?

Using two sources of data, we review methodologic issues pertinent to family studies of attention deficit hyperactivity disorder to evaluate whether such studies define attention deficit hyperactivity disorder as a familial disorder. We systematically evaluate the relevant literature and provide a detailed overview of the Massachusetts General Hospital family-genetic studies of attention deficit disorder as defined in DSM-III and attention deficit hyperactivity disorder as defined in DSM-III-R. The available literature, and our double-blind, controlled studies indicate that attention deficit disorder and attention deficit hyperactivity disorder are familial. Moreover, the pattern of transmission of comorbid disorders suggests that attention deficit hyperactivity disorder is, from a familial perspective, distinct from anxiety disorders and learning disabilities. In contrast, attention deficit hyperactivity disorder with conduct disorder appears to be a familial subtype, and major depression appears to be a variable expression of the familial predisposition to attention deficit hyperactivity disorder. Although the available literature provides strong evidence for the familial transmission of attention deficit hyperactivity disorder, the mode of transmission requires further clarification. In addition, attention deficit hyperactivity disorder appears to be genetically heterogeneous, indicating that more work is needed to delineate genetically homogeneous subtypes and to describe the range of expression of their underlying genotypes. Family-genetic studies will continue to clarify the etiology and nosology of attention deficit hyperactivity disorder.     

Genetic studies in narcolepsy, a disorder affecting REM sleep

OBJECTIVE: To report the clinical and histopathologic characteristics of BK virus (BKV) retinitis. DESIGN: Case report. TESTING: The clinical features of bilateral retinitis in a 29-year-old homosexual white male with the acquired immune deficiency syndrome (AIDS) included focal, mottled fundus pigmentation, and haloes, as documented by fundus photography. After death of the patient, the left eye was studied by light microscopic and immunohistochemical examination. The nested polymerase chain reaction (PCR) was used to detect viral deoxyribonucleic acid (DNA) in the right eye and other nonocular tissues. The specificity was then confirmed by restriction enzyme analysis. RESULTS: The retina of the left eye showed focal necrosis and contained cells with intranuclear staining for the BKV VP1 protein. In the right eye, BKV DNA was detected in the retina and other tissues by nested PCR. Autopsy showed that BKV infection was also present in the brain, kidneys, and peripheral blood mononuclear cells. CONCLUSIONS: A number of pathogens may cause retinitis in patients with AIDS. The authors have shown that BKV should be included among those pathogens and that some clinical features may suggest the presence of BKV retinitis.     

Imaging studies of the pelvic floor

A variety of imaging modalities complement the history and physical examination in the investigation of pelvic floor dysfunction in women. Current fluoroscopic techniques, including defocography, can reveal underlying pelvic floor defects by reproducing normal daily activities that cause symptoms. Magnetic resonance imaging provides fine musculoskeletal detail of this region in anatomic plane not well seen via computerized tomography. Ultrasound is used primarily in assessment of the anal sphincter muscles. Cystourethroscopy provides direct visualization of the lower urinary tract. This article describes the clinical applications and technique of each modality.     

Atypical familial microcytosis: a familial and genetic study

The characteristics of familiar atypical microcytosis studied during one year were evaluated. Out of 149 patients with microcytosis in whom iron deficiency was ruled out, a heterogenous beta-thalassemia was diagnosed in 72 cases, a heterozygous delta beta-thalassemia in 16 cases and a hemoglobinopathy in 3 cases. The microcytosis was related to an inflammatory anemia in 12 cases and to an hemopathy in 9 cases. An atypical microcytosis was detected in 37 patients. A familiar and molecular analysis was carried out to detect alpha-thalassemia in cases with atypical microcytosis. It was possible to complete the familiar and molecular analysis in 35 out of 37 cases, and an alpha-thalassemia was observed in 31 patients. Most cases proved to be heterozygous or homozygous-alpha 3.7-thalassemia. No patient with heterozygous alpha zero-thalassemia was found. Most cases of familiar atypical microcytosis in our country are due to -alpha 3.7-thalassemia. Bearing these findings in mind, this analysis should only be used in situations where a problem of prenatal diagnosis is present. Moreover, systematic molecular analysis of familiar atypical microcytosis could be justified if the MCV is lower than 75 fl.     

Obsessive compulsive disorder. Clinical and epidemiologic studies

Until recently, Obsessive-Compulsive Disorder (OCD) was considered rare trouble with rather poor outcome. Currently progress in behavioral psychology, psychopharmacology and methodology of epidemiologic studies multiplying by 50 the traditional prevalence rates, give an impetus to the interest in this pathology. Recent clinical and epidemiologic data in OCD are reported in this paper. Multiple questions are evoked such as the issue of OCD homogeneity, the meaning of comorbidity with other psychological disorders: depression, panic attacks, schizophrenia, Gilles de la Tourette syndrome, the reality of OCD prevalence rate in general and psychiatric populations, the usefulness of classical demarcation between psychosis/neurosis in the treatment of OCD, and finally the search for a genetic diathesis and risk factors implicated in predisposition to OCD. A close relationship between clinical, epidemiologic and genetic approaches seems to be required in order to answer these questions and constitutes a first step prior to carrying on basic and applied research.     

On the pathogenesis of Bartter's syndrome: report of studies in a patient with this disorder

A 25 year old male with features typical of Bartter's syndrome is described. Studies were performed to evaluate the pathogenesis of this disorder. In response to oral water loading the subject excreted free water normally. Normal renal sodium conservation was documented. Autonomy of the reninangiotensin-aldosterone system was excluded by demonstrating appropriate directional changes in plasma renin activity and aldosterone excretion in response to alterations in sodium and potassium intake. During aminoglutethimide inhibition of aldosterone synthesis the subject was able to maintain potassium balance at a normal serum potassium concentration on a potassium intake of 130 mEq/day which suggests that aldosterone is the major cause of the potassium wasting. Decreased vascular responses to intra-arterial infusions of angiotensin II and norepinephrine were documented in the absence of extracellular volume depletion. These findings argue against tachyphylaxis as the explanation for the vascular insensitivity and implicate a defect at some step in the sequence between agonist-receptor interaction and the contractile response. It is proposed that the vascular defect plays a primary role in the pathogenesis of the hyperreninemia by interrupting pressure-mediated inhibition of renin secretion and/or impairing direct feedback inhibition of renin secretion by angiotensin II. A unique finding in our case was the lack of a postural influence on plasma renin activity and plasma aldosterone. An accentuated plasma aldosterone circadian rhythm was observed independent of plasma renin activity and plasma potassium concentration. Dexamethasone suppression of ACTH reduced but did not abolish the circadian rhythm. Thus some factor in addition to plasma renin activity, potassium and ACTH appears to influence aldosterone secretion in this patient.     

FH Tulsa-1 and -2: two unique alleles for familial hypercholesterolemia presenting in an affected two-year-old African-American male

A two-year-old African American boy presented with cutaneous xanthomata and extreme hypercholesterolemia. Subsequent studies revealed that the LDL-cholesterol was 1,001 mg/dl and apoB 507 mg/dl. LDL-receptor activity was almost undetectable, which is compatible with the finding of two newly described defective alleles on exon 4 of the LDL-receptor gene coding for part of the ligand-binding domain. One allele contained a 21 base-pair insertion from codon 200 to 207 whereas the other had a point mutation at codon 207. The rarity of genes for FH reported in individuals of African ancestry is discussed.     

Outcome studies in industry: cost-effectiveness of cumulative trauma disorder prevention

Cost-effectiveness analysis (CEA) is a method for choosing between alternative strategies to achieve a specified outcome in an environment of limited resources. This paper discusses the use of CEA in evaluating prevention strategies in industrial settings, using cumulative trauma disorder (CTD) prevention programs as an example. Methodologic issues in designing studies of cost-effectiveness for preventive interventions are discussed. A decision analysis model of a CTD prevention program is described as a means of studying the program's cost-effectiveness. The relationship between CEA and outcomes research, and the strengths and limitations of CEA in evaluating occupational health prevention programs is considered.     

The problem of validity in field studies of psychological disorder.

Results of over 25 attempts to count untreated cases of psychological disorder in community populations are reviewed, and the problem of validity in the measures of disorder is analyzed. Evidence of validity is found to be scant. The position is taken that, with no generally accepted criteria available, and no universe of content agreed upon, construct validity takes on added importance. A lead to 1 possible nomological net for the construct of psychological disorder is the consistent finding that the lowest socioeconomic stratum has the highest rate of symptomatology. This lead is developed with reference to the transcience of symptomatology found in extreme situations, in contrast to the persistence of symptomatology observed in patients and in studies of experimental neurosis. (77 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neonatal diagnosis of familial hypercholesterolemia in newborns born to a parent with a molecularly defined heterozygous familial hypercholesterolemia

This study was designed to compare blood lipid levels in newborn individuals with molecularly defined heterozygous familial hypercholesterolemia [FH] to those in non-affected babies and to clarify the value of lipid determinations in assessment of diagnosis of FH at birth and 1 year of age. Twenty-five babies were born to 21 parents with DNA-documented heterozygous FH. Analysis of their cord blood samples revealed 11 newborns with the FH-North Karelia [FH-NK] mutation, 3 newborns with the FH-Helsinki [FH-HKI] mutation, and 11 nonaffected newborns. Cord serum total [TC] and LDL cholesterol [LDL-C] levels (mean +/- SD) in affected newborns (2.60 +/- 0.70 and 1.77 +/- 0.56, respectively) were significantly (P < .001) higher than those in nonaffected ones (1.54 +/- 0.23 and 0.78 +/- 0.15, respectively) and another cohort of 30 randomly selected control samples from apparently healthy newborns (1.84 +/- 0.46 and 1.03 +/- 0.30, respectively). However, there was overlapping of individual lipid levels in these three groups precluding the use of TC or LDL-C determinations in neonatal diagnosis of FH. In contrast, 1 year follow-up samples from 10 affected and 7 nonaffected individuals, as well as additional samples collected from another group of 8 affected and 9 nonaffected individuals, indicated that serum cholesterol levels showed much greater increment in children with FH. Thus, at the age of 1 year the mean serum TC and LDL-C levels in the affected infants (8.38 +/- 1.18 and 7.02 +/- 1.07, respectively) were much higher (P < .001) than the corresponding levels (4.40 +/- 0.66 and 2.89 +/- 0.68, respectively) in the nonaffected infants, and the individual ranges of TC and LDL-C levels were nonoverlapping in these two groups. Serum HDL cholesterol [HDL-C] levels in 1-year-old children with FH (0.95 +/- 0.14) were approximately 20% lower than those of their similar at birth. In conclusion, phenotypic expression of heterozygous FH, as defined by molecular analysis of genomic DNA, is evident in serum LDL-C (but not HDL-C) levels already at birth, but for diagnostic purposes blood lipid determinations carried out at the age of 1 year are highly superior to those performed at birth.     

Universal dyschromatosis: a familial case

INTRODUCTION: Universal dyschromatosis is a generalized leucomelanodermia recognised in Japan in 1933. We report a family with universal dyschromatosis, demonstrating the mode of transmission. The ultrastructural aspects are compatible with a functional melanogenesis anomaly. CASE REPORT: A 9-year-old girl was hospitalized for recently diagnosed insulin-dependent diabetes mellitus. She was born to non-consanguinous parents and her past medical history was uneventful. Her father was of mixed ethnic origin. The physical examination revealed generalized leukomelanoderma identified since the first year of life. Zones of small achromatic maculae alternated with zones of pigmented maculae of variable size and color. Lesions were diffuse but predominated on the trunk and did not involve the face, the hands or the feet. Neither the child nor her father who also has leukomelanoderma were photosensitive. A skin biopsy from the gluteal region revealed alternating zones of hyper- and hypopigmentation. The ultrastructural analysis showed that the number of melanocytes was not significantly different in the different pigmented zones and the pigment transfer to adjacent keratinocytes was intact. There were three other girls in the kinhood and two, as well as a few other individuals in the family, had a localized form of the disease. DISCUSSION: Universal dyschromatosis is a rare genodermatosis. The familial cases reported here illustrate the variable clinical presentations of this pigmentary abnormality. The pedigree in this family demonstrated incomplete penetrance of hereditary leukomelanoderma with autosomal dominant inheritance. The localized forms reported to date under different names would actually appear to correspond to incomplete expression of the dermatosis. The skin manifestations in universal dyschromatosis would appear to be similar to those in a few other skin diseases, mainly xeroderma pigmentosum, especially the localized forms; for generalized forms however, there is little room for confusion as photosensitivity is absent and lesions predominate in unexposed zones. The ultrastructure investigations showed different levels of melanocyte activity without abnormal pigment production or transfer. This abnormality has variable expression, explaining the multitude of clinical presentations.     

Transmission of two novel mutations in a pedigree with familial lecithin:cholesterol acyltransferase deficiency: structure-function relationships and studies in a compound heterozygous proband

Two novel mutations were identified in a compound heterozygous male with lecithin:cholesterol acyltransferase (LCAT) deficiency. Exon sequence determination of the LCAT gene of the proband revealed two novel heterozygous mutations in exons one (C110T) and six (C991T) that predict non-conservative amino acid substitutions (Thr13Met and Pro307Ser, respectively). To assess the distinct functional impact of the separate mutant alleles, studies were conducted in the proband's 3-generation pedigree. The compound heterozygous proband had negligible HDL and severely reduced apolipoprotein A-I, LCAT mass, LCAT activity, and cholesterol esterification rate (CER). The proband's mother and two sisters were heterozygous for the Pro307Ser mutation and had low HDL, markedly reduced LCAT activity and CER, and the propensity for significant reductions in LCAT protein mass. The proband's father and two daughters were heterozygous for the Thr13Met mutation and also displayed low HDL, reduced LCAT activity and CER, and more modest decrements in LCAT mass. Mean LCAT specific activity was severely impaired in the compound heterozygous proband and was reduced by 50% in individuals heterozygous for either mutation, compared to wild type family members. It is also shown that the two mutations impair both catalytic activity and expression of the circulating protein.