Growth hormone deficiency in Costello syndrome

We report on three patients with Costello syndrome and isolated growth hormone (GH) deficiency treated with biosynthetic GH. To our knowledge, these are the only patients with Costello syndrome who have been successfully treated for GH deficiency. We review the pathophysiology of Costello syndrome and highlight the recent recommendations of tumor screening and cardiac surveillance in this population, of particular relevance to those receiving GH therapy.     

The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region

We have recently reported isolation of the gene responsible for X- linked Opitz G/BBB syndrome, a defect of midline development. MID1 is located on the distal short arm of the human X chromosome (Xp22. 3) and encodes a novel member of the B box family of zinc finger proteins. We have now cloned the murine homolog of MID1 and performed preliminary expression studies during development. Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal and urogenital systems suggests that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome. We have also found that Mid1 is located within the mouse pseudoautosomal region (PAR) in Mus musculus , while it seems to be X- specific in Mus spretus. Therefore, Mid1 is likely to be a recent acquisition of the M. musculus PAR. Genetic and FISH analyses also demonstrated a high frequency of unequal crossovers in the murine PAR, creating spontaneous deletion/duplication events involving Mid1. These data provide evidence for the first time that genetic instability of the PAR may affect functionally important genes. In addition, we show that MID1 is the first example of a gene subject to X-inactivation in man while escaping it in mouse. These data contribute to a better understanding of the molecular content and evolution of the rodent PAR.      

Determination of the parent of origin in nine cases of prenatally detected chromosome aberrations found after intracytoplasmic sperm injection

Prenatal cytogenetic analysis of 71 fetuses conceived by intracytoplasmic sperm injection (ICSI) resulted in the detection of nine (12.7%) chromosome aberrations including two cases of 47,XXY, four cases involving a 45,X cell line and three autosomal trisomies. Molecular analysis of the parental origin of the deleted or supernumerary chromosome was performed by using polymorphic microsatellite markers. Six cases involving a sex chromosome abnormality were found to be of paternal origin while the two trisomic cases that could be analysed were of maternal origin. Two cases involved the same infertile couple who had two consecutive ICSI pregnancies terminated because of a chromosome abnormality. The replaced embryos in both cases originated from a single batch of ICSI fertilized oocytes of which part was used to initiate the first pregnancy and part was cryopreserved and used to initiate the second pregnancy.      

Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next‐generation sequencing

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A‐related leukodystrophy, Peroxisomal biogenesis disorders, POLR3‐related Leukodystrophy, Vanishing White Matter, and Pelizaeus‐Merzbacher Disease. Despite the relative frequency of these conditions, carrier‐screening laboratories regularly test only 20 of the 55 leukodystrophy‐related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.     

Control and controllability: beliefs and behaviour in high and low expressed emotion relatives

BACKGROUND: Expressed emotion (EE) is a measure of the family environment that is a well replicated psychosocial predictor of psychiatric relapse. Theoretical models of EE place heavy emphasis on the notion of control. We explored the extent to which high and low EE relatives made both attributions of control about patients and engaged in controlling behaviours. METHODS: Trained raters who were blind to information about EE coded interviews with 35 relatives of patients with schizophrenia and 42 relatives of patients with unipolar depression. Relatives were rated on two reliable scales that assessed relatives' tendencies to make illness controllability attributions and relatives' efforts to exert direct behavioural control over patients. RESULTS: In both the schizophrenia and depressed groups, high-EE relatives attributed more control to their ill family members than did low EE relatives. They also behaved in a more controlling manner. Examination of patients' clinical outcomes during a 9-month follow-up period revealed that high levels of behavioural control on the part of relatives significantly predicted relapse in patients with schizophrenia but not in patients with depression. CONCLUSIONS: These findings support the attribution-based model of EE. They further suggest that controlling behaviours on the part of relatives may mediate the EE-relapse link in schizophrenia. Such behaviours may be important targets for modification in family-based interventions for schizophrenia.     

Cervicovaginal (Papanicolaou) smear findings in patients with malignant mixed Müllerian tumors

Malignant mixed Müllerian tumor is a rare neoplasm that occurs most frequently in elderly patients. It is characterized by a mixture of malignant epithelial and sarcomatous components. Little has been published about Papanicolaou smear findings pertaining to malignant mixed Müllerian tumors. We present our experience, with an emphasis on cytologic detail. Nine patients (median age, 65 yr) met our study criteria. All available smears and surgical specimens were reviewed. Four smears were positive for malignancy, with a sensitivity of 44% (3 adenocarcinoma, and 1 squamous-cell carcinoma, small-cell type). The results of our study showed that Papanicolaou smear findings pertaining to malignant mixed Müllerian tumors are seen in patients with advanced-stage disease with involvement of the lower uterine segment or cervix. The usual finding is large numbers of high-grade epithelial malignant cells in a necrotic background. The mesenchymal component rarely sheds cells visible on Papanicolaou smear.     

Differential expression of CD22 (Lyb8) on murine B cells

Previous studies have established the distribution, biochemistryand functional attributes of human CD22, a B cell-restrictedglycoprotein. Recently, molecular cloning of the murine CD22equivalent revealed this molecule to be the same as the previouslydescribed Lyb8 alloantigen. Using the anti-Lyb8 mAb Cy34.1.2,the present report documents the expression patterns of CD22within the murine B cell compartment. The results demonstratethat in the bone marrow, murine CD22 is absent on the surfaceof pro-B cells, pre-B cells and newly emerging lgM⁺ B cells.CD22 is present at a low density on immature IgM^hi B cells andfully expressed on mature recirculating B cells. In the periphery,murine CD22 is expressed at mature levels on all B cell subsetsincluding follicular, marginal zone, B1 and switched B cells.Further studies showed CD22 to be retained on activated murineB cells for extended periods. Finally, in combination with CD23and heat stable antigen, CD22 can be used to delineate the immaturesplenic B cells, and distinguish them from follicular and marginalzone cells. Together, the results demonstrate murine CD22 tobe a useful pan marker for all mature B cell subsets.     

Identification of mutations in TCOF1: use of molecular analysis in the pre- and postnatal diagnosis of Treacher Collins syndrome

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of facial development, which results from mutations in TCOF1. TCS comprises conductive hearing loss, hypoplasia of the mandible and maxilla, downward sloping palpebral fissures and cleft palate. Although, there is usually a reasonable degree of bilateral symmetry, a high degree of both inter- and intrafamilial variability is characteristic of TCS. The wide variation in the clinical presentation of different patients, together with the fact that more than 60% of cases arise de novo, can complicate the diagnosis of mild cases and genetic counselling. In the current study, we describe how molecular techniques have been used to facilitate pre- and postnatal disease diagnoses in 13 TCS families.     

Ethics education in U.S. medical schools: a study of syllabi.

PURPOSE: Despite attempts to describe the "ideal" medical ethics curriculum, few data exist describing current practices in medical ethics education to guide curriculum directors. This study aimed to determine the scope and content of required, formal ethics components in the curricula of U.S. medical schools. METHOD: A questionnaire sent to all curriculum directors of four-year medical schools in the U.S. (n = 121) requested course syllabi for all required, formal ethics components in the four-year curriculum. Syllabi were coded and analyzed to produce a profile of course objectives, teaching methods, course contents, and methods for assessing students. RESULTS: Questionnaires were returned by 87 representatives of the schools (72%). A total of 69 (79%) required a formal ethics course, and 58 (84%) provided their ethics course syllabi. Analysis and codification of all syllabi identified ten course objectives, eight teaching methods, 39 content areas, and six methods of assessing students. The means for individual schools were three objectives, four teaching methods, 13 content areas, and two methods of assessment. The 58 syllabi either required or recommended 1,191 distinct readings, only eight of which were used by more than six schools. CONCLUSIONS: Ethics education is far from homogeneous among U.S. medical schools, in both content and extensiveness. While the study of syllabi demonstrates significant areas of overlap with recent efforts to identify an "ideal" ethics curriculum for medical students, several areas of weakness emerged that require attention from medical educators.