A child of high intelligence with the Johanson-Blizzard syndrome.

In this article, a boy is presented with the Johanson-Blizzard syndrome and high intelligence. In the literature, a wide range of intellectual abilities of children with the Johanson-Blizzard syndrome is reported. To obtain optimal conditions for the development of a child with the Johanson-Blizzard syndrome, early diagnosis of potential problems that may prevent this normal growth and development is recommended. The acquisition of more knowledge concerning the hypothetic reasons for intellectual impairment is of vital importance for families involved, in the light of genetic counseling.     

Cytopathology of exocrine pancreatic carcinoma in effusions.

The cytomorphologic features were analyzed in 26 fluid samples (18 peritoneal and 8 pleural fluids) obtained in vivo from 20 patients with pancreatic carcinoma. All tumors were ductal adenocarcinomas, as proven histologically on autopsy samples. The basic cytomorphologic pattern in the smears was that of a malignant glandular tumor, consisting of cell groups with various degrees of cohesiveness. The most prominent feature was a linear arrangement (the so-called "Indian file") of tumor cells showing nuclear molding; these aggregates were frequently closely associated with the flat round clusters of cells. Other nonspecific features of adenocarcinoma included eccentric hyperchromatic nuclei, abundant, often well-preserved vacuolated cytoplasm, a variable amount of fibrin and a reactive background. Review of the autopsy specimens also revealed the presence of an "Indian-file" pattern in most cases, especially when a conspicuous desmoplastic reaction was present. These findings suggest that pancreatic carcinoma should be included in the differential diagnosis of positive serous effusions showing these cytomorphologic features.     

Acute eosinophilic leukemia. An ultrastructural study.

Observations on a 32 year old male are described. Hematological examination demonstrated leukocytosis with circulating blastosis and dystrophic hypereosinophilia of the blood and bone marrow, with cells at various stages of maturation. Cytotoxic chemotherapy led to complete remission for 5 months followed by a terminal relapse. No features in favor of an "eosinophilic collagenosis" were revealed at autopsy. Repetitive ultrastructural studies performed during evolution of the illness demonstrated considerable anomalies of the eosinophil line. The present observation thus shows the clinical, evolutional, cytological and autopsy criteria of an acute eosinophilic leukemia.     

Mohr-Majewski syndrome (orofaciodigital syndrome type IV) in five sibs.

We present a girl and autopsy finding of her sister with Mohr-Majewski syndrome (Orofaciodigital syndrome type IV). The parents were first cousins and their two sons died of similar findings. The only healthy child of the family was mildly effected from this syndrome who had cleft palate. These features show the heterogenity of the syndrome.     

Giant-cell carcinoma of the lung. A cytologic study

A case of giant-cell carcinoma of the lung, confirmed at autopsy, is presented. The cytologic features seen in sputum samples, bronchial washings and brushings and fine needle aspiration biopsy material as well as the histologic findings are described. The possible relationship to bronchioloalveolar carcinoma is discussed. The cytologic features of giant-cell carcinoma of the lung, when seen in the context of the clinical and radiologic setting, should allow the cytologic identification of the tumor prior to surgical intervention.     

Accuracy of clinical diagnosis in a Canadian teaching hospital.

Two hundred autopsies were investigated to determine the correlation between the clinical and pathological diagnoses in three categories--major underlying disease, cause of death and significant incidental pulmonary findings. There was concurrence in diagnosis of the major underlying disease in 76% of cases, with 12% of disagreements being considered minor and 12% major. In only three cases might different management have affected the outcome had the correct diagnosis of the major underlying disease been made during life. There was concurrence of the diagnosis of the cause of death (which was often different from the underlying disease) in 64% of cases, and in 10% of cases the outcome might have been different had the clinical diagnosis been accurate. The clinical opinion that lung disease was the cause of death was confirmed at autopsy in 54% of cases, and 45% of the pulmonary causes of death as determined at autopsy had been recognized clinically. Major incidental pulmonary findings diagnosed clinically were confirmed in 76% of cases, and major pulmonary findings diagnosed at autopsy had been recognized clinically in 83%. The major sources of these discrepancies were pulmonary embolism and pneumonia. If autopsies are to play a role in patient management, clinicians will have to be made aware of discrepancies between clinical and autopsy diagnosis. The real test of efficacy would be modification of patient management for the good.     

Prenatal ultrasonographic diagnosis of a recurrent case of Johanson-Blizzard syndrome

We report on ultrasonographic prenatal diagnosis of a recurrent case of Johanson-Blizzard syndrome. The pregnancy was terminated at 21 weeks'. This observation highlights the great variability of the expression of this syndrome, including in the same family, and the necessity of collaborating with an experienced geneticist in all antenatal diagnosis of any complex of abnormalities.     

Lymphocyte subpopulations in Lynch syndrome II: an immunocytochemical study on gastrointestinal biopsies. Preliminary report

Gastrointestinal biopsies from 18 members of a family with Lynch Syndrome II were evaluated and immunocytochemical studies were made to characterize the phenotypic expression of the tissue's immune populations. The intestinal findings suggest polyclonal B-cell activation related to the T-helper distribution. Our evaluation provides no specific information so far on the management of patients with Lynch Syndrome II.     

LIMK1 and CLIP-115: linking cytoskeletal defects to Williams syndrome

Williams Syndrome is a developmental disorder that is characterized by cardiovascular problems, particular facial features and several typical behavioral and neurological abnormalities. In Williams Syndrome patients, a heterozygous deletion is present of a region on chromosome 7q11.23 (the Williams Syndrome critical region), which spans approximately 20 genes. Two of these genes encode proteins that regulate dynamic aspects of the cytoskeleton of the cell, either via the actin filament system (LIM kinase 1, or LIMK1), or through the microtubule network (cytoplasmic linker protein of 115 kDa, or CLIP-115). The recent findings that knockout mice lacking LIMK1 or CLIP-115 have distinct neurological and behavioural phenotypes, indicates that cytoskeletal defects might play a role in the development of neurological symptoms in Williams Syndrome patients. In this review, we discuss the properties of LIMK and CLIP family proteins, their function in the regulation of the actin and microtubule cytoskeletal systems, respectively, and the relationship with neurodevelopmental aspects of Williams Syndrome.     

Metastatic medullary thyroid carcinoma in sputum. A light and electron microscopic study

Medullary thyroid carcinoma (MTC) was diagnosed in a 43-year-old male by light microscopy, electron microscopy and immunohistochemistry. Five years after thyroidectomy, malignant cells with the typical cytologic and electron microscopic features of MTC were seen in his sputum, and extensive pulmonary metastases from MTC were subsequently documented at autopsy. Sputum examination is a useful diagnostic technique in patients with MTC in whom pulmonary metastases are suspected.     

Bacterial endocarditis of the mitral valve associated with annual calcification.

Bacterial endocarditis, caused mainly by Staphylococcus aureus, was found at autopsy in five patients who had a calcified posterior mitral valve annulus. Clincopathologic correlation indicates that the infection should be suspected in elderly patients with a calcified mitral annulus, the murmur of mitral insufficiency, fever, anemia, polymorphonuclear leukocytosis and a positive blood culture, regardless of evidence of peripheral embolism or of another disease that could cause the last four features. Pertinent pathologic findings are a calcified mitral valve annulus, vegetations of bacterial endocarditis towards the base of the posterior leaflet associated with leaflet perforation and an annulus abscess, and no other valvular disease. The infection may develop on the atrial aspect of a leaflet ulcerated by the calcium mass or may begin on its ventricular aspect, subsequently perforating the leaflet and infecting its atrial surface.     

Atrial Septal Defect in a Bonnet Macaque (Macaca radiata)

Atrial Septal Defect was detected at autopsy in a subadult bonnet macaque (Macaca radiata). Case history and autopsy findings were described.     

Optic nerve histopathology in a case of Wolfram Syndrome: A mitochondrial pattern of axonal loss

Mitochondrial dysfunction in Wolfram Syndrome (WS) is controversial and optic neuropathy, a cardinal clinical manifestation, is poorly characterized. We here describe the histopathological features in postmortem retinas and optic nerves (ONs) from one patient with WS, testing the hypothesis that mitochondrial dysfunction underlies the pathology. Eyes and retrobulbar ONs were obtained at autopsy from a WS patient, and compared with those of a Leber hereditary optic neuropathy (LHON) patient and one healthy control. Retinas were stained with hematoxylin & eosin for general morphology and ONs were immunostained for myelin basic protein (MBP). Immunostained ONs were examined in four “quadrants”: superior, inferior, nasal, and temporal. The WS retinas displayed a severe loss of retinal ganglion cells in the macular region similar to the LHON retina, but not in the control. The WS ONs, immunostained for MBP, revealed a zone of degeneration in the temporal and inferior quadrants. This pattern was similar to that seen in the LHON ONs but not in the control. Thus, the WS patient displayed a distinct pattern of optic atrophy observed bilaterally in the temporal and inferior quadrants of the ONs. This arrangement of axonal degeneration, involving primarily the papillomacular bundle, closely resembled LHON and other mitochondrial optic neuropathies, supporting that mitochondrial dysfunction underlies its pathogenesis.     

Identification of the First ATRIP–Deficient Patient and Novel Mutations in ATR Define a Clinical Spectrum for ATR–ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR–Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR–ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR–ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP–deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR–deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR–ATRIP deficient sub-class of Seckel Syndrome. ATR–ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR–SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR–ATRIP Seckel Syndrome to be defined.     

Proposal of a novel diabetogenic mechanism involving the serpin PAI-1

Metabolic Syndrome is a cluster of risk factors (including obesity, hypertension and insulin resistance), which is associated with late-onset diabetes and coronary heart disease. Elevated levels of the protease inhibitor PAI-1 are well-known molecular markers of the Metabolic Syndrome. Here, however, we present a hypothesis that PAI-1 acts as a causative factor in the development of Metabolic Syndrome and its clinical sequelae. We propose that PAI-1 inhibits the activity of members of the proprotein convertase (PC) class of serine proteases and that this underlies, at a molecular level, many of the other features of the Metabolic Syndrome cluster.     

Renal tubular dysgenesis with hypoplastic calvaria: report of two cases

Renal tubular dysgenesis (RTD), a rare, lethal, autosomal recessive disorder, is characterized by short and poorly differentiated proximal tubules and associated with hypoplastic calvaria. We report two cases of RTD with hypoplasia of the calvaria. Microscopically, proximal tubules in the kidneys were not seen on routine H&E stain. Almost all tubules in the cortex were stained for epithelial membrane antigen (EMA), confirming the absence of proximal tubule differentiation. The autopsy findings, microscopic features and the etiology of this rare condition is discussed and compared with literature data.     

Efficacy of the treatment of sleep apnea using naltrexone. A clinical, polygraphic and gasometric study

Twelve patients with clinical, polysomnographic and oxymetric features of Sleep Apnoea Syndrome (S.A.S.) were recorded, after a 2-week wash-out period, during 2 nights without treatment and 2 nights after receiving 50 mg naltrexone at bed-time. Clinical symptoms improved immediately in four patients, within one month in three patients and after 3 months of treatment in the remaining five ones. Sleep Apnoea index as well as the number, duration and intensity of hypoxic events were dramatically improved by this treatment that has now been prescribed to 25 patients, for more than 2 years in 14 of them.     

A cardio-facio-cutaneous syndrome case with tight Achilles tendons

Cardio-facio-cutaneous syndrome (CFCS) is a multiple congenital anomaly disorder characterized by craniofacial features, cardiac defects, ectodermal anomalies and neurocognitive delay. Clinical findings of patients with CFCS show similarities to those of patients with Costello Syndrome (CS). CFCS and CS are caused by mutations in genes encoding proteins of the RAS-MAPK signaling pathway. Musculoskeletal findings including tight Achilles tendons and contractures of elbows, shoulders or hips have been reported in CS patients. However, limited extension of joints were observed in some patients with CFCS. According to the literature, no tight Achilles tendons have been reported in CFCS patients so far. In this case report, we present a male CFCS patient with tight Achilles tendons with a de-novo heterozygote N581D mutation in the BRAF gene detected by DNA sequence analysis.     

Partial duplication of 18q including a distal critical region for Edwards Syndrome in a patient with normal phenotype and oligoasthenospermia: case report

Several authors have attempted to construct a phenotype map for duplications of different portions of chromosome 18 to identify a possible critical region (CR) for Edwards Syndrome. Partial duplications of 18q have been reported in the literature involving the distal CR in patients with some clinical features of Edwards Syndrome. Here, we describe a phenotypically normal male with a large duplication on chromosome 18 that involves the proposed distal CR. The lack of clinical features is remarkable, except for pathological semen analysis, which suggests that terminal 17.4 Mb of 18q do not contain the Edwards Syndrome CR. Alternatively, unknown modifier factors or undetected somatic mosaicism might cause incomplete penetrance of this duplication.     

Insulin dependent diabetes mellitus accompanied by nephrocalcinosis and renal failure.

Renal failure was found in a five-year-old patient who had been treated with insulin since he was diagnosed as having insulin dependent diabetes mellitus (IDDM) at 3 years of age. Laboratory data showed that his renal failure was caused by a renal tubular dysfunction. The autopsy findings of his pancreas were compatible with those of IDDM. The kidneys were atrophied with an innumerable number of crystals in the proximal tubuli. Staining by Kossa indicated that the crystals contained calcium salt. The calcium content of his kidneys was significantly higher than that of control. The nephrocalcinosis seems to be caused by hypercalciuria associated with IDDM.