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PubMed2026

Beyond Heritable PAH: Pulmonary Hypertension in Genetic Syndromes.

Pulmonary hypertension (PH) may complicate a broad range of genetic syndromes beyond the established spectrum of heritable pulmonary arterial hypertension. Although these conditions are individually rare, together they represent an emerging field at the crossroads of developmental biology, vascular medicine, and precision genomics. In many cases, PH may be the presenting feature or may remain unrecognized because it occurs within complex multisystem disorders involving congenital heart disease, developmental lung abnormalities, parenchymal lung disease, vascular malformations, or extra-pulmonary manifestations. Recent advances in human genetics have expanded the spectrum of genes and syndromes associated with PH, including disorders involving altered lung and vascular development, dysregulated hypoxia signaling, smooth muscle dysfunction, chromosomal abnormalities, and syndromic vasculopathies.In this review, we summarize the main genetic syndromes associated with PH and discuss their underlying mechanisms, clinical phenotypes, diagnostic clues, and therapeutic implications. We paid particular attention to conditions that illustrate the marked heterogeneity of syndromic PH such as FLNA-related disorders, neurofibromatosis type 1, Noonan syndrome, Down syndrome, Alagille syndrome, Cantú syndrome, Chuvash polycythaemia, cobalamin C deficiency, multisystemic smooth muscle dysfunction syndrome, alveolar capillary dysplasia with misalignment of pulmonary veins, and Moya Moya syndrome.

Journal Article↗

PubMedDate not supplied

Torticollis and hip dislocation.

Reports in the literature suggest that there is an association between two childhood disorders: torticollis, an easily recognized clinical deformity, and developmental dislocation or dysplasia of the hip, an occult disorder. The identification of the obvious disease, torticollis, may prompt a search for the occult disease, developmental dislocation of the hip. If the association of these two disorders is common, it may be justified to expend resources to diagnose the occult disorder in all cases in which the more obviously noticed disorder is recognized. The reported association varies between 2 and 29%. We retrospectively reviewed 70 patients with the diagnosis of congenital muscular torticollis to determine the incidence of hip dislocation or subluxation in these patients. Fifty-four patients had radiographs of their hips. Forty-one patients were available for follow-up at an average of age 3+4 years. Six patients were noted to have hip subluxation or dislocation, all at presentation. Of these, four had been referred for diagnosed hip disease, whereas two were referred for torticollis, and the hip disease was then diagnosed by the pediatric orthopaedist. No patient had abnormal radiographs or physical findings at follow-up. We conclude that the rate of hip disease in those with torticollis is approximately 8% and is lower than the 20% often quoted.

Child↗

PubMed1977

Symptoms and signs of cancer in the school-age child.

The American Cancer Society's seven warning signs of cancer are: 1. Unusual bleeding or discharge. 2. A lump or thickening in the breast or elsewhere. 3. A sore that does not heal. 4. Change in bowel or bladder habits. 5. Hoarseness or cough. 6. Indigestion or difficulty in swallowing. 7. Change in size or color of a wart or mole. These signs apply to children as well as to adults. Cancer in children, however, is often more insidious than in adults and may well mimic many other diseases, developmental processess, or childhood psychologic problems. The knowledge that cancer kills more children than any other disease and the awareness of the presenting symptoms and signs may well save a child's life. Early detection with prompt, aggressive therapy is of paramount importance in achieving cures in childhood cancer.

Adolescent↗

PubMed1983

[Prognosis in children with infantile seizures and possible factors influencing it].

Different developments (good n = 8, poor n = 15 and very poor n = 27) in 50 former patients with infantile myoclonic seizures are compared with findings from the acute phase of the disease after 11.1 +/- 4.1 years. It has been confirmed that it is sensible with regard to intellectual development to distinguish idiopathic (very seldom) and symptomatic cases in infantile myoclonic seizures. An early beginning of the disease, developmental backwardness as well as pathological and neurological findings as signs of a cerebral damage or disease (symptomatic cases) suggest a poor prognosis.

Adolescent↗

PubMed2005

Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome.

The expression of a gene requires not only a normal coding sequence but also intact regulatory regions, which can be located at large distances from the target genes, as demonstrated for an increasing number of developmental genes. In previous mutation studies of the role of FOXL2 in blepharophimosis syndrome (BPES), we identified intragenic mutations in 70% of our patients. Three translocation breakpoints upstream of FOXL2 in patients with BPES suggested a position effect. Here, we identified novel microdeletions outside of FOXL2 in cases of sporadic and familial BPES. Specifically, four rearrangements, with an overlap of 126 kb, are located 230 kb upstream of FOXL2, telomeric to the reported translocation breakpoints. Moreover, the shortest region of deletion overlap (SRO) contains several conserved nongenic sequences (CNGs) harboring putative transcription-factor binding sites and representing potential long-range cis-regulatory elements. Interestingly, the human region orthologous to the 12-kb sequence deleted in the polled intersex syndrome in goat, which is an animal model for BPES, is contained in this SRO, providing evidence of human-goat conservation of FOXL2 expression and of the mutational mechanism. Surprisingly, in a fifth family with BPES, one rearrangement was found downstream of FOXL2. In addition, we report nine novel rearrangements encompassing FOXL2 that range from partial gene deletions to submicroscopic deletions. Overall, genomic rearrangements encompassing or outside of FOXL2 account for 16% of all molecular defects found in our families with BPES. In summary, this is the first report of extragenic deletions in BPES, providing further evidence of potential long-range cis-regulatory elements regulating FOXL2 expression. It contributes to the enlarging group of developmental diseases caused by defective distant regulation of gene expression. Finally, we demonstrate that CNGs are candidate regions for genomic rearrangements in developmental genes.

Animals↗

PubMedDate not supplied

A novel missense Norrie disease mutation associated with a severe ocular phenotype.

Clinical findings and pedigree analysis led to the diagnosis of severe Norrie disease in two brothers. DNA sequencing demonstrated a novel missense mutation (703G>T) that significantly alters predicted protein structure. Less severe retinal developmental disease may be associated with milder mutations in the Norrie disease gene.

Blindness↗

PubMed2000

Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma.

The forkhead transcription factor gene FOXC1 (formerly FKHL7) is responsible for a number of glaucoma phenotypes in families in which the disease maps to 6p25, although mutations have not been found in all families in which the disease maps to this region. In a large pedigree with iris hypoplasia and glaucoma mapping to 6p25 (peak LOD score 6.20 [recombination fraction 0] at D6S967), no FOXC1 mutations were detected by direct sequencing. However, genotyping with microsatellite repeat markers suggested the presence of a chromosomal duplication that segregated with the disease phenotype. The duplication was confirmed in affected individuals by FISH with markers encompassing FOXC1. These results provide evidence of gene duplication causing developmental disease in humans, with increased gene dosage of either FOXC1 or other, as yet unknown genes within the duplicated segment being the probable mechanism responsible for the phenotype.

Chromosomes, Human, Pair 6↗

PubMedDate not supplied

[Reccurrent lingual hemiatrophy].

The author reported a 45-year-old woman with numerous developmental anomalies in whom lingual hemiatrophy preceded by strong occipital headaches followed tonsillectomy. After treatment considerable regeneration of tongue nuscle took place. The course of the disease was recurrent. In the differential diagnosis the author considered inflammatory processes, neoplastic diseases, developmental anomalies and toxic effect of procaine used in tonsillectomy as well as the possibility of deeply situated adhaesions in the vicinity of the hypoglossal nerve.

Atrophy↗

PubMed1991

The dawn of Darwinian medicine.

While evolution by natural selection has long been a foundation for biomedical science, it has recently gained new power to explain many aspects of disease. This progress results largely from the disciplined application of what has been called the adaptations program. We show that this increasingly significant research paradigm can predict otherwise unsuspected facets of human biology, and that it provides new insights into the causes of medical disorders, such as those discussed below: 1. Infection. Signs and symptoms of the host-parasite contest can be categorized according to whether they represent adaptations or costs for host or parasite. Some host adaptations may have contributed to fitness in the Stone Age but are obsolete today. Others, such as fever and iron sequestration, have been incorrectly considered harmful. Pathogens, with their large populations and many generations in a single host, can evolve very rapidly. Acquisition of resistance to antibiotics is one example. Another is the recently demonstrated tendency to change virulence levels in predictable ways in response to changed conditions imposed incidentally by human activities. 2. Injuries and toxins. Mechanical injuries or stressful wear and tear are conceptually simpler than infectious diseases because they are not contests between conflicting interests. Plant-herbivore contests may often underlie chemical injury from the defensive secondary compounds of plant tissues. Nausea in pregnancy, and allergy, may be adaptations against such toxins. 3. Genetic factors. Common genetic diseases often result from genes maintained by other beneficial effects in historically normal environments. The diseases of aging are especially likely to be associated with early benefits. 4. Abnormal environments. Human biology is designed for Stone Age conditions. Modern environments may cause many diseases-for example, deficiency syndromes such as scurvy and rickets, the effects of excess consumption of normally scarce nutrients such as fat and salt, developmental diseases such as myopia, and psychological reactions to novel environments. The substantial benefits of evolutionary studies of disease will be realized only if they become central to medical curricula, an advance that may at first require the establishment of one or more research centers dedicated to the further development of Darwinian medicine.

Adaptation, Physiological↗

PubMed1995

[Etiology of the infectious process in pulmonary and mixed forms of mucoviscidosis in children].

The specific features of an infectious process were studied in 150 children treated for mucoviscidosis at the State Pulmonology Research Center, Ministry of Health and Medical Industry of the Russian Federation. Hemophilic bacilli, Staphylococcus aureus, and Pseudomonas aeruginosa were fond to play the leading role in the etiology of the infectious process in the bronchopulmonary system. Pneumococcal infection was first ascertained to be important in the course of the disease. Developmental stages of a pyoinfectious process from the onset of its contamination, acute infection to chronic one were followed up. The most severe, prognostically unfavourable course of the disease was demonstrated to be associated with Pseudomonas aeruginosa infection.

Adolescent↗

PubMed2000

Early diagnosis of schizophrenia--the first step towards secondary prevention.

OBJECTIVE: To review current knowledge of risk factors associated with schizophrenia and the development of diagnostic markers aimed at the delay or attenuation of the first psychotic episode. METHOD: Studies relating to the development of disease and the risk factors that could inform predictive markers are reviewed, including high-risk studies, birth-cohort studies, and retrospective and follow-back studies. RESULTS: Future schizophrenic patients present with delayed developmental milestones, speech and behavioural difficulties, and lower IQ scores than non-cases. CONCLUSION: Results are consistent with the notion that schizophrenia is a developmental disease and that such antecedents are present; further research is required to improve the specificity of diagnostic markers and predictive power before these can be used to prevent or delay psychotic episodes of schizophrenia.

Humans↗

PubMed2003

Olfactory biopsies demonstrate a defect in neuronal development in Rett's syndrome.

Rett's Syndrome (RTT) is a neurodevelopmental disorder resulting from mutation in the mecp2 gene that encodes methyl CpG binding protein 2, a transcriptional repressor. Because this disease primarily affects neurons, tissue is not available during active disease. We used the olfactory system as a model to investigate abnormalities in neuronal development in RTT, because olfactory receptor neurons (ORNs) are replaced throughout life by ongoing postnatal neurogenesis. Thus, even in the adult, the olfactory epithelium contains neurons at various developmental stages. We obtained biopsies of nasal epithelium containing ORNs from RTT patients and age-matched controls to study the status of the neuronal population using antibodies to stage-specific developmental markers. There were no postprocedure complications. Compared with age-matched controls, there were far fewer mature ORNs, as defined by olfactory marker protein expression, and significantly greater numbers of immature neuron-specific tubulin-positive ORNs present. In RTT biopsies, olfactory marker protein-positive neurons displayed abnormal structure. These results suggest that dysfunction of MeCP2 results in decreased survival of mature ORNs with a compensatory increase in neurogenesis, or a failure of immature neurons to mature. Our study indicates that olfactory biopsies provide a method to study neuronal developmental diseases in adults and children.

Adolescent↗

PubMed1999

[Genetic anomalies of the gonadotropic axis].

Some forms of isolated hypogonadotropic hypogonadism are caused by mutations of the GnRH receptor gene. These mutations lead to inactivation of the receptor and are recessive. A unique disease that associates hypogonadotropic hypogonadism and congenital hyperplasia is caused by mutations in the DAX-1 gene, situated on chromosome X. The pathogenesis to these endocrine defects remains now elusive. Kallmann syndrome represents the association of hypogonadotropic hypogonadism due to GnRH deficiency, and anosmia. Additional developmental anomalies can be present. Three modes of inheritance have been described: X-linked, autosomal recessive and autosomal dominant. The X-linked KAL-1 gene has been cloned. It encodes an extracellular matrix protein, anosmin-1, the study of which should lead to a better understanding of this developmental disease.

Female↗

PubMedDate not supplied

[Chronic diseases in adolescence].

INTRODUCTION: The prevalence of chronic diseases in adolescence is constantly increasing, especially in the last two decades. Adolescence is a period of important changes: body growth and development, sexual development, development of cognitive abilities, change in family relations and between peers, formation of personal identity and personal system of values, making decisions on future occupation etc. CHRONIC DISEASES IN ADOLESENCE: Chronic disorders affect all development issues and represent an additional burden for adolescents. The interaction between chronic disorders and various development issues is complex and two-way: the disease may affect development, and development may affect the disease. Developmental, psychosocial and family factors are of great importance in the treatment of adolescents with chronic disorders. Chronic disorders affect all aspects of adolescent life, including relations with peers, school, nutrition, learning, travelling, entertainment, choice of occupation, plans for the future. Physicians should keep in mind that chronic diseases and their treatment represent only one aspect of person's life. Adolescents with chronic diseases have other needs as well, personal priorities, social roles and they expect these needs to be recognised and respected. Adolescent health care should be adjusted to the life style of adolescents.

Adolescent↗

PubMed1985

Handedness and alcoholism.

One hundred thirty-six alcoholic men and 48 alcoholic women admitted consecutively to an adult alcohol and substance abuse unit were studied in an attempt to replicate previous reports of an association between alcoholism and handedness. Each individual received a structured admission interview, and handedness was determined by a modification of the Edinburgh Inventory. Left-handedness was more frequent in men with alcoholic fathers and in first-born men. These data are discussed in the context of a recent theory relating left-handedness, immune disease, developmental learning disorders, and fetal testosterone.

Adult↗

PubMed1981

Receptor dysfunctions in human disease.

The characterization of binding parameters of hormones and drugs to specific receptors at various human cell types have introduced an interesting approach for the evaluation of pathogenic mechanisms involved in endocrine and metabolic disorders. The dysregulation of cellular receptors in those disease include changes in receptor number, changes in binding affinity and production of antibodies against receptor molecules. It can be concluded from these observations that altered receptor physiology may be of important value for abnormalities in cellular recognition and control mechanisms which can be observed in neoplastic, inflammatory, immune and developmental diseases.

Adenylyl Cyclases↗

PubMed1995

The use of MR contrast agents in the evaluation of disease of the spine.

In the last decade, magnetic resonance (MR) of the spine has become the imaging modality of choice, superseding both computed tomography (CT) and myelography, for the evaluation of a broad spectrum of disease entities. The capability for multiplanar imaging, the use of nonionizing radiation, and the ability to obtain a myelographic-like image (without intrathecal contrast injection) all provide distinct advantages. This article reviews the current applications of intravenous contrast media in MR for evaluation of the spine and its contents. In many instances, contrast enhancement plays a valuable role in developmental disease, trauma (e.g., disk herniation, both before and after surgery), infection, vascular disease, neoplasia, degenerative disease (e.g., neurogenic claudication), and demyelinative processes (e.g., multiple sclerosis).

Contrast Media↗

PubMed2001

Kallmann syndrome: towards molecular pathogenesis.

Gonadotropin Releasing Hormone (GnRH) is a key regulator of reproduction and sexual behaviour. During the last decade, embryological studies have clarified the question of the early development of GnRH-synthesising neurones before the onset of neurosecretion. These studies have revealed the existence of a topographical link between GnRH-synthesising neurones and the embryonic olfactory system, thereby shedding new light on Kallmann syndrome, a developmental disease characterised by the association of hypogonadotropic hypogonadism and anosmia (or hyposmia). Although Kallmann syndrome was identified as an inherited disease in the forties, familial cases of the disease are infrequent. However, the identification, by positional cloning strategies, of the gene underlying the X-chromosome linked form of the disease (KAL-1) has opened the way to molecular pathophysiology. KAL-1 encodes an extracellular glycoprotein of compound modular structure. The protein, named anosmin-1, has been produced in a transfected mammalian cell line and purified. Polyclonal and monoclonal antibodies have been generated, which allowed us to study the distribution of the protein during the period of human organogenesis (4--10 embryonic weeks), by immunohistofluorescence. During this developmental period, anosmin-1 is a locally restricted component of various extracellular matrices (interstitial matrices and basement membranes). Later in embryonic life, KAL-1 expression apparently becomes restricted to definite neuronal populations. Based on the distribution of anosmin-1 in the early olfactory system, the pathogenesis of the olfactory loss and GnRH deficiency in X-linked Kallmann syndrome is discussed.

Cell Adhesion Molecules↗