Carney complex- why thorough medical history taking is so important - report of three cases and review of the literature.

PURPOSE: To present a new case series and to review the literature on Carney complex (CNC) with an emphasis on highlighting key clinical features of the disease and pointing out possibilities of shortening the diagnostic process. METHOD: Searches of PubMed, identifying relevant reports up to April 2022. RESULTS: CNC is a rare, autosomally dominant inherited neoplasia -endocrinopathy syndrome with high clinical variability, even among members of the same family. Data on length of diagnostic process are scarce with numerous case series reporting a diagnostic delay of decades. Suggestions to shorten the diagnostic process includes awareness of the multi-faceted clinical presentations of CNC, thorough history taking of index patients and family members and awareness of diagnostic pitfalls. Importantly, unusual symptom combinations should alert the clinician to suspect a rare endocrinopathy syndrome such as CNC. Already present and coming on the horizon are databases and novel phenotyping technologies that will aid endocrinologists in their quest for timely diagnosis. CONCLUSION: In this review, we examine the current state of knowledge in CNC and suggest avenues for shortening the diagnostic journey for the afflicted patients.

Low Impact of Urinary Cortisol in the Assessment of Hydrocortisone Replacement Therapy.

Hydrocortisone replacement therapy is a cornerstone in the treatment of adrenal insufficiency (AI). While urinary cortisol has been used as a diagnostic tool for AI, it remains unclear whether it is a useful parameter to monitor hydrocortisone replacement therapy. Aim of this study was to evaluate possible differences in cortisol metabolism between adrenal insufficient patients and healthy subjects and to assess the value of urinary cortisol in AI management. In a case-control study, urinary cortisol excretion was determined in 14 patients with primary and secondary AI receiving hydrocortisone infusions from midnight to 8:00 AM. Results were correlated with serum cortisol levels and compared to urinary values obtained from 53 healthy volunteers. Urinary cortisol excretion in healthy subjects was 14.0±7.8 µg/8 h (range: 0.24-35.4), levels did not differ between 3 groups aged 20-34 years, 35-49 years, and ≥50 years. Patients with AI receiving hydrocortisone infusions demonstrated significantly higher rates of urinary cortisol excretion (51.6±37.8 µg/8 h; range 17.1-120.0, p<0.001); the values correlated with serum cortisol levels (r(2)=0.98). Of interest, patients with secondary AI showed significantly higher serum cortisol levels after hydrocortisone infusion than those with primary AI, conceivably due to residual adrenal function. In conclusion, we showed that: (i) there is a wide inter-individual variability in urinary cortisol excretion rates; (ii) cortisol metabolism in adrenal insufficient patients differs when compared to controls; (iii) there is a strong correlation between urinary and serum cortisol levels; and (iv) urinary cortisol levels despite their variability may help to discriminate between secondary and primary adrenal insufficiency.

[Individualized treatment of osteoporosis]. / Individualisierte Therapie der Osteoporose.

Osteoporosis is the most common clinical disorder of bone metabolism. Treatment decisions should be made on an individual basis, taking into consideration the relative benefits and risks in different patient populations. Drug selection should be based on the form (primary/secondary) and severity of osteoporosis, age, sex, the specific contraindications and precautions for using the various available medications, and existing comorbidities.

Headache and Depression in Patients with Hypothalamic-pituitary Disorders-etiology and Risk Factors.

INTRODUCTION: Headache and depression are common problems in patients with hypothalamic-pituitary disorders (HPD). AIM: To determine the prevalence of headache and depression in patients with HPD and the specific characteristics in affected individuals in comparison to patients with cardiovascular problems (CD). METHODS: Patients with HPD and CD were asked to complete a questionnaire regarding headache and depression. RESULTS: There were no significant differences between the HPD and the CD group. Prevalence of headache was not associated with the treatment modality of pituitary disease, hormone excess syndromes or any hormonal replacement therapy. However, ACTH, TSH and GH deficiency were associated with less headache when compared to patients with adequate secretion. Interestingly, patients who had prior surgery suffered significantly more often from depression. In addition, headache and depression were significantly more common in patients with microadenomas than in macroadenomas. DISCUSSION: The risk for headache and depression is mainly influenced by a combination of factors, but a specific pituitary hormone deficiency may decrease risk for headache.

[Cardiac myopathy due to overt hypothyroidism]. / Kardiale Myopathie bei manifester Hypothyreose.

HISTORY AND ADMISSION FINDINGS: A 51-year-old man presented with progressive tiredness, proximal muscle weakness, hair loss and weight gain for months. The patient showed mild pretibial myxedema and dry skin. Laboratory findings revealed strongly elevated cardiac enzymes as well as marked hypothyroidism. INVESTIGATIONS: The electrocardiogram, echocardiography, abdominal sonography and chest X-ray were unremarkable. Thyroid ultrasound demonstrated features of Hashimoto thyroiditis. TREATMENT AND COURSE: The findings supported the diagnosis of an overt hypothyroidism with myxedema and rhabdomyolysis. After starting levothyroxine and volume substitution laboratory parameters and clinical condition slowly normalized. CONCLUSION: Severe overt hypothyroidism may rarely present primarily as myopathy with myositis and cardiac involvement.

Headache and pituitary disease: a systematic review.

Headache is very common in pituitary disease and is reported to be present in more than a third of all patients with pituitary adenomas. Tumour size, cavernous sinus invasion, traction or displacement of intracranial pain-sensitive structures such as blood vessels, cranial nerves and dura mater, and hormonal hypersecretion are implicated causes. The present review attempts to systematically review the literature for any combination of headache and pituitary or hormone overproduction or deficiency. Most data available are retrospective and/or not based on the International Headache Society (IHS) classification. Whereas in pituitary apoplexy a mechanical component explains the almost universal association of the condition with headaches, this correlation is less clear in other forms of pituitary disease and a positive impact of surgery on headaches is not guaranteed. Similarly, invasion into the cavernous sinus or local inflammatory changes have been linked to headaches without convincing evidence. Some studies suggest that oversecretion of GH and prolactin may be important for the development of headaches, and treatment, particularly with somatostatin analogues, has been shown to improve symptoms in these patients. Otherwise, treatment rests on general treatment options for headaches based on an accurate clinical history and a precise classification which includes assessment of the patient's psychosocial risk factors.

[Endocrine emergencies during pregnancy]. / Endokrine Notfälle in der Schwangerschaft.

Endocrine emergencies during pregnancy can become life-threatening for both mother and fetus. In addition to some pregnancy-linked endocrine disorders, several pre-existing forms of endocrinopathy, such as Grave's disease, type 1 diabetes and adrenal insufficiency might deteriorate acutely during pregnancy. Early diagnosis and management are challenging because the classical symptoms are often modified by pregnancy. Laboratory tests are subject to altered physiological ranges and pharmacological options are limited while therapeutic goals are stricter than in the non-pregnant patient. This article focuses on endocrine emergencies complicating pregnancy.

Hypopituitarism in a HIV affected patient.

BACKGROUND: The clinical picture of pituitary abscesses may resemble features of other pituitary pathologies including endocrine deficiencies. The characteristic radiological changes, namely the ring enhancement, may aid in the diagnostic work-up of this very rare condition. CASE REPORT: A 40-year-old patient with longstanding HIV infection presented with headache and fatigue. Testing for pituitary function confirmed panhypopitutarism. MRI scanning demonstrated an inhomogeneous pituitary gland with ring-like enhancement and sphenoid sinus mucosa thickening. Transsphenoidal surgery was performed. Histologically CD68 positive macrophages were found supporting the diagnosis of infectious hypophysitis. Under hormone replacement therapy and retroviral treatment the patient clinically normalized. CONCLUSION: A pituitary abscess due to infectious hypophysitis is a rare cause of pituitary failure. Diagnostic signs on imaging may help to rapidly distinguish the cause of pituitary deficiency in patients with HIV infection.

Fatal pneumocystis jirovecii pneumonia in a case of ectopic Cushing's syndrome due to neuroendocrine carcinoma of the kidney.

Immunosuppression with subsequent opportunistic infections is a well-recognized complication of severe hypercortisolism. We report a case of fatal pneumocystis jirovecii pneumonia (formerly pneumocystis carinii pneumonia) in a case of ectopic Cushing's syndrome caused by a neuroendocrine carcinoma of the kidney. The 36-year old male patient had consulted a physician because of weight gain. Further endocrine diagnostic work-up revealed ACTH-dependent hypercortisolism of non-pituitary origin. Because of rapid clinical deterioration therapy with metyrapone was initiated. A neuroendocrine carcinoma of the right kidney with regional lymph node infiltration was identified and was suspected to be the source of the ACTH excess. Before any causal therapy could be initiated, the patient developed severe pneumocystis jirovecii pneumonia and died shortly thereafter from multiorgan failure one month after he first consulted a physician. Pneumocystosis has been reported in only a few cases of Cushing's syndrome. There seems to be a relationship between the degree of hypercortisolism and the susceptibility to opportunistic infections. Since ACTH concentrations may be excessively high in ectopic Cushing's syndrome and pneumocystosis may deteriorate as a consequence of decreasing circulating cortisol levels under adrenolytic therapy, prophylaxis against pneumocystis jirovecii infection should be considered.

Phosphorylation of the vasodilator-stimulated phosphoprotein regulates its interaction with actin.

The vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cyclic nucleotide-dependent kinases in platelets and other cardiovascular cells. It promotes actin nucleation and binds to actin filaments in vitro and associates with stress fibers in cells. The VASP-actin interaction is salt-sensitive, arguing for electrostatic interactions. Hence, phosphorylation may significantly alter the actin binding properties of VASP. This hypothesis was investigated by analyzing complex formation of recombinant murine VASP with actin after phosphorylation with cAMP-dependent kinase in different assays. cAMP-dependent kinase phosphorylation had a negative effect on both actin nucleation and VASP interaction with actin filaments, with the actin nucleating capacity being more affected than actin filament binding and bundling. Replacing VASP residues known to be phosphorylated in vivo by acidic residues to mimic phosphorylation had similar although less dramatic effects on VASP-actin interactions. In contrast, phosphorylation had no significant effect on VASP oligomerization or its interaction with its known ligands profilin, vinculin, and zyxin. When overexpressing VASP mutants in eukaryotic cells, they all showed targeting to focal contacts and stress fibers. Our results imply that VASP phosphorylation may act as an immediate negative regulator of actin dynamics.

Characterization of the actin binding properties of the vasodilator-stimulated phosphoprotein VASP.

The vasodilator-stimulated phosphoprotein (VASP) colocalizes with the ends of stress fibers in cell-matrix and cell-cell contacts. We report here that bacterially expressed murine VASP directly interacts with skeletal muscle actin in several test systems including cosedimentation, viscometry and polymerization assays. It nucleates actin polymerization and tightly bundles actin filaments. The interaction with actin is salt-sensitive, indicating that the complex formation is primarily based on electrostatic interactions. Actin binding is confined to the C-terminal domain of VASP (EVH2). This domain, when expressed as a fusion protein with EGFP, associates with stress fibers in transiently transfected cells.

Role of proteins of the Ena/VASP family in actin-based motility of Listeria monocytogenes.

Intracellular propulsion of Listeria monocytogenes is the best understood form of motility dependent on actin polymerization. We have used in vitro motility assays of Listeria in platelet and brain extracts to elucidate the function of the focal adhesion proteins of the Ena (Drosophila Enabled)/VASP (vasodilator-stimulated phosphoprotein) family in actin-based motility. Immunodepletion of VASP from platelet extracts and of Evl (Ena/VASP-like protein) from brain extracts of Mena knockout (-/-) mice combined with add-back of recombinant (bacterial or eukaryotic) VASP and Evl show that VASP, Mena, and Evl play interchangeable roles and are required to transform actin polymerization into active movement and propulsive force. The EVH1 (Ena/VASP homology 1) domain of VASP is in slow association-dissociation equilibrium high-affinity binding to the zyxin-homologous, proline-rich region of ActA. VASP also interacts with F-actin via its COOH-terminal EVH2 domain. Hence VASP/ Ena/Evl link the bacterium to the actin tail, which is required for movement. The affinity of VASP for F-actin is controlled by phosphorylation of serine 157 by cAMP-dependent protein kinase. Phospho-VASP binds with high affinity (0.5 x 10(8) M-1); dephospho-VASP binds 40-fold less tightly. We propose a molecular ratchet model for insertional polymerization of actin, within which frequent attachment-detachment of VASP to F-actin allows its sliding along the growing filament.

The interaction of the cell-contact proteins VASP and vinculin is regulated by phosphatidylinositol-4,5-bisphosphate.

BACKGROUND: Focal adhesion sites are cell-matrix contacts that are regulated by phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent pathways. Vinculin is a major structural component of these sites and is thought to be engaged in multiple ligand interactions at the cytoplasmic face of these contacts. Cytoplasmic vinculin is considered to be inactive due to its closed conformation involving intramolecular head-tail interactions. Recently, the vasodilator-stimulated phosphoprotein (VASP), a substrate of cyclic AMP-dependent or cyclic GMP-dependent kinases and a component of focal adhesion sites, was shown to bind to vinculin. RESULTS: VASP-vinculin complexes could be immunoprecipitated from cell lysates and, using immunofluorescence, both proteins were found to colocalize in nascent focal adhesions. Consistent with the view that vinculin must be activated at these sites, we found that PIP2, levels of which are elevated during the early stages of adhesion, bound to two discrete regions in the vinculin tail, disrupting the intramolecular head-tail interaction and inducing vinculin oligomerization. Vinculin-VASP complex formation was greatly enhanced by PIP2 and both the EVH1 and EVH2 domains of VASP participated in vinculin binding. CONCLUSIONS: Focal contact assembly involves interaction between VASP and vinculin, which is enhanced by PIP2-induced vinculin activation and oligomerization. Given that vinculin and VASP both bind to F-actin, vinculin-VASP complexes might bundle the distal ends of actin filaments in focal contacts. We propose that PIP2-dependent signalling modulates microfilament organization at cellular adhesion sites by regulating vinculin-VASP complexes.