Molecular and Cellular Bases of Lipodystrophy Syndromes.

Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.

Treatment results for lumbar epidural lipomatosis: Does fat matter?

PURPOSE: The lumbar epidural lipomatosis (LEL) is a rare disease that can cause sciatic pain syndrome or neurological deficits comparable to symptoms caused by a classical spinal canal stenosis. In severe cases surgical decompression was conducted. However, the outcome after decompressive surgery has only been investigated in small case series. In this study we compared the outcome of LEL patients after microsurgery with the outcome of patients with classical spinal stenosis (CSS). METHODS: Patients with LEL (n = 38) and patients with CSS (n = 51), who received microsurgical decompression, were followed in a prospective observational study for 3 years. The clinical results including the Oswestry Disability Index, Numeric Pain Rating Scale (NRS), Roland and Morris Disability Questionnaire, the Short Form-36 Score and the Walking Distance were analysed and compared between both groups. RESULTS: Patients with LEL improved significantly after microsurgical decompression in a 3-year follow-up concerning back pain, leg pain and pain-associated disability equal to patients with CSS (NRSback_LEL_preop. = 6.4; NRSback_CSS_preop. = 6.3; NRSback_LEL_3-years = 3.2; NRSback_CSS_3-years = 3.6; NRSleg_LEL_preop. = 6.3; NRSleg_CSS_preop. = 6.5; NRSleg_LEL_3-years = 2.5; NRSleg_CSS_3-years = 2.9; ODILEL_preop. = 52.7; ODICSS_preop = 51.8; ODILEL_3-years = 32.3; ODICSS_3-years = 27.6). The microsurgical decompression had a positive effect on the health-related quality of life, and patient satisfaction was high in both groups (LEL group-71%, CSS group-69%). CONCLUSIONS: LEL can influence the quality of life dramatically and cause a high degree of disability. A surgical decompression is a safe and effective procedure with a good clinical outcome comparable to the results in patients with an osteoligamentous spinal stenosis. Therefore, microsurgical decompression can be recommended in patients with LEL if conservative treatment fails. These slides can be retrieved under Electronic Supplementary Material.

Association of fatty pancreas with pancreatic endocrine and exocrine function.

AIM: The purpose of this study was to clarify whether fatty pancreas might lead to impaired pancreatic endocrine or exocrine function. MATERIAL AND METHODS: The study involved 109 participants who had undergone the glucagon stimulation test and N-benzoyl-L-tyros-p-amino benzoic acid (BT-PABA) test to assess pancreatic function as well as unenhanced abdominal computed tomography (CT). Pancreatic endocrine impairment was defined as ΔC peptide immunoreactivity less than 2 [mmol/L] in the glucagon stimulation test, and pancreatic exocrine impairment was defined as a urinary PABA excretion rate less than 70% on the BT-PABA test. We defined as the mean CT value of pancreas / CT value of spleen (P/S ratio) as a marker to assess fatty pancreas. We analyzed the association between fatty pancreas and pancreatic impairment using the logistic regression model. The odds ratio (OR) is shown per 0.1 unit. RESULTS: Pancreatic endocrine function was impaired in 33.0% of the participants, and 56.9% of those were regarded as having pancreatic exocrine impairment. The P/S ratio was significantly correlated with pancreatic endocrine impairment in univariate analysis (OR = 0.61, 95% confidence interval (CI) = 0.43-0.83, P = 0.0013) and multivariate analysis (OR = 0.38, 95% CI = 0.22-0.61, P < .0001) for all participants. Similar significant relationships were observed in both univariate (OR = 0.70, 95% CI = 0.49-0.99, P = 0.04) and multivariate (OR = 0.39, 95% CI = 0.21-0.66, P = 0.0002) analyses for the participants without diabetes (n = 93). The amount of pancreatic fat was not associated with exocrine impairment in univariate analysis (OR = 0.80, 95% CI = 0.59-1.06, P = 0.12). CONCLUSION: Fatty pancreas was associated with pancreatic endocrine impairment but did not have a clear relationship with pancreatic exocrine impairment.

Lipomatosis infiltrante facial asociada a síndrome de Cowden incompleto / Facial infiltrating lipomatosis associated with incomplete Cowden syndrome

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Lumbar epidural lipomatosis is associated with visceral fat and metabolic disorders.

PURPOSE: Lumbar spinal epidural lipomatosis (LEL) is a condition characterized by excessive deposition of epidural fat in the spinal canal. Metabolic abnormalities may be associated with LEL, but few validated reports exist. Thus, we investigated the association between LEL and metabolic disorders in this study. METHODS: A total of 218 patients who had neurological symptoms due to neural compression in the lumbar spinal canal were examined by magnetic resonance imaging (MRI), abdominal computed tomography (CT) scans and blood tests. We evaluated the epidural fat, dural sac and spinal canal areas using MRI, and the visceral fat and subcutaneous fat areas using abdominal CT. We compared the patients' demographics and the radiological parameters between the LEL and non-LEL patients. RESULTS: There were 58 LEL patients and 160 non-LEL patients. The LEL group included more men than women. In the MRI measurement, the dural sac area was similar between the LEL and non-LEL patients; however, the epidural fat/spinal canal ratio was much greater in the LEL group. In the LEL patients, factors associated with metabolic disorders, such as visceral fat area, uric acid (UA) and insulin levels, were significantly greater, compared to the non-LEL patients. In the logistic regression analysis, UA and visceral fat area were the independent explanatory factors in the pathogenesis of LEL. CONCLUSIONS: LEL patients had significantly more visceral fat and increased levels of insulin, UA and ferritin, which are closely related with metabolic disorders. This study indicates that the increased epidural fat in the spinal canal seen in the LEL patients is associated with metabolic syndrome. These slides can be retrieved under Electronic Supplementary material.

Mesenchymal stromal cells from Shwachman-Diamond syndrome patients fail to recreate a bone marrow niche in vivo and exhibit impaired angiogenesis.

Shwachman-Diamond syndrome (SDS) is a rare multi-organ recessive disease mainly characterised by pancreatic insufficiency, skeletal defects, short stature and bone marrow failure (BMF). As in many other BMF syndromes, SDS patients are predisposed to develop a number of haematopoietic malignancies, particularly myelodysplastic syndrome and acute myeloid leukaemia. However, the mechanism of cancer predisposition in SDS patients is only partially understood. In light of the emerging role of mesenchymal stromal cells (MSCs) in the regulation of bone marrow homeostasis, we assessed the ability of MSCs derived from SDS patients (SDS-MSCs) to recreate a functional bone marrow niche, taking advantage of a murine heterotopic MSC transplant model. We show that the ability of semi-cartilaginous pellets (SCPs) derived from SDS-MSCs to generate complete heterotopic ossicles in vivo is severely impaired in comparison with HD-MSC-derived SCPs. Specifically, after in vitro angiogenic stimuli, SDS-MSCs showed a defective ability to form correct networks, capillary tubes and vessels and displayed a marked decrease in VEGFA expression. Altogether, these findings unveil a novel mechanism of SDS-mediated haematopoietic dysfunction based on hampered ability of SDS-MSCs to support angiogenesis. Overall, MSCs could represent a new appealing therapeutic target to treat dysfunctional haematopoiesis in paediatric SDS patients.

Refining the phenotype associated with biallelic DNAJC21 mutations.

Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes involved in genomic stability. Although they may be recognized by the association of typical clinical features, variable penetrance and expressivity are common, and clinical diagnosis is often challenging. DNAJC21, which is involved in ribosome biogenesis, was recently linked to bone marrow failure. However, the specific phenotype and natural history remain to be defined. We correlate molecular data, phenotype, and clinical history of 5 unreported affected children and all individuals reported in the literature. All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities. Additional features present in some individuals include retinal abnormalities, pancreatic insufficiency, liver cirrhosis, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, and cryptorchidism. We suggest that DNAJC21-related diseases constitute a distinct IBMFS, with features overlapping Shwachman-Diamond syndrome and Dyskeratosis congenita, and additional characteristics that are specific to DNAJC21 mutations. The full phenotypic spectrum, natural history, and optimal management will require more reports. Considering the aplastic anemia, the possible increased risk for leukemia, and the multisystemic features, we provide a checklist for clinical evaluation at diagnosis and regular follow-up.

Diagnóstico morfológico y funcional de una rara entidad: pseudohipertrofia lipomatosa del páncrea / The morphological and functional diagnosis of a rare entity: lipomatous pseudohypertrophy of the pancreas

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Urodynamic characteristics of pelvic lipomatosis with glandular cystitis patients correlate with morphologic alterations of the urinary system and disease severity.

AIMS: To explore urodynamic characteristics and their clinical value in pelvic lipomatosis (PL) patients. METHODS: We reviewed the clinical information of 84 PL patients. A voiding pressure-flow study was used to classify patients into nonoutlet obstruction (NOO), latter-half-section obstruction (LHSO), or whole-section bladder outlet obstruction (BOO) groups. Urinary morphologic features were measured by imaging examination and cystoscopy. RESULTS: A unique LHSO that presented as sudden increasing detrusor pressure (Pdet) and decreasing flow rate in the latter half of voiding was observed for 52.4% (44 of 84) patients. Overall, 27.4% (23 of 84 patients) were diagnosed with BOO with whole-section increasing Pdet and decreasing flow rate. According to the morphologic feature analyses, the NOO patients had the largest angle of anteroposterior vesical walls (P < 0.001) and the least severe thickened bladder trigone (P = 0.015). The external compression at the bladder neck and thickened bladder trigone caused a prolonged and strictured bladder outlet tract (see the Supplementary video). There were 0, 5, and 4 urinary diversions performed in the NOO, LHSO, and BOO groups at diagnosis (P = 0.055). No patients in the NOO group, seven in the LHSO group, and two patients in the BOO group had disease progression at follow-up. Two LHSO patients and one BOO patients without hydronephrosis at diagnosis developed to hydronephrosis during follow-up. CONCLUSIONS: Morphologic alterations of the urinary system of PL patients lead to unique LHSO or BOO on UDS. The presences of LHSO and BOO are associated with disease severity and progression.

Severe infantile isolated exocrine pancreatic insufficiency caused by the complete functional loss of the SPINK1 gene.

Exocrine pancreatic insufficiency (EPI) is rare in children, with most if not all cases occurring as part of syndromic conditions such as cystic fibrosis and Shwachman-Diamond syndrome. Here we report two cases, both presenting with severe EPI around 5 months of age. Characterized by diffuse pancreatic lipomatosis, they otherwise exhibited no remarkable deficiencies in other organs. Novel non-identical homozygous variants (a deletion removing the entire SPINK1 gene and an insertion of a full-length inverted Alu element into the 3'-untranslated region of the SPINK1 gene) resulting in the complete functional loss of the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) were identified in each patient. Having correlated our findings with current knowledge of SPINK1's role in exocrine pancreas pathophysiology, we propose that complete and partial functional losses of the SPINK1 gene are associated with quite distinct phenotypes, the former causing a new pediatric disease entity of severe infantile isolated EPI.

Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in aShwachman-Diamond like syndrome.

BACKGROUND: For the final step of the maturation of the ribosome, the nascent 40S and 60S subunits are exported from the nucleus to the cell cytoplasm. To prevent premature association of these ribosomal subunits, eukaryotic initiation factor 6 (eIF6) binds the 60S subunit within the nucleus. Its release in the cytoplasm requires the interaction of EFL1 and SDBS proteins. In Shwachman-Diamond syndrome (SDS), a defective SDBS protein prevents eIF6 eviction, inhibiting its recycle to the nucleus and subsequent formation of the active 80S ribosome. OBJECTIVE: This study aims to identify the molecular basis of an SDS-like disease, manifested by pancytopenia, exocrine pancreatic insufficiency and skeletal abnormalities in six patients from three unrelated families. METHODS: Whole exome analysis was used for mutation identification. Fluorescence microscopy studies assessed the localisation of Tif6-GFP, the yeast eIF6 homologue, in yeast WT and mutant cells. Human and yeast EFL1 proteins, WT and mutants, were expressed in Saccharomyces cerevisiae BCY123 strain, and circular dichroism and small-angle X-ray scattering were used to assess the folding and flexibility of these proteins. Green malachite colorimetric assay was performed to determine the GTPase activity of WT and Efl1 mutants. RESULTS: Four patients were homozygous for p.R1095Q variant and two patients were homozygous for p.M882K variant in EFL1. Residue R1095 and M882 are conserved across species. Neither the GTPase activity of the mutant proteins nor its activation by the SDBD protein or the 60S ribosomal subunit were affected. Complementation of efl1Δ yeast cells with the EFL1 mutants rescued the slow growth phenotype. Nonetheless, Tif6-GFP was relocalised to the cytoplasm in mutant yeast cells in contrast to its nuclear localisation in WT cells. CONCLUSIONS: Mutations in EFL1 clinically manifest as SDS-like phenotype. Similar to the molecular pathology of SDS, mutant EFL1 proteins do not promote the release of cytoplasmic Tif6 from the 60S subunit, likely preventing the formation of mature ribosomes.

Gastroduodenal Lipomatosis in Familial Multiple Lipomatosis.

OBJECTIVE: To present a case of gastroduodenal lipomatosis associated with familial multiple lipomatosis (FML). CLINICAL PRESENTATION AND INTERVENTION: A 58-year-old male presented with FML that manifested as multiple, painless, subcutaneous lipomas on his body; his mother had subcutaneous lipoma without a diagnosis of gastroduodenal lipomatosis. His lipid profile was normal. Abdominal computed tomography showed multiple, submucosal, polypoid lesions (of uniform density) of fat in the stomach and duodenum, and a small, similar lesion in the ileum. CONCLUSION: This case shows that gastrointestinal lipomatosis can manifest as FML.

A unique case of Shwachman-Diamond syndrome presenting with congenital hypopituitarism.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive bone marrow failure syndrome typically characterized by neutropenia and pancreatic dysfunction, although phenotypic presentations vary, and the endocrine phenotype is not well-described. We report a unique case of a patient with SDS who initially presented with hypoglycemia and micropenis in the newborn period and was diagnosed with congenital hypopituitarism. We are not aware of any other cases of SDS documented with this combination of complex endocrinopathies.

Lipomatous Atrial Septal Hypertrophy: A Review of Its Anatomy, Pathophysiology, Multimodality Imaging, and Relevance to Percutaneous Interventions.

Lipomatous atrial septal hypertrophy (LASH) is a histologically benign cardiac lesion characterized by excessive fat deposition in the region of the interatrial septum that spares the fossa ovalis. The etiology of LASH remains unclear, though it may be associated with advanced age and obesity. Because of the sparing of the fossa ovalis, LASH has a pathognomonic dumbbell shape. LASH may be mistaken for various tumors of the interatrial septum. Histologically, LASH is composed of both mature and brown (fetal) adipose tissue, but the role of brown adipose tissue remains unclear. In interventional procedures requiring access to the left atrium, LASH may interfere with transseptal puncture, as traversing the thickened area can reduce the maneuverability of catheters and devices. This may cause the needle to enter the epicardial space, causing dangerous pericardial effusions. LASH was once considered a contraindication to percutaneous device closure of atrial septal defects because of an associated increased risk for incorrect device deployment. However, careful attention to preprocedural imaging and procedural intracardiac echocardiography enable interventional cardiologists to perform procedures in patients with LASH without serious complications. In this review article, the authors describe anatomic and functional aspects of LASH, with emphasis on their roles in percutaneous interventions.

Shwachman-Diamond syndrome presenting with early ichthyosis, associated dermal and epidermal intracellular lipid droplets, hypoglycemia, and later distinctive clinical SDS phenotype.

Shwachman-Diamond syndrome (SDS) is a recessive ribosomopathy, characterized by bone marrow failure and exocrine pancreatic insufficiency (ePI) often associated with neurodevelopmental and skeletal abnormalities. The aim of this report is to describe a SDS patient with early ichthyosis associated with dermal and epidermal intracellular lipid droplets (iLDs), hypoglycemia and later a distinctive clinical SDS phenotype. At 3 months of age, she had ichthyosis, growth retardation, and failure to thrive. She had not cytopenia. Ultrasonography (US) showed pancreatic diffuse high echogenicity. Subsequently fasting hypoketotic hypoglycemia occurred without permanent hepatomegaly or hyperlipidemia. Continuous gavage feeding was followed by clinical improvement including ichthyosis and hypoglycemia. After 14 months of age, she developed persistent neutropenia and ePI consistent with SDS. The ichthyotic skin biopsy, performed at 5 months of age, disclosed iLDs in all epidermal layers, in melanocytes, eccrine sweat glands, Schwann cells and dermal fibroblasts. These iLDs were reminiscent of those described in Dorfman-Chanarin syndrome (DCS) or Wolman's disease. Both LIPA and CGI-58 analysis did not revealed pathogenic mutation. By sequencing SBDS, a compound heterozygous for a previously reported gene mutation (c.258 + 2T>C) and a novel mutation (c.284T>G) were found. Defective SBDS may hypothetically interfere as in DCS, with neutral lipid metabolism and play a role in the SDS phenotype such as ichthyosis with dermal and epidermal iLDs and hypoglycemia. This interference with neutral lipid metabolism must most likely occur in the cytoplasm compartment as in DCS and not in the lysosomal compartment as in Wolman's disease. © 2016 Wiley Periodicals, Inc.

Novel myopathy in a newborn with Shwachman-Diamond syndrome and review of neonatal presentation.

Shwachman-Diamond-Bodian syndrome (SDS) is a pleiotropic disorder in which the main features are bone marrow dysfunction and pancreatic insufficiency. Skeletal changes can occur, and in rare cases manifest as severe congenital thoracic dystrophy. We report a newborn boy with asphyxia, narrow thorax, and severe hypotonia initially suggesting a neuromuscular disease. The muscle biopsy showed myopathic changes with prominent variability in muscle fiber size and abnormal expression of developmental isoforms of myosin. The myofibrils showed focal loss and disorganization of myofilaments, and thickening of the Z-discs including some abortive nemaline rods. The boy became permanently dependent on assisted ventilation. Pancreatic insufficiency was subsequently diagnosed, explaining the malabsorption and failure to thrive. Except transitory thrombocytopenia and leukopenia, no major hematological abnormalities were noted. He had bilateral nephrocalcinosis with preserved renal function. Transitory liver dysfunction with elevated transaminase levels and parenchymal changes on ultrasound were registered. The clinical diagnosis was confirmed by detection of compound heterozygous mutations in SBDS using whole-exome sequencing: a recurrent intronic mutation causing aberrant splicing (c.258+2T>C) and a novel missense variant in a highly conserved codon (c.41A>G, p.Asn14Ser), considered to be damaging for the protein structure by in silico prediction programs. The carrier status of the parents has been confirmed. This case illustrates the challenges in differential diagnosis of pronounced neonatal hypotonia with asphyxia and highlights the muscular involvement in SDS. To our knowledge, this is the first report of myopathy evidenced in a patient with clinically and molecularly confirmed SDS.

Encephalocraniocutaneous lipomatosis.

Encephalocraniocutaneous lipomatosis (ECCL) is an unusual condition marked by characteristic dermatologic and neurologic findings presenting in a mosaic fashion. These are now being found to be due to specific genetic mutations. Traditionally, the diagnostic features include ocular dermoids, scalp changes, and spinal lipomas. While there are other similar diagnostic considerations, ECCL, is sufficiently distinct clinically to allow differentiation. Such information is of use when considering pathogenesis and in counseling. Consideration of possible associated clinical findings is key for correct clinical assessment and management. The condition highlights the need for a collaborative approach to diagnosis and management. Dermatology, ophthalmology, genetics, neurology, and neurosurgery can be engaged in the care of such patients.