Next generation sequencing aids diagnosis and management in a case of encephalocraniocutaneous lipomatosis.

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder caused by somatic FGFR1 and KRAS variants. It shares significant phenotypic overlap with several closely related disorders caused by mutations in the RAS-MAPK pathway (mosaic RASopathies). We report a diagnostically challenging case of ECCL in which next-generation sequencing of affected tissue identified a pathologic FGFR1 p.K656E variant, thereby establishing a molecular diagnosis. Patients with FGFR1-associated ECCL carry a risk of developing malignant brain tumors; thus, genetic testing of patients with suspected ECCL has important management implications.

Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: biological insights and clinical advances.

Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The pathobiology of SDS results from impaired ribosomal maturation due to the deficiency of SBDS and the inability to evict the antiassociation factor eIF6 from the 60S ribosomal subunit. Clinical outcomes for patients with SDS who develop myeloid malignancies are extremely poor because of high treatment-related toxicities and a high rate of refractory disease/relapse even after allogeneic hematopoietic stem cell transplant (HSCT). Registry data indicate that outcomes are improved for patients with SDS who undergo routine bone marrow surveillance and receive an HSCT before developing an overt malignancy. However, the optimal approach to hematologic surveillance and the timing of HSCT for patients with SDS is not clearly established. Recent studies have elucidated distinct patterns of somatic blood mutations in patients with SDS that either alleviate the ribosome defect via somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints, resulting in increased leukemogenic potential (heterozygous TP53 inactivation). Genomic analysis revealed that most myeloid malignancies in patients with SDS have biallelic loss-of-function TP53 mutations. Single-cell DNA sequencing of SDS bone marrow samples can detect premalignant biallelic TP53-mutated clones before clinical diagnosis, suggesting that molecular surveillance may enhance the detection of incipient myeloid malignancies when HSCT may be most effective. Here, we review the clinical, genetic, and biologic features of SDS. In addition, we present evidence supporting the hematologic surveillance for patients with SDS that incorporates clinical, pathologic, and molecular data to risk stratify patients and prioritize transplant evaluation for patients with SDS with high-risk features.

RASopathies.

RASopathies are a group of disorders characterized by mutations in the RAS-MAPK pathway. RAS-MAP signaling plays a critical role in cell differentiation, proliferation, and survival. Germline mutations can result in distinctive syndromes, including Noonan syndrome, Costello syndrome, and neurofibromatosis type 1. Mosaic RASopathies can present as localized cutaneous lesions like epidermal nevi and nevus sebaceous, or more extensive conditions such as encephalocraniocutaneous lipomatosis. We review the heterogenous presentation of RAS mutations, discuss new targeted therapies, and highlight areas of uncertainty, including carcinogenesis risk and appropriate screening.

[Segmental overgrowth syndromes and therapeutic strategies]. / Les syndromes de surcroissance segmentaire et les stratégies thérapeutiques.

Overgrowth syndromes are a large group of rare disorders characterized by generalized or segmental excessive growth. Segmental overgrowth syndromes are mainly due to genetic anomalies appearing during the embryogenesis and leading to mosaicism. The numbers of patients with segmental overgrowth with an identified molecular defect has dramatically increased following the recent advances in molecular genetic using next-generation sequencing approaches. This review discusses various syndromes and pathways involved in segmental overgrowth syndromes and presents actual and future therapeutic strategies.

TITLE: Les syndromes de surcroissance segmentaire et les stratégies thérapeutiques. ABSTRACT: Les syndromes de surcroissance sont un groupe de pathologies caractérisées par une croissance excessive généralisée ou segmentaire. Les syndromes de surcroissance segmentaires sont principalement dus à des anomalies génétiques apparaissant durant l'embryogenèse et aboutissant à un mosaïcisme. Le nombre de patients atteints d'un syndrome de surcroissance avec une mutation identifiée a fortement augmenté grâce à des avancées récentes en génétique moléculaire, en utilisant le séquençage de nouvelle génération (NGS). Cette revue détaille les différents syndromes de surcroissance segmentaire ainsi que les voies moléculaires impliquées et les options thérapeutiques envisageables.

Spinal Epidural Lipomatosis: Weight Loss Cure.

A 47-year-old male patient presented at our neurosurgery unit with neurogenic claudication symptoms. The patient had a history of low back pain and lower extremity pain for 2 years. He had a body mass index of 38. Magnetic resonance imaging of the lumbar spine demonstrated severe stenosis due to spinal epidural lipomatosis. The patient was treated conservatively, and after weight loss in 13 months (body mass index of 29) he had full recovery of neurologic symptoms. A follow-up magnetic resonance image obtained 14 months after showed complete resolution of spinal epidural lipomatosis.

Incidental diagnosis of breast cancer in the pursuit of the treatment of intestinal obstruction

Intestinal lipomatosis is rare and often asymptomatic but can present with intestinal obstruction. Occasionally, metastatic breast cancer is identified in the ovary before a breast primary is discovered. We report the case of a 50-year-old woman diagnosed with synchronous intestinal obstruction due to lipomatosis, and incidental ovarian metastases from breast cancer. The patient presented with a 12-day history of nausea, diffuse abdominal pain, and constipation. An abdominal x-ray showed air-fluid levels, and computed tomography documented small bowel distention. An explorative laparotomy was performed, which revealed small bowel distention, an obstructive lesion of the ileocecal valve, three terminal ileum lesions, ascites, and heterogeneous ovaries. Right ileocolic resection and left oophorectomy were performed. The pathological diagnosis revealed lipomatous submucosal lesion of the ileocecal valve and ileum, and 17 lymph nodes, which were all negative for malignant cells. The oophorectomy revealed ovarian metastasis from breast carcinoma. Ascitic fluid was positive for malignant cells. Mammography and breast/axillary ultrasonography showed a solid nodule of the left breast, ductal carcinoma, and multiple enlarged left axillary lymph nodes, which were positive for neoplastic cells. Immunohistochemical evaluation showed hormonal receptor positivity and C-erb2 negativity. Breast magnetic resonance imaging showed a 14 mm left nodule and a positron emission tomography scan revealed 18F-FDG uptake in the left breast, left axillary lymph nodes, right ovary, and peritoneum. The tumor was staged as stage IV ductal breast carcinoma, cT1N1M1, Grade 2, Luminal B-like. The multidisciplinary oncological meeting proposed chemotherapy, and a re-staging breast MRI after chemotherapy, which showed a complete response. The patient started treatment with letrozole and remains disease-free 22 months after finishing chemotherapy.

Shwachman-Diamond Syndrome: Molecular Mechanisms and Current Perspectives.

Shwachman-Diamond syndrome (SDS) is a rare inherited disease mainly caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. However, it has recently been reported that other genes, including DnaJ heat shock protein family (Hsp40) member C21 (DNAJC21), elongation factor-like 1 (EFL1) and signal recognition particle 54 (SRP54) are also associated with an SDS-like phenotype. Interestingly, SBDS, DNAJC21, EFL1 and SRP54 are involved in ribosome biogenesis: SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21 stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking. These findings strengthen the postulate that SDS is a ribosomopathy. SDS is a multiple-organ disease mainly characterized by bone marrow failure, bone malformations, pancreatic insufficiency and cognitive disorders. Almost 15-20% of patients with SDS present myelodysplastic syndrome with a high risk of acute myeloid leukemia (AML) transformation. Unfortunately, besides bone marrow transplantation, no gene-based therapy for SDS has yet been developed. This review aims to recapitulate the recent findings on the molecular mechanisms of SDS underlying bone marrow failure, hematopoiesis and AML development and to draw a realistic picture of current perspectives.

[Shwachman-Diamond syndrome: a case report]. / Le syndrome de Shwachman-Diamond : à propos d'un cas.

Shwachman-Diamond syndrome is a constitutional disorder characterized by exocrine pancreatic failure and neutropenia with dysgranulopoiesis. It is a rare disease, with less than 100 cases reported in France. Here we report the case of a 23-year-old woman with this syndrome. The clinical feature and the diagnostic steps are described, as well as the evolution and management in medical and laboratory medicine practice.

Diagnosis, Treatment, and Molecular Pathology of Shwachman-Diamond Syndrome.

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome classically associated with exocrine pancreatic dysfunction and neutropenia, with a predisposition toward progressive marrow failure, risk of myelodysplastic syndrome, and leukemia. Most patients carry biallelic mutations in the Shwachman-Bodian-Diamond Syndrome gene, which is an integral component of ribosome maturation and biogenesis. This article reviews the diagnosis, clinical characteristics, and treatment modalities of SDS, and reports advances in the understanding of the molecular pathophysiology of SDS.

Shwachman-Diamond syndrome: Nationwide survey and systematic review in Japan.

BACKGROUND: Shwachman-Diamond syndrome (SDS) is a rare multisystem disorder associated with exocrine pancreatic insufficiency. The present study reports the results of a nationwide survey and a systematic review on SDS to develop consensus guidelines for intractable diarrhea including SDS. METHODS: Questionnaires were sent to 616 departments of pediatrics or of pediatric surgery in Japan in a nationwide survey. A second questionnaire was sent to doctors who had treated SDS patients and included questions on clinical information. Additionally, a systematic review was performed using digital literature databases to assess the influence of medical (i.e. non-surgical) treatment on SDS prognosis. RESULTS: Answers were received from 529 institutions (85.9%), which included information on 24 patients with SDS (median age, 10.4 years; male, n = 15) treated from January 2005 to December 2014. Although 75% of patients received pancreatic enzyme replacement therapy, there was no significant association between treatment and prognosis. Systematic review identified one clinical practice guideline, two case series, eight case reports and 26 reviews. Patient information from those studies was insufficient for meta-analysis. CONCLUSIONS: The rarity of SDS makes it difficult to establish evidence-based treatment for SDS. According to the limited information from patients and published reports, medical treatment for malabsorption due to SDS should be performed to improve fat absorption and stool condition, but it is not clear whether this treatment improves the prognosis of malabsorption.

Current Trends in Management of Submental Liposis: A Pooled Analysis and Survey.

IMPORTANCE: Since its approval by the US Food and Drug Administration for treatment of moderate to severe submental liposis in April 2015, deoxycholic acid (Kybella) has received significant media attention as a novel aesthetic treatment. Four phase 3 clinical trials have published data demonstrating the safety and efficacy of the drug compared with placebo; however, no study has juxtaposed the product with submental liposuction. OBJECTIVE: To evaluate the efficacy of injectable deoxycholic acid in the treatment of isolated submental liposis. EVIDENCE REVIEW: A pooled analysis of the data from the 2 European and 2 North American phase 3 clinical trials was performed by grouping the study participants by treatment arm to analyze efficacy, adverse effects, and treatment variables. Members of the American Academy of Facial Plastic and Reconstructive Surgery (AAFPRS) were also surveyed regarding their clinical use of deoxycholic acid, fees, and adverse events. FINDINGS: The pooled analysis included 1738 unique patients (348 men [20.0%] and 1390 women [80.0%]; mean [SD] age, 47.7 [1.6] years) and revealed that all studies demonstrated efficacy compared with placebo. However, a significant number of patients experienced pain, edema, and numbness after injection. The clinical trial population was injected with a mean (SD) of 186.0 (106.6) mg of drug per patient during the course of treatment. A total of 102 members responded to the survey, representing 4% of AAFPRS membership. Based on the results of the survey, clinicians reported charging a mean (SD) of $691.04 ($168.68) per 20-mg vial of deoxycholic acid, resulting in a cost of $6426.35 per study participant. The survey revealed a mean (SD) total cost to the patient for submental liposuction to be $2976.56 ($1041.62). CONCLUSIONS AND RELEVANCE: Although the clinical trials demonstrated functional drug efficacy, the large volume of drug used precluded cost-effectiveness. The survey found clinical practice to differ from the protocols used in the trials. Deoxycholic acid may be only fiscally efficacious for patients with mild to moderate submental liposis who require only 20 to 30 mg of drug per treatment for 3 treatment sessions. LEVEL OF EVIDENCE: 1.

Lipomatosis congénita infiltrante de la cara: reporte de un caso y revisión de la literatura / Congenital infiltrating lipomatosis of the face: case reporte and literature review

La lipomatosis congénita infiltrante de la cara (CLIF) es una enfermedad de origen congénito de baja prevalencia. Sus características clínicas son bien definidas. Éstas generan asimetrías faciales evidentes en los individuos que las padecen, las que pueden observarse clínicamente así como también en radiografías y estudios histopatológicos. El diagnóstico de lipomatosis se hace al nacimiento o a edades muy tempranas y su tratamiento también comienza cuando los pacientes son muy pequeños. Es de gran importancia el trabajo en equipo con cirujanos plásticos, cirujanos maxilofaciales, ortodoncistas, cirujanos dentistas y sicólogos. Este trabajo presenta el caso clínico de una niña chilena con diagnóstico de lipomatosis congénita infiltrante de la cara y el tratamiento que se le ha realizado hasta la fecha.

Congenital infiltrating lipomatosis of the face (CLIF) is a present at birth disease of low prevalence. Its clinical characteristics are well defined. They generate evident facial asymmetries in individuals who suffer from them which can be seen clinically as well as in X-rays or histopathological studies. Diagnosis of lipomatosis is made at birth or at very early stages and its treatment also starts when the patients are very young. It is of great importance the teamwork with plastic surgeons, maxillofacial surgeons, orthodontists, dental surgeons and psychologists. This paper shows the case of a Chilean girl with diagnosis of congenital infiltrating lipomatosis of the face and the treatment that she has received up to date.

First experience of hematopoietic stem cell transplantation treatment of Shwachman-Diamond syndrome using unaffected HLA-matched sibling donor produced through preimplantation HLA typing.

The only proven cure for Shwachman-Diamond syndrome (SDS) bone marrow failure is allogeneic hematopoietic stem cell transplantation (HSCT). However HSCT with donors other than HLA-identical siblings is associated with high mortality and unfavorable prognosis. This paper presents the first experience of HSCT treatment of SDS using an unaffected HLA-identical sibling produced through preimplantation genetic diagnosis (PGD). The patient was a 6-year-old blood transfusion-dependent SDS baby girl with secondary myelodysplastic syndrome, for whom no HLA-identical donor was available. As a result of PGD, two unaffected HLA matched embryos were identified; one of them was randomly selected for transfer, resulting in a clinical pregnancy and birth of an apparently healthy child. The patient underwent allogeneic transplantation of cord blood hematopoietic stem cells, together with bone marrow from this sibling, resulting in complete hemopoietic recovery. The patient was no longer transfusion-dependent and had normal blood values 160 days after transplantation.

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.

[Pelvic lipomatosis]. / Lipomatosis pelvis.

Pelvic lipomatosis is a rare benign disease characterized by increased pelvic fatty tissue of unknown origin, which leads to encroachment on the pelvic organs. This can lead to symptoms due to narrowing of the bladder and in some cases also of the rectum as well as distal obstruction of the ureter. Symptomatic disease seems to occur more commonly in men with unspecific lower urinary tract symptoms, constipation and hydronephrosis. Obstruction of the upper urinary tract necessitates operative treatment. As the etiology is unclear an appropriate causal treatment is not available.

Allogeneic hematopoietic stem cell transplantation for inherited bone marrow failure syndromes.

Inherited bone marrow failure (IBMF) syndromes are a heterogeneous group of rare hematological disorders characterized by the impairment of hematopoiesis, which harbor specific clinical presentations and pathogenic mechanisms. Some of these syndromes may progress through clonal evolution, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Most prominent are failures of DNA repair such as Fanconi Anemia and much rarer failure of ribosomal apparatus, e.g., Diamond Blackfan Anemia or of telomere elongation such as dyskeratosis congenita. In these congenital disorders, hematopoietic stem cell transplantation (HSCT) is often a consideration. However, HSCT will not correct the underlying disease and possible co-existing extra-medullary (multi)-organ defects, but will improve BMF. Indications as well as transplantation characteristics are most of the time controversial in this setting because of the rarity of reported cases. The present paper proposes a short overview of current practices.