A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome.

Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to a heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: (i) intrauterine growth retardation and postnatal short stature, (ii) feeding difficulties and/or gastro-oesophageal reflux, (iii) microcephaly, (iv) intellectual disability, and (v) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and 3 in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for 20 cases which do not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counselling.

Myhre syndrome.

Myhre syndrome (MS) is a developmental disorder characterized by typical facial dysmorphism, thickened skin, joint limitation and muscular pseudohypertrophy. Other features include brachydactyly, short stature, intellectual deficiency with behavioral problems and deafness. We identified SMAD4 as the gene responsible for MS. The identification of SMAD4 mutations in Laryngotracheal stenosis, Arthropathy, Prognathism and Short stature (LAPS) cases supports that LAPS and MS are a unique entity. The long-term follow up of patients shows that these conditions are progressive with life threatening complications. All mutations are de novo and changing in the majority of cases Ile500, located in the MH2 domain involved in transcriptional activation. We further showed an impairment of the transcriptional regulation via TGFß target genes in patient fibroblasts. Finally, the absence of SMAD4 mutations in three MS cases may support genetic heterogeneity.

Unequal Impact of COL1A1 and COL1A2 Variants on Dentinogenesis Imperfecta.

Dentinogenesis imperfecta (DI) is the main orodental manifestation of osteogenesis imperfecta (OI) caused by COL1A1 or COL1A2 heterozygous pathogenic variants. Its prevalence varies according to the studied population. Here, we report the molecular analysis of 81 patients with OI followed at reference centers in Brazil and France presenting COL1A1 or COL1A2 variants. Patients were submitted to clinical and radiographic dental examinations to diagnose the presence of DI. In addition, a systematic literature search and a descriptive statistical analysis were performed to investigate OI/DI phenotype-genotype correlation in a worldwide sample. In our cohort, 50 patients had COL1A1 pathogenic variants, and 31 patients had COL1A2 variants. A total of 25 novel variants were identified. Overall, data from a total of 906 individuals with OI were assessed. Results show that DI was more frequent in severe and moderate OI cases. DI prevalence was also more often associated with COL1A2 (67.6%) than with COL1A1 variants (45.4%) because COL1A2 variants mainly lead to qualitative defects that predispose to DI more than quantitative defects. For the first time, 4 DI hotspots were identified. In addition, we showed that 1) glycine substitution by branched and charged amino acids in the α2(I) chain and 2) substitutions occurring in major ligand binding regions-MLRB2 in α1(I) and MLBR 3 in α2(I)-could significantly predict DI (P < 0.05). The accumulated variant data analysis in this study provides a further basis for increasing our comprehension to better predict the occurrence and severity of DI and appropriate OI patient management.

SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients.

BACKGROUND: Individuals with pathogenic variants in SATB2 display intellectual disability, speech and behavioral disorders, dental abnormalities and often features of Pierre Robin sequence. SATB2 encodes a transcription factor thought to play a role in bone remodeling. The primary aim of our study was to systematically review the skeletal manifestations of SATB2-associated syndrome. For this purpose, we performed a non-interventional, multicenter cohort study, from 2017 to 2018. We included 19 patients, 9 females and 10 males ranging in age from 2 to 19 years-old. The following data were collected prospectively for each patient: clinical data, bone markers and calcium and phosphate metabolism parameters, skeletal X-rays and bone mineral density. RESULTS: Digitiform impressions were present in 8/14 patients (57%). Vertebral compression fractures affected 6/17 patients (35%). Skeletal demineralization (16/17, 94%) and cortical thinning of vertebrae (15/17) were the most frequent radiological features at the spine. Long bones were generally demineralized (18/19). The distal phalanges were short, thick and abnormally shaped. C-telopeptide (CTX) and Alkaline phosphatase levels were in the upper normal values and osteocalcin and serum procollagen type 1 amino-terminal propeptide (P1NP) were both increased. Vitamin D insufficiency was frequent (66.7%). CONCLUSION: We conclude that SATB2 pathogenic variants are responsible for skeletal demineralization and osteoporosis. We found increased levels of bone formation markers, supporting the key role of SATB2 in osteoblast differentiation. These results support the need for bone evaluation in children and adult patients with SATB2-associated syndrome (SAS).

[Neonatal renal venous thrombosis in 2008]. / Thrombose néonatale des veines rénales en 2008.

Venous thromboses are rare in childhood. In the neonatal period, these are mainly neonatal renal venous thromboses (NRVT). We propose a synthesis of the main recent reviews on NRVT published over the last 15 years. These studies reported the higher male prevalence, the predominance of left kidney vein involvement, the increasing incidence in premature newborns, and a high level of thrombophilia in screened newborns. The usual presentation of NRVT, which associates abdominal mass, macroscopic hematuria, and thrombocytopenia, has been progressively modified by these new epidemiological features. The abdominal Doppler ultrasound scan is widely used for diagnosis and must be systematically associated with a transfontanellar ultrasound to look for cerebral hemorrhage, which should be a contraindication for anticoagulation. Recent consensus recommends at least prophylactic heparin therapy in the majority of cases to prevent thrombus extension. Fibrinolysis should be reserved for bilateral thrombosis with systemic effects. Despite improvements in screening and care, mean-term and long-term sequellae such as kidney atrophia, moderate renal insufficiency, systemic hypertension, and relapses in case of thrombophilia are still frequent and severe. A systematic follow-up by pediatric nephrologists is recommended.

[Multiple Bowen disease of the lower limbs in elderly women: a rare clinical subset involving therapeutic difficulties]. / Maladies de Bowen multiples des membres inférieurs chez les femmes âgées : une forme clinique particulière et de traitement difficile.

BACKGROUND: Cutaneous Bowen's disease (CBD) is a form of intraepithelial squamous cell carcinoma that usually presents as a solitary lesion. We report four similar cases of a peculiar and well-delimited clinical subset of multiple Bowen's disease seen in the lower limbs in elderly women and associated with specific therapeutic problems. OBSERVATIONS: Four women aged over 70 years presented with multiple CBD limited to the lower limbs associated with squamous cell and superficial basal cell carcinomas along with actinic keratosis. No significant aetiological factors were present apart from chronic sun exposure other than one case possibly involving immunodeficiency. The four patients were treated using photodynamic therapy, and partial clinical response and good tolerance were observed. DISCUSSION: These four cases share numerous clinical similarities: elderly women, markers of chronic sun exposure, lack of other aetiological factors such as arsenic or irradiation, localization of the lesions (multiple and/or continuous layer pattern, restricted to the lower limbs in all cases) and a chronic course. The frequency of this subset is probably underestimated due to absence of biopsies or to inconclusive histology reports. Photodynamic therapy yields valuable results with a good efficacy/safety ratio compared to imiquimod or 5-fluorouracil. However, while this treatment could be considered a first-line option in multiple CBD, its therapeutic value requires more detailed evaluation.

Gnathodiaphyseal dysplasia with a novel R597I mutation of ANO5: Mandibular reconstruction strategies.

Gnathodiaphyseal Dysplasia (GDD) is a rare, often misdiagnosed, autosomal-dominant disorder due to point mutations in the ANO5 gene. GDD combines craniofacial fibro-osseous lesions, dental loss and progressive curvature and cortical thickening of long bones and vertebra, causing pathological fractures. Diagnosis is based on bone pathology and mutation screening. Here we report three GDD cases within a single family with a novel ANO5 mutation: c.1790 G > T (p.Arg597Ile, i.e. R597I) on exon 16. Microsurgical mandibular reconstructions were performed in the three cases. We reviewed the literature on jaw reconstruction in this condition and discussed the challenges of craniofacial reconstruction in GDD due to the diffuse bone anomalies affecting potential flap donor zones and a specific risk for jawbone osteomyelitis.

Perinatal and infantile hypophosphatasia: clinical features and treatment.

Hypophosphatasia (HPP) is a rare hereditary disease characterized by defective skeletal mineralization, and with a broad severity spectrum. The perinatal forms, lethal and non-lethal, are associated with severe neonatal respiratory distress, potential seizures, hypotrophy and marked hypotonia. The diagnosis is rapidly suggested by a combination of typical radiological signs, hypercalcemia, hyperphosphatemia and low alkaline phosphatase (ALP) activity. In the infantile form, the clinical signs appear before the age of six months, but the patients usually have no or very mild signs at birth. The diagnosis should be considered in the event of early deformation of the pectus, feeding difficulties, hypotonia, frequent respiratory tract infections, hypercalcemia, and even early constitution of craniosynostosis. Radiological signs may be less obvious characterized by irregular metaphyses and generalized hypomineralization. Management is initially symptomatic, and adjusted to the symptoms. Care should be provided by a multidisciplinary team, in close collaboration with Reference Centers experts for the disease. Currently, recombinant enzyme replacement therapy (ERT) is under development for the severe form of HPP. The course of the disease, depending on the degree of severity and the various types of management, requires long-term evaluation through joint prospective follow-up to assess the long-term outcomes of these patients. Multidisciplinary follow up is needed to identify the medical and socio-economic outcomes of children and adults affected by HPP.

[About twins: Epidemiological, genetic, and obstetrical aspects, specific risks, and outcome]. / Le monde des jumeaux : aspects épidémiologiques et génétiques, enjeux obstétricaux, risques spécifiques et devenir.

The incidence of twin pregnancies has increased steadily for the last 40 years due to assisted reproductive technology and increased maternal childbearing age. Multiple pregnancies, especially monochorionic twin pregnancies, carry a high risk for the mother and the fetuses and require close follow-up. Twins are exposed to a higher risk of perinatal anoxia, in utero fetal demise, preterm birth, congenital malformations, fetal growth restriction, and vascular complications. Compared to singletons, twins are at higher risk of perinatal mortality and impaired neurodevelopmental outcome, justifying a thorough follow-up by pediatricians, including assessment and management of familial and psychosocial impact. This paper discusses the epidemiological, obstetrical, and genetic issues raised by twin pregnancies and reviews the data on the perinatal and neurological long-term outcomes of twins, as well as the psychosocial impact of multiple births on twins and their families.

Secondary localisation of an intra-thoracic benign mesenchymoma in the fossa poplitea: a rare paediatric case.

Thymomas are tumours that rarely occur in children, are almost invariably benign, and are usually discovered incidentally in the anterior mediastinum on chest X-rays. Whereas in adults these tumours are often associated with myasthenia gravis and other autoimmune diseases, this occurrence is very rare in the paediatric population. Multiple localisation and/or extra-thoracic recurrence of thymomas in children also appears to be exceptional with no reported cases in the English literature. We report one rare paediatric case.

[Diagnosis and treatment of soft-tissue tumors]. / Prise en charge des tumeurs des parties molles de l'appareil locomoteur de l'adulte.

The diagnostic and therapeutic management of patients with soft-tissue tumors would be similar to the approach used for bone tumors if it were not for one crucial factor: the absolute necessity to recognize a sarcoma. The predominant features are the size of the tumor and its superficial or deep localization. If the tumor is small and superficial, biopsy can be associated with immediate resection without risk of dissemination to the deep tissues: this is the biopsy-resection approach. If the tumor is deep or superficial but large sized, search for locoregional spread with MRI is necessary before undertaking any surgical procedure. MRI can help guide the biopsy and plan resection if the tumor is a sarcoma. A first biopsy is necessary to establish the histological diagnosis and elaborate the therapeutic strategy. Samples should be sent immediately to the pathology lab which should examine sterile fresh tissue. Experience has demonstrated that proper rules for diagnosis and treatment are not necessarily applied initially in approximately one-fourth of all subjects with a malignant soft-tissue tumor. Besides the medical problems caused by this situation, the patient loses a chance for cure. When the tumor is a sarcoma, surgery is the basis of treatment. Complementary radiation therapy may be necessary, particularly for high-grade tumors or if the surgical margin was insufficient. Systemic or locoregional chemotherapy can also be used for high-grade or non-resectable tumors.

Taenia crassiceps invasive cysticercosis: a new human pathogen in acquired immunodeficiency syndrome?

A fluctuant, painful, subcutaneous, and intermuscular tumor developed in a 38-year-old man with severe acquired immunodeficiency syndrome (AIDS) in which immunodeficiency was severe. Surgery revealed lesions that formed a multilocular pouch embedded in deep tissues in the forearm filled with tapiocalike material containing a viscous fluid, granules, and cysticercilike small vesicles. Pathologic and parasitologic evaluation showed cysticerci embedded in a fibrocollagen reaction with inflammatory granulomatous reaction. Each cysticercus contained an invaginated scolex with two rows of small (i.e., 80 microm) and large (i.e., 114 microm) rostellar hooks, identical to larva of Taenia crassiceps. All clinical, parasitologic, and pathologic features of these cysticerci were very different from those of all other larval cestode (i.e., Taenia solium cysticercosis, coenurosis, sparganosis, cysticercosis due to Taenia saginata [Cysticercus bovis], primary and secondary hydatidosis [Echinococcus species]). T crassiceps cysticerci usually develop in subcutis and pleuroperitoneal cavities of rodents, whereas the adult tapeworm is commonly found in the digestive tract of foxes. Biologic properties of T crassiceps cysticerci and epidemiologic characteristics of pandemic human immunodeficiency virus (HIV) could eventually indicate new potential cases of T crassiceps cysticercosis in humans.

Spinal abscess and spondylitis due to actinomycosis.

STUDY DESIGN: Report of a rare case of spinal actinomycosis in a young immunocompetent woman. OBJECTIVE: To show the difficulties in diagnosing spinal actinomycosis. SUMMARY OF BACKGROUND DATA: Spinal actinomycosis is rare and usually occurs as a result of a contiguous (abdominal, pelvic, or thoracic) spread of the infection. This localization represents less than 5% of the infectious sites and was mainly, before the penicillin era, a postmortem discovery. METHODS: A case is reported of a 34-year-old Algerian woman who had fever, persistent cough, right-side thoracic pain, and progressive severe back pain. Radiographs, computed tomographic scan, and magnetic resonance imaging demonstrated lytic areas on the vertebral bodies of T11 and T12 and a paravertebral mass, without disk involvement. A surgical biopsy of T12 and the paravertebral abscess was performed. RESULTS: Presence of characteristic sulfur granules and gram-positive filamentous bacteria in surgical biopsy tissues and isolation of Actinobacillus actinomycetemcomitans in cultures led to the diagnosis of vertebral actinomycosis. The patient was virtually free of pain and fever after a 3-month regimen of ofloxacin and rifampicin (Rifadine, Marion-Merell, France) and was without recurrence after 18 months of follow-up. CONCLUSIONS: Actinomycosis of the spine, caused by the spread of a paraspinal abscess, is extremely rare. The previously poor prognosis has been transformed by antibiotics.

[Jaffe-Campanacci syndrome. Report of a case]. / Syndrome de Jaffé-Campanacci. A propos d'un cas.

Jaffe-Campanacci syndrome is a rare entity characterized by disseminated non ossifying fibromas in association with extraskeletal congenital anomalies: cutaneous, genital, ocular and cardiovascular. Mental retardation is also frequently observed. Pathological fractures are the usual mode of revelation. We report one case original because of causal discovery during orthodontic check-up and because of extraskeletal anomalies not previously described. In fact the true incidence of this syndrome is probably underestimated because of unrecognized features.

[Chronic recurrent multifocal osteomyelitis of the mandible. A case report]. / Ostéomyélite chronique multifocale récurrente. A propos d'un cas de la mandibule.

UNLABELLED: Chronic recurrent multifocal osteomyelitis (CRMO) is a disorder rarely localized to the lower jaw. CASE REPORT: A fourteen-year-old boy complained of a swollen of his lower jaw. After a CT Scan, a bone biopsy was performed and yielded S. oralis against which an adapted intravenous antibiotherapy was administered without efficacy. The absence of malignant process and the revelation of an other focus of fixation at the Tc bone scan localized on humerus called to mind the diagnosis of CRMO. CONCLUSION: The diagnosis of this disease is difficult and based on a number of concording arguments:clinical and radiological signs of osteomyelitis, multifocal presentation, recurrent relapses and remissions, inaction of antibiotics, elimination of the other differential diagnosis, in particular the infectious osteitis.

[Familial dyskeratotic comedone]. / Dyskératose comédonienne familiale.

INTRODUCTION: Familial dyskeratotic comedones is a rare affection of autosomal transmission and characterized by pseudo-comedone papules predominantly on the limbs. We report a new familial case characterized by its clinical and histological profile. CASE REPORT: A 6 year-old boy presented with a papular, pseudo-comedone eruption that had appeared shortly after birth and had progressively extended symmetrically to both legs. The child's father complained of a similar eruption since childhood. Histological examination of the papules revealed a pseudo-follicular invagination, obstructed by keratin and associated with areas of focal dyskeratosis. Treatment with local retinoids was ineffective. DISCUSSION: Since it is often asymptomatic, the prevalence of dyskeratosis comedones is probably underestimated. A review of the literature on the preceding observations is presented. The dermatites that would represent differential diagnoses because of the presence of comedone-like lesions and/or histological dyskeratosis are discussed.